MOLECULAR TETRAHEDRON NANOCAGE, ITS PREPARATION, AND USES THEREOF
20230303472 · 2023-09-28
Inventors
- Severin T. SCHNEEBELI (South Burlington, VT, US)
- Jianing Li (South Burlington, VT, US)
- Mona SHARAFI (Winooski, VT, US)
Cpc classification
International classification
Abstract
The present application is directed to a nanocage of Formula (I): wherein A and R are as described herein. The present application is also directed to a process for preparation of a nanocage of Formula (I). Methods of utilizing the nanocage for detecting an analyte in a fluid and for functionalizing a polymer are also described.
##STR00001##
Claims
1. A nanocage of Formula (I): wherein ##STR00062## each A is independently selected and has the formula ##STR00063## ##STR00064## is the point of attachment of A to R; each R is independently selected and has the formula ##STR00065## ##STR00066## indicates the point of attachment of R to A; R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, b C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, — Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-.sub.6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, — CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, -CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; p is 1 to 3; n is 1 to 10; and m is 1 to 10.
2. The nanocage of claim 1, wherein the nanocage is T.sub.d-symmetric.
3. The nanocage of claim 1, wherein the nanocage has a height from 15 Å to 40 Å.
4. The nanocage of claim 1, wherein the nanocage has a height from 20 Å to 25 Å.
5. The nanocage of claim 1, wherein R.sup.1, R.sup.2, and R.sup.3 are Me, R.sup.4 is —OMe, R.sup.5 is — O(CH.sub.2).sub.4—(OCH.sub.2CH.sub.2).sub.3—OMe.
6. A process for preparation of a nanocage of Formula (I): ##STR00067## wherein each A is independently selected and has the formula ##STR00068## ##STR00069## is the point of attachment of A to R; each R is independently selected and has the formula ##STR00070## ##STR00071## indicates the point of attachment of R to A; R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, -Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, -CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; p is 1 to 3; n is 1 to 10; and m is 1 to 10, said process comprising: providing one or more compounds of Formula (II) having the structure: ##STR00072## forming the nanocage of Formula (I) from the one or more compounds of Formula (II).
7. The process according to claim 6, wherein said forming the nanocage of Formula (I) comprises: reacting the one or more compounds of Formula (II) with one or more compounds of Formula (III): ##STR00073## to produce the nanocage of Formula (I).
8. The process according to claim 7, wherein the compound of Formula (III) has the following structure: ##STR00074## .
9. The process according to claim 6 further comprising: providing one or more compounds of Formula (IV) having the structure: ##STR00075## forming the one or more compounds of Formula (II) from the one or more compounds of Formula (IV).
10. The process according to claim 9, wherein said forming the one or more compounds of Formula (II) comprises: reacting the one or more compounds of Formula (IV) with a hydrazine source to produce the one or more compounds of Formula (II).
11. The process according to claim 9 further comprising: providing one or more compounds of Formula (VI) having the structure: ##STR00076## forming the one or more compounds of Formula (IV) from the one or more compounds of Formula (VI).
12. The process according to claim 11, wherein said forming the one or more compounds of Formula (IV) comprises: esterifying the one or more compounds of Formula (VI) to produce the one or more compounds of Formula (IV).
13. The process according to claim 12, wherein said esterifying the one or more compounds of Formula (VI) comprises: reacting the one or more compounds of Formula (VI) with MeOH to produce the one or more compounds of Formula (IV).
14. The process according to claim 11 further comprising: providing one or more compounds of Formula (VII) having the structure: ##STR00077## forming the one or more compounds of Formula (VI) from the one or more compounds of Formula (VII).
15. The process according to claim 14, wherein said forming the one or more compounds of Formula (VI) comprises: reacting the compound of Formula (VII) with an oxidizing agent to produce the one or more compounds of Formula (VI).
16. The process according to claim 15, wherein the oxidizing agent is selected from the group consisting of NaClO.sub.2, oxone, H.sub.5IO.sub.6, H.sub.2O.sub.2, O.sub.2, sodium perborate, and KMnO.sub.4.
17. The process according to claim 6 further comprising: providing one or more compounds of Formula (VIII) having the structure: ##STR00078## forming the one or more compounds of Formula (VII) from the one or more compounds of Formula (VIII).
18. The process according to claim 17, wherein said forming the one or more compounds of Formula (VII) comprises: reacting the one or more compounds of Formula (VIII) with one or more compounds of Formula (IX): ##STR00079## wherein LG is a suitable leaving group, to produce the one or more compounds of Formula (VII).
19. The process according to claim 18, wherein the one or more compounds of Formula (IX) has the formula: ##STR00080## wherein Hal is Cl or Br.
20. The process according to claim 17 further comprising: providing one or more compounds of Formula (X) having the structure: ##STR00081## forming the one or more compounds of Formula (VIII) from the one or more compounds of Formula (X).
21. The process according to claim 20, wherein said forming the one or more compounds of Formula (VIII) comprises: reacting the one or more compounds of Formula (X) with a compound of Formula (XI): ##STR00082## to produce the compound of Formula (VIII).
22. The process according to claim 20 further comprising: providing one or more compounds of Formula (XII) having the structure: ##STR00083## forming the one or more compounds of Formula (X) from the one or more compounds of Formula (XII).
23. The process according to claim 22, wherein said forming the one or more compounds of Formula (X) comprises: reacting the one or more compounds of Formula (XII) with a formylating agent to produce the one or more compounds of Formula (X).
24. The process according to claim 23, wherein the formylating agent is selected from the group consisting of DMF/POCl.sub.3 and paraformaldehyde/BF.sub.3.
25. A method for detecting an analyte in a fluid comprising: providing a sensor comprising a nanocage of Formula (I): ##STR00084## wherein each A is independently selected and has the formula ##STR00085## ##STR00086## is the point of attachment of A to R; each R is independently selected and has the formula ##STR00087## ##STR00088## indicates the point of attachment of R to A; R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, -Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, — CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, -CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; p is 1 to 3; n is 1 to 10; and m is 1 to 10; providing a fluid containing an analyte; and contacting a fluid containing the analyte with the sensor to capture the analyte in the nanocage and detect the analyte in the fluid.
26. The method according to claim 25, wherein the sensor further comprises: a substrate having a surface with a layer of the nanocage of Formula (I) covering at least 5% of the surface.
27. The method according to claim 25, wherein the sensor further comprises: a substrate having a surface with a layer of the nanocage of Formula (I) covering at least 10% of the surface.
28. The method according to claim 25 further comprising: providing a signal generator operatively associated with said sensor, said method further comprising: producing a signal with the signal generator when said analyte is captured by said sensor.
29. The method according to claim 25, wherein the analyte is selected from the group consisting of polyvinylpyrrolidone (PVP), poly(isobutylene-alt-n-octyl maleimide) (POI), picrocrocin, curcumin, and components of chinese tea.
30. A method of functionalizing a polymer comprising: providing a polymer; providing a nanocage of Formula (I): ##STR00089## wherein each A is independently selected and has the formula ##STR00090## ##STR00091## is the point of attachment of A to R; each R is independently selected and has the formula ##STR00092## ##STR00093## indicates the point of attachment of R to A; R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, — Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, — CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; p is 1 to 3; n is 1 to 10; and m is 1 to 10; providing a functionalizing reagent; reacting the polymer with the functionalizing reagent within the nanocage having a Formula (I) to produce a functionalized polymer.
31. The method of claim 30, wherein said providing a polymer comprises providing a mixture of polydisperse polymers.
32. The method of claim 30, wherein the nanocage of Formula (I) has a void space suitable to receive and functionalize the provided polymer.
33. The method of claim 30, wherein the nanocage having a Formula (I) is provided in the amount of 0.01 wt% to 50 wt%.
34. The method of claim 30, wherein the functionalizing reagent is selected from the group consisting of nitrophenyl-3,5-dinitrobenzoate and nitrophenyl acetate.
35. The method of claim 30, wherein the polymer is acylated.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
[0135] One aspect of the present application relates to a nanocage of Formula (I):
##STR00023##
wherein [0136] each A is independently selected and has the formula is the point of attachment of A to R; [0138] each R is independently selected and has the formula indicates the point of attachment of R to A; [0140] R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-penfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0141] R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC1-20 alkyl, —OC2-20 alkenyl, —OC2-20 alkynyl, -O-perfluorinated C1-20 alkyl, Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20alkyl, C.sub.2-20alkenyl, C.sub.2-20alkynyl, perfluorinated C.sub.1-20alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20alkynyl,-O-perfluorinated C.sub.1-20alkyl, —Oaryl, —COOC.sub.1-20alkyl, —COO perfluorinated C.sub.1-20alkyl, -COOaryl, —CONHC.sub.1-20alkyl, —CONHC.sub.2-20alkenyl, —CONHC.sub.2-.sub.20alkynyl, -CONH perfluorinated C.sub.1-20alkyl, -CONH-aryl, -CONH-heteroaryl, and ---CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0142] R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-.sub.6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1..sub.20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; [0143] R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1..sub.20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl,CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, --CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and ---CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0144] R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; [0145] X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; [0146] p is 1 to 3; [0147] n is 1 to 10; and [0148] m is 1 to 10.
[0149] As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this technology belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0150] The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched. When not otherwise restricted, the term refers to an alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and the like.
[0151] The term “alkenyl” means an aliphatic hydrocarbon group containing a carboncarbon double bond and which may be straight or branched having about 2 to about 20 carbon atoms in the chain. Particular alkenyl groups have 2 to about 10 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. The term “alkenyl” may also refer to a hydrocarbon chain having 2 to 6 carbons containing at least one double bond and at least one triple bond.
[0152] The term “alkynyl” means an aliphatic hydrocarbon group containing a carboncarbon triple bond and which may be straight or branched having about 2 to about 20 carbon atoms in the chain. Particular alkynyl groups have 2 to about 10 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.
[0153] As used herein, the term “alkane” refers to aliphatic hydrocarbons of formula C.sub.nH.sub.2n+.sub.2, which may be straight or branched having about 1 to about 40 (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8) carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkanes include methane, ethane, n-propane, i-propane, n-butane, t-butane, n-pentane, and 3-pentane. The term “alkylene” refers to a divalent group formed from an alkane by removal of two hydrogen atoms. Exemplary alkylene groups include, but are not limited to, divalent groups derived from the alkanes described above.
[0154] As used herein, the term “cycloalkane” refers to aliphatic hydrocarbons of formula C.sub.nH.sub.2n, which may be straight or branched having about 3 to about 8 carbon atoms in the chain. Exemplary cycloalkanes include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. The term “cycloalkylene” refers to a divalent group formed from a cycloalkane by removal of two hydrogen atoms. Exemplary cycloalkylene groups include, but are not limited to, divalent groups derived from the cycloalkanes described above.
[0155] As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to 18-membered ring (radical) which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For purposes of this application, the heterocycle may be a monocyclic, or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Examples of such heterocycles include, without limitation, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, N.Y. (1984), which is hereby incorporated by reference in its entirety.
[0156] The term “monocyclic” used herein indicates a molecular structure having one ring.
[0157] The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structure having two or more rings, including, but not limited to, fused, bridged, or spiro rings.
[0158] The term “aryl” means an aromatic monocyclic or multi-cyclic (polycyclic) ring system of 6 to about 19 carbon atoms, or of 6 to about 10 carbon atoms, and includes arylalkyl groups. The ring system of the aryl group may be optionally substituted. Representative aryl groups include, but are not limited to, groups such as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.
[0159] The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ring system of about 5 to about 19 ring atoms, or about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multi-cyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “heteroaryl”. Particular heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen, carbon, or sulfur atom in the heteroaryl ring may be optionally oxidized; the nitrogen may optionally be quaternized. Representative heteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[l,2-α]pyridinyl, pyrazolo[1,5-α]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-α]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.
[0160] The terms “arylalkyl” and “heteroarylalkyl” mean an alkyl substituted with one or more aryl or heteroaryl groups, wherein the alkyl, aryl, and heteroaryl groups are as herein described. One particular example is an arylmethyl or heteroarylmethyl group, in which a single carbon spacer unit is attached to an aryl or heteroaryl group, where the carbon spacer and the aryl or heteroaryl group can be optionally substituted as described herein.
[0161] The term “heterocyclylalkyl” mean an alkyl substituted with one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups are as herein described.
[0162] The term “arylene” means a group obtained by removal of a hydrogen atom from an aryl group. Non-limiting examples of arylene include phenylene and naphthylene.
[0163] The term “halogen” means fluoro, chloro, bromo, or iodo.
[0164] The term “perfluorinated C.sub.1..sub.20 alkyl” means both branched and straight-chain alkyl substituted with one or more fluorine atoms, wherein the alkyl group is as herein described.
[0165] The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom’s normal valency is not exceeded, and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
[0166] The term “a derivative thereof refers to a salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N oxide thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.
[0167] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both (E)- and (Z)- geometric isomers. Likewise, all tautomeric forms are also intended to be included.
[0168] Compounds described herein contain hydrazone bonds. All possible cis/trans/s-cis/s-trans isomers of the hydrazone bonds are intended to be encompassed within the scope of the present application. This technology is meant to include all such possible isomers, as well as mixtures thereof.
[0169] Compounds described herein may also contain isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (.sup.3H), iodine-125 (.sup.12I), carbon-14 (.sup.14C), carbon-11 (.sup.11C), or fluorine-18 (.sup.18F). All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
[0170] In one embodiment, at least one A in the nanocage of Formula (I) is different from the other A.
[0171] In another embodiment, all R in the nanocage of Formula (I) are the same.
[0172] In another embodiment, all R in the nanocage of Formula (I) are different.
[0173] In yet another embodiment, at least one R in the nanocage of Formula (I) is different from the other R.
[0174] In a further embodiment, the nanocage is T.sub.d-symmetric.
[0175] The height of the nanocage can be determined with standard molecular modeling tools with the “measure distance” application programming interfaces (APIs) (Humphrey et al., “VMD—Visual Molecular Dynamics,” J. Molec. Graphics. 14:33-38 (1996); Hanwell et al., “Avogadro: An Advanceed Semantic Chemical Editor, Visualization, and Analysis Platform,” J. Cheminform. 4:17 (2012); Guex et al., “SWISS-MODEL and the Swiss-PDB Viewer: An Environment for Comparative Protein Modeling,” Electrophoresis 18:2714-2723 (1997); Pirhadi et al., “Open Source Molecular Modeling,” J. Mol. Graphics Modell. 69:127-143 (2016), which are hereby incorporated by reference in their entirety).
[0176] According to the present application, the nanocage has a height from 15 Å to 40 Å. Preferably, the nanocage has a height from 15 Å to 39 Å, from 15 Å to 38 Å, from 15 Å to 37 Å, from 15 Å to 36 Å, from 16 Å to 35 Å, from 17 Å to 34 Å, from 18 Å to 33 Å, from 19 Å to 32 Å, from 20 Å to 31 Å, from 20 Å to 30 Å, from 20 Å to 29 Å, from 20 Å to 28 Å, from 20 Å to 27 Å, from 20 Å to 26 Å, from 20 Å to 25 Å. More preferably, the nanocage has a height from 21 Å to 25 Å, from 22 Å to 25 Å, from 23 Å to 25 Å, from 24 Å to 25 Å, 21 Å to 24 Å, from 22 Å to 24 Å, from 23 Å to 24 Å, from 24 Å to 25 Å, 21 Å to 23 Å, from 21 Å to 22 Å, from 22 Å to 23 Å.
[0177] One embodiment relates to the nanocage of Formula (I), wherein R.sup.1, R.sup.2, and R.sup.3 are Me, R.sup.4 is —OMe, R.sup.5 is —O(CH.sub.2).sub.4—(OCH.sub.2CH.sub.2).sub.3—OMe.
[0178] In one embodiment, the nanocage of Formula (I) is stable in water.
[0179] In another embodiment, the nanocage of Formula (I) is stable in water at elevated temperatures. For example, the nanocage of Formula (I) is stable in water at 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., or 100° C.
[0180] Another aspect of the present application relates to a process for preparation of a nanocage of Formula (I):
##STR00028##
wherein [0181] each A is independently selected and has the formula is the point of attachment of A to R; [0183] each R is independently selected and has the formula indicates the point of attachment of R to A; [0185] R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-penfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0186] R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, — Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1..sub.20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-penfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0187] R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-.sub.6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1..sub.20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; [0188] R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1..sub.20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, — CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, ---CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0189] R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; [0190] X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; [0191] p is 1 to 3; [0192] n is 1 to 10; and [0193] m is 1 to 10,said process comprising: [0194] providing one or more compounds of Formula (II) having the structure: [0195] forming the nanocage of Formula (I) from the one or more compounds of Formula (II).
[0196] In accordance with the embodiment, forming the nanocage of Formula (I) may comprise reacting the one or more compounds of Formula (II) with one or more compounds of Formula (III):
##STR00034##
to produce the nanocage of Formula (I).
[0197] In one embodiment, the compound of Formula (III) has the following structure:
##STR00035##
[0198] Another embodiment of the present invention comprises providing one or more compounds of Formula (IV) having the structure:
##STR00036##
forming the one or more compounds of Formula (II) from the one or more compounds of Formula (IV).
[0199] In accordance with the embodiment, forming the one or more compounds of Formula (II) comprises reacting the one or more compounds of Formula (IV) with a hydrazine source to produce the one or more compounds of Formula (II).
[0200] The hydrazine source that can be used according to the present application includes, but is not limited to, hydrazine, hydrazine hydrate, or hydrazine salts (for example hydrazine monohydrochloride).
[0201] In one embodiment, the hydrazine source is a compound of Formula (V):
##STR00037##
[0202] Another embodiment of the present invention further comprises providing one or more compounds of Formula (VI) having the structure:
##STR00038##
forming the one or more compounds of Formula (IV) from the one or more compounds of Formula (VI).
[0203] In accordance with this embodiment, forming the one or more compounds of Formula (IV) comprises esterifying the one or more compounds of Formula (VI) to produce the one or more compounds of Formula (IV).
[0204] In accordance with this embodiment, esterifying the one or more compounds of Formula (VI) comprises reacting the one or more compounds of Formula (VI) with MeOH or MeI to produce the one or more compounds of Formula (IV).
[0205] Another embodiment of the present invention further comprises providing one or more compounds of Formula (VII) having the structure:
##STR00039##
forming the one or more compounds of Formula (VI) from the one or more compounds of Formula (VII).
[0206] In accordance with the embodiment, forming the one or more compounds of Formula (VI) comprises reacting the one or more compounds of Formula (VII) with an oxidizing agent to produce the one or more compounds of Formula (VI). Suitable oxidizing agents include, but are not limited to, NaClO.sub.2, oxone (potassium peroxymonosulfate), H.sub.5IO.sub.6, H.sub.2O.sub.2, O.sub.2, sodium perborate, and KMnO.sub.4.
[0207] Another embodiment of the present invention further comprises providing one or more compounds of Formula (VIII) having the structure:
##STR00040##
forming the one or more compounds of Formula (VII) from the one or more compounds of Formula (VIII).
[0208] In accordance with the embodiment, forming the one or more compounds of Formula (VII) comprises reacting the one or more compounds of Formula (VIII) with one or more compounds of Formula (IX): LG-(CH.sub.2)n-(OCH.sub.2CH.sub.2)m-OC.sub.1..sub.6 alkyl (IX), [0209] wherein LG is a suitable leaving group, [0210] to produce the one or more compounds of Formula (VII).
[0211] Suitable leaving groups that can be used according to the present application include, but not limited to halogen, mesylate, tosylate, triflate, or nosylate.
[0212] In one embodiment, the one or more compounds of Formula (IX) has the formula: Hal-(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl,
[0213] wherein Hal is Cl or Br.
[0214] Another embodiment of the present invention further comprises providing the one or more compounds of Formula (X) having the structure:
##STR00041##
forming the one or more compounds of Formula (VIII) from the one or more compounds of Formula (X).
[0215] In accordance with the embodiment, forming the one or more compounds of Formula (VIII) comprises reacting the one or more compounds of Formula (X) with a compound of Formula (XI): BCl.sub.3 (XI),
[0216] to produce the one or more compounds of Formula (VIII).
[0217] Another embodiment of the present invention further comprises providing one or more compounds of Formula (XII) having the structure:
##STR00042##
forming the one or more compounds of Formula (X) from the one or more compounds of Formula (XII).
[0218] In accordance with the embodiment, forming the one or more compounds of Formula (X) comprises reacting the one or more compounds of Formula (XII) with a formylating agent to produce the one or more compounds of Formula (X). Suitable formylating agents include, but are not limited to, DMF/POCl.sub.3 and paraformaldehyde/BF.sub.3.
[0219] Another aspect of the present application relates to a method for detecting an analyte in a fluid. This method includes: providing a sensor comprising a nanocage of Formula (I):
##STR00043##
wherein [0220] each A is independently selected and has the formula is the point of attachment of A to R; [0222] each R is independently selected and has the formula indicates the point of attachment of R to A; [0224] R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-penfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-.sub.20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0225] R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1..sub.20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, — Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2- 20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, —CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0226] R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; [0227] R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, — CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, — COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0228] R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; [0229] X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; [0230] X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; [0231] p is 1 to 3; [0232] n is 1 to 10; and [0233] m is 1 to 10; [0234] providing a fluid containing an analyte; and [0235] contacting a fluid containing the analyte with the sensor to capture the analyte in the nanocage and detect the analyte in the fluid.
[0236] In one embodiment, the method further comprises providing a signal generator operatively associated with said sensor, said method further comprising:
[0237] producing a signal with the signal generator when said analyte is captured by said sensor.
[0238] Suitable analytes that can be detected in accordance with the present application include, but are not limited to, polyvinylpyrrolidone (PVP), poly(isobutylene-alt-n-octyl maleimide) (POI), picrocrocin, curcumin, and components of chinese tea.
[0239] According to the present application, the sensor further comprises a substrate having a surface with a layer of the nanocage of Formula (I) covering at least 1% of the surface. Preferably, the layer of the nanocage of Formula (I) covers at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25% of the substrate’s surface.
[0240] According to the present application, the suitable substrates include paper, plastics (e.g., photoresist materials, acrylic polymers, carbonate polymers, etc.), glass, silicon based materials (e.g., silicon, silicon dioxide, silicon nitride, etc.) and metals.
[0241] In one embodiment, the substrate is a paper strip.
[0242] In another embodiment, the sensor further comprises a fluorescent polymer.
[0243] Suitable fluorescent polymers that can be used according to the present application include, but are not limited to, dye-functionalized glycol polymers (e.g. polyethylene glycol, polypropylene glycol, polybutylene glycol, etc.), poly-alkyl-imides (including polyisobutylene-alt-n-octyl imide), and polyacrylates.
[0244] In one embodiment, a fluorescent dye is attached to a nanocage of Formula (I). Suitable fluorescent dyes that can be used include, but are not limited to, Cy3-azide, Cy5-azide, Cy3-alkyne, Cy5-alkyne, Azide-fluor 488, Azide-fluor 545, Azide cyanine dye 728, DBCO-Cy3, Azide MegaStokes dye 673.
[0245] In another embodiment, a fluorescent dye is attached to an alkylene-containing nanocage of Formula (I) using click chemistry.
[0246] In yet another embodiment, the sensor also contains polymers containing fluorescent dies. Suitable polymers that can be used according to the present application include glycol polymers, poly-alkyl-imides, and polyacrylates.
[0247] In one embodiment, the method for detecting an analyte in a fluid can provide detection in real time.
[0248] In another embodiment, detection of an analyte in a fluid by the sensor will result in a change in color that could be directly observed by a naked eye. Alternatively, the change in color can be observed by applying a light source.
[0249] Suitable light sources that can be used in accordance to the present invention include, but are not limited to, light emitting diodes (LED), flash lamps, cold-cathode fluorescent lamps, and electroluminescent lamps. The illumination may be multiplexed and/or collimated. In some cases, the illumination may be pulsed to reduce any background interference. Further, illumination may be continuous or may combine continuous wave (CW) and pulsed illumination where multiple illumination beams are multiplexed (e.g., a pulsed beam is multiplexed with a CW beam), permitting signal discrimination between a signal induced by the CW source and a signal induced by the pulsed source.
[0250] In one embodiment, detection of an analyte in a fluid by the sensor will result in a change in color that could be observed by using yellow LED lamp.
[0251] According to the present application, qualitative, quantitative, or semi-quantitative determination of the presence or concentration of an analyte may be achieved.
[0252] In another embodiment, the color change is concentration-dependent. The higher concentration of the analyte, the bigger is the change in color.
[0253] In a further embodiment, the sensor is a nanosensor.
[0254] In yet another embodiment, the sensor tests the quality of saffron.
[0255] During the manufacture of sensor, a sensor material comprising the nanocage of Formula (I) is placed on the substrate. This sensor material may be deposited, coated, or otherwise applied on the substrate.
[0256] Different sensing elements can be deposited in different areas of the substrate to form sensing arrays. Analyte samples of different quality then lead to specific fingerprints of color patterns with the sensing arrays under blue, yellow, green, or red, LED illumination. The color patterns can be recorded with a smartphone camera and analyzed (see, for an example, Kim et al., “Prediction of Key Aroma Development in Coffees Roasted to Different Degrees by Colorimetric Sensor Array,” Food Chem. 240:808-816 (2018), which is hereby incorporated by refererence in its entirety) with standard pattern recognition techniques to determine the sample origin/quality in a semi-quantitative/quantitative manner.
[0257] Another aspect of the present application relates to a method of functionalizing a polymer. This method includes: [0258] providing a polymer; [0259] providing a nanocage of Formula (I): wherein [0260] each A is independently selected and has the formula is the point of attachment of A to R; [0262] each R is independently selected and has the formula indicates the point of attachment of R to A; [0264] R.sup.1, R.sup.2, and R.sup.3 are each independently selected from the group consisting of H, halogen, OH, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, —O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, -CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,—O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0265] R.sup.4, R.sup.4′, and R.sup.4″ are each independently selected from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl, -O-perfluorinated C.sub.1-20 alkyl, — Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, —CONH-aryl, —CONH-heteroaryl, and —CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and — CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0266] R.sup.5, R.sup.5′, and R.sup.5″ are each independently selected from the group consisting of H, halogen, OH, —O(CH.sub.2).sub.n-(OCH.sub.2CH.sub.2).sub.m-OC.sub.1-6 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, -0-perfluorinated C.sub.1-20 alkyl, —Oaryl, and —NR.sup.10R.sup.11; [0267] R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently selected at each occurrence from the group consisting of H, halogen, C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, OH, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —O-perfluorinated C.sub.1-20 alkyl, —OC.sub.2-20 alkynyl, aryl, heteroaryl, heterocyclyl, and —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, —COOaryl, —CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, -CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl, wherein each C.sub.1-20 alkyl, C.sub.2-20 alkenyl, C.sub.2-20 alkynyl, perfluorinated C.sub.1-20 alkyl, aryl, hereroaryl, heterocyclyl, —OC.sub.1-20 alkyl, —OC.sub.2-20 alkenyl, —OC.sub.2-20 alkynyl,-O-perfluorinated C.sub.1-20 alkyl, —Oaryl, —COOC.sub.1-20 alkyl, —COO perfluorinated C.sub.1-20 alkyl, -COOaryl, -CONHC.sub.1-20 alkyl, —CONHC.sub.2-20 alkenyl, —CONHC.sub.2-20 alkynyl, —CONH perfluorinated C.sub.1-20 alkyl, -CONH-aryl, -CONH-heteroaryl, and -CONH-heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, halogen, OH, C.sub.1-6 alkyl, aryl, and arylalkyl; [0268] R.sup.10 and R.sup.11 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl can be optionally substituted from 1 to 3 times with a substituent selected from the group consisting of H, C.sub.1-6 alkyl, heteroarylalkyl, heterocyclylalkyl, and arylalkyl; [0269] X.sup.1 and X.sup.2 are absent or are independently selected from the group consisting of C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene, wherein C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene, and arylene can be optionally substituted from 1 to 3 times with H or C.sub.1-6 alkyl; [0270] p is 1 to 3; [0271] n is 1 to 10; and [0272] m is 1 to 10; [0273] providing a functionalizing reagent; [0274] reacting the polymer with the functionalizing reagent within the nanocage having a Formula (I) to produce a functionalized polymer.
[0275] In one embodiment, one kind of polymer is provided. In another embodiment, a mixture of polydisperse polymers is provided.
[0276] Polymers that can be functionalized according to the present invention include, but are not limited to, amine-functionalized polyimides, amine-functionalized glycol polymers, amine-functionalized acrylate polymers, amine-functionalized polyolefins, amine-functionalized polyesters, amine-functionalized polylisocyanates, and amine-functionalized polyamides as well as co-polymers thereof.
[0277] In another embodiment, the nanocage of Formula (I) has a void space suitable to receive and functionalize the provided polymer.
[0278] According to the present application, functionalization of a polymer can be carried out in any suitable solvent, including, but not limited to deuterated dichloromethane (CD.sub.2Cl.sub.2), dichloromethane, deuterated chloroform (CDCl.sub.3), chloroform, pentanes, heptanes, octanes, nonanes, acetonitrile, tetrahydrofuran, ethyl acetate, diethyl ether, dipropyl ether, diphenyl ether, tetrachloroethane, carbon tetrachloride, and nitrobenzene, or the mixture thereof.
[0279] Functionalization of a polymer can be carried out at room temperature or at an elevated temperature. Preferably, the temperature is below 60° C., below 55° C., below 50° C., below 45° C., below 40° C., below 35° C., below 30° C. More preferably, functionalization of a polymer is carried out at room temperature.
[0280] According to the present application, the nanocage of Formula (I) is provided in the amount of 0.01 wt% to 50 wt%. Preferably, the nanocage of Formula (I) is provided in the amount of 0.01 wt% to 50 wt%, 0.1 wt% to 45 wt%, 1 wt% to 40 wt%, 5 wt% to 40 wt%, 10 wt% to 40 wt%, 15 wt% to 40 wt%, 20 wt% to 40 wt%, 25 wt% to 50 wt%, 30 wt% to 40 wt%. More preferably, the nanocage of Formula (I) is provided in the amount of 0.01 wt% to 30 wt%, 0.01 wt% to 20 wt%, 0.01 wt% to 10 wt%, 0.1 wt% to 10 wt%.
[0281] In a further embodiment, the functionalizing reagent is selected from the group consisting of nitrophenyl-3,5-dinitrobenzoate and nitrophenyl acetate.
[0282] In yet another embodiment, the polymer is acylated.
[0283] The above disclosure is general. A more specific description is provided below in the following examples. The examples are described solely for the purpose of illustration and are not intended to limit the scope of the present application. Changes in form and substitution of equivalents are contemplated as circumstances suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.
EXAMPLES
[0284] The following Examples are presented to illustrate various aspects of the present application, but are not intended to limit the scope of the claimed application.
Example 1 - General Methods and Materials
[0285] All commercially available starting materials were purchased from Sigma Aldrich, Fisher Scientific, or Oakwood Chemical. Unless notes otherwise, all reagents were used as received without further purification. When needed, tetrahydrofuran (THF), dichloromethane (CH.sub.2CI2), dimethylformamide (DMF), and toluene were dried using a Glass Contour solvent purification system by SG Water USA, LLC. HPLC grade acetonitrile (CH.sub.3CN) and trifluoroacetic acid (TFA) were used as received from Fisher Scientific. Poly(isobutylene-alt-maleic anhydride) was purchased from Sigma Aldrich and Alfa Aesar, respectively. The 5′-(2,4-dimethoxyphenyl)-2,2″,4,4″-tetramethoxy-2′,4′,6′-trimethyl-1,1′:3′,1″-terphenyl (Syn-1) was synthesized according to the published (Sharafi et al., “Crystal-Packing-Driven Enrichment of Atropoisomers,” Angew. Chem. Int. Ed. 56:7097-7101 (2017), which is hereby incorporated by reference in its entirety) solid-state-amplification protocol. If necessary, air and/or moisture sensitive reactions were carried out under an inert atmosphere of nitrogen. Removal of solvents was accomplished on a Büchi R-210 rotary evaporator and further concentration was attained under a Fisher Scientific Maxima C-Plus vacuum line. Column chromatography was performed manually with Sorbent grade 60 silica with a mesh size between 230-400 using a forced flow of indicated solvents, or automatically with a Teledyne CombiFlash® Rf+ chromatography system. Preparative size exclusion chromatography was performed with columns filled with Bio-Beads™ S-X1 Support (200-400 mesh). DLS measurements were performed on Zetasizer Nano ZPS instrument, using a hellma quartz cuvette (ZEN2112).
[0286] All .sup.1H-NMR spectra were recorded at 298 K on a Varian Unity Inova 500 (500 MHz) spectrometer or on a Bruker ARX 500 (500 MHz) spectrometer. .sup.13C-NMR spectra were recorded on a Bruker ARX 500 (125 MHz) spectrometer. Samples for NMR spectroscopy were dissolved in CDC1.sub.3, CD.sub.2Cl.sub.2, DMSO-d6, or D.sub.2O. The spectra were referenced to the residual solvent peak (CDCl.sub.3: 7.26 ppm for .sup.1H- and 77.16 ppm for .sup.13C-NMR; CD.sub.2Cl.sub.2: 5.32 ppm for .sup.1Hand 53.5 ppm for .sup.13C-NMR), or to tetramethylsilane (TMS, 0.00 ppm for .sup.1H- and .sup.13C-NMR) as the internal standard. Chemical shift values were recorded in parts per million (ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak), coupling constants (Hz), and number of protons.
Example 2 - Synthesis of 15-bromo-2,5,8,11-tetraoxapentadecane (S2)
[0287] ##STR00053##
[0288] The synthesis of S2 was carried out using conditions reported previously for the synthesis of a similar compound, 18-bromo-2,5,8,11-tetraoxaoctadecane (Chinwangso et al., “Structure, Wettability, and Thermal Stability of Organic Thin-Films on Gold Generated from the Molecular Self-Assembly of Unsymmetrical Oligo(ethylene glycol) Spiroalkanedithiols,” Langmuir 33:1751-1762 (2017), which is hereby incorporated by reference in its entirety). A mixture of triethylene glycol monomethyl ether (S1, 3.18 g, 19.40 mmol) and an aqueous sodium hydroxide solution (1.6 g in 1.6 mL of water) was stirred at 100° C. under argon for 30 min. The mixture was then added to 1,4-dibromobutane (8.42 g, 39.0 mmol) and the reaction was stirred at 100° C. for 12 hours. Next, the reaction mixture was cooled to room temperature and diluted with 100 mL of water. The resulting solution was extracted with EtOAc (3 × 75 mL) and the organic phases were combined and washed with water (1 × 100 mL) and brine (1 × 100 mL). The organic layer was dried over anhydrous MgSO.sub.4, filtered, and evaporated to dryness. Purification of the crude product was performed by column chromatography over silica gel (eluent: 0 to 50 vol-% EtOAc in hexanes) to afford S2 (3.38 g, 14.750 mmol) as a colorless oil in 58% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 3.68 - 3.61 (m, 8H), 3.56 (ddd, J= 14.6, 6.1, 3.0 Hz, 4H), 3.49 (t, J = 6.3 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H), 3.37 (s, 3H), 1.98 - 1.90 (m, 2H), 1.76 -1.67 (m, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 72.2, 70.8, 70.8, 70.5, 70.4, 59.3, 34.0, 29.9, 28.4. HRMS (ESI) calcd. for C.sub.11H.sub.24BrO.sub.4: m/z = 299.0858 [M + H].sup.+; found: 299.0858.
Example 3 - Synthesis of Syn-(1′r,3′s)-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-(hydrazinecarbonyl)-2-methoxyphenyl)-6,6″ -dimethoxy-2′,4′,6′ -trim ethyl- [1,1 ′:3′,1 “-terphenyl]-3,3″-dicarbohydrazide (Syn-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-(hydrazinecarbonyl)-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbohydrazide)(Syn-7)
Synthesis of Syn-(1S,3′S)-5′-((R)-5-formyl-2,4-dimethoxyphenyl)-4,4″,6,6″-tetramethoxy-2′,4′,6′-trimethyl-[1,1′:3′,l″-terphenyl]-3,3″-dicarbaldehyde (Syn-5′-((R)-5-formyl-2,4-dimethoxyphenyl)-4,4″,6,6″-tetramethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde)(Syn-2)
[0289] Syn-1 (0.71 g, 1.345 mmol) was dissolved in anhydrous DMF (37 mL) followed by the dropwise addition of POC1.sub.3 (6.0 mL) at 0° C. The reaction mixture was warmed to room temperature and left stirring. After 20 hours, the reaction was quenched by adding 10 mL of a 1 N aqueous NaOH solution. The precipitated solid was filtered and washed with deionized water to afford syn-2 (0.815 g, 1.330 mmol) as a colorless solid in 98% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.30 (s, 3H), 7.54 (s, 3H), 6.52 (s, 3H), 3.99 (s, 9H), 3.86 (s, 9H), 1.65 (s, 9H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 188.3, 163.2, 162.9, 135.1, 134.5, 132.7, 123.6, 118.7, 94.8, 55.9, 55.8, 18.8. HRMS (ESI) calcd. for C.sub.36H.sub.37O.sub.9: m/z = 613.2438 [M + H].sup.+; found: 613.2441.
Synthesis of Syn-(1′r,3′s)-5′-(5-formyl-4-hydroxy-2-methoxyphenyl)-4,4″-dihydroxy-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde (Syn-5′-(5-formyl-4-hydroxy-2-methoxyphenyl)-4,4″-dihydroxy-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde)(Syn-3)
[0290] Syn-2 (0.815 g, 1.330 mmol) was dissolved in 40 mL of anhydrous CH.sub.2Cl.sub.2. A 1 M BCl.sub.3 solution in CH.sub.2Cl.sub.2 (20.0 mL) was then added dropwise to the reaction mixture under an argon atmosphere. After stirring at room temperature for 24 hours, 15 mL of H.sub.2O was added to quench the reaction mixture. The resulting biphasic mixture was extracted with CH.sub.2Cl.sub.2, the combined organic layers were dried over anhydrous MgSO.sub.4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: 0 to 30 vol-% EtOAc in CH.sub.2Cl.sub.2) to afford syn-3 (0.68 g, 1.190 mmol) as a colorless solid in 89% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 11.51 (s, 3H), 9.71 (s, 3H), 7.21 (s, 3H), 6.55 (s, 3H), 3.85 (s, 9H), 1.71 (s, 9H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 194.4, 164.4, 163.9, 135.9, 135.5, 134.3, 123.5, 115.0, 99.4, 56.1, 18.8. HRMS (ESI) calcd. for C.sub.33H.sub.31O.sub.9: m/z = 571.1968 [M + H].sup.+; found: 571.1970.
Synthesis of Syn-(1′r,3′s)-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-formyl-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde (Syn-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-formyl-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde)(Syn-4)
[0291] Syn-3 (0.68 g, 1.190 mmol), 15-bromo-2,5,8,11-tetraoxapentadecane (S2, 2.69 g, 7.140 mmol), and K.sub.2CO.sub.3 (1.38 g, 10.0 mmol) were added to a round-bottomed flask containing anhydrous DMF (15 mL) and the reaction mixture was stirred at 40° C. for 72 hours. Then, the reaction mixture was quenched by adding 50 mL of a 1 M aqueous HCl solution. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3 × 30 mL) and the combined organic layers were washed with brine (4 × 75 mL), dried over anhydrous MgSO.sub.4, filtered, and evaporated under reduced pressure. Excess S2 was removed by column chromatography (eluent: 10 vol-% MeOH in CH.sub.2Cl.sub.2) to afford syn-4 (1.24 g, 1.012 mmol) as a yellow oil in 85% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.34 (s, 3H), 7.53 (s, 3H), 6.50 (s, 3H), 4.14 (t, J= 6.2 Hz, 6H), 3.83 (s, 9H), 3.65 -3.52 (m, 42H), 3.36 (s, 9H), 1.96 (m, 6H), 1.81 (m, 6H), 1.63 (s, 9H)..sup.13C-NMR (125 MHz, CDCl.sub.3) δ 188.0, 163.1, 162.5, 134.9, 134.4, 131.7, 123.5, 118.5, 95.4, 71.9, 70.7, 70.6, 70.5, 70.4, 70.1, 68.4, 58.9, 55.8, 26.2, 26.0, 18.6. HRMS (ESI) calcd. for C.sub.66H.sub.97O.sub.21: m/z = 1225.6522 [M + H].sup.+; found: 1225.6537.
Synthesis of Syn-(1′r,3′s)-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-carboxy-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,l″-terphenyl]-3,3″-dicarboxylic acid (Syn-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5-carboxy-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylic acid)(Syn-5)
[0292] Syn-4 (1.24 g, 1.010 mmol) was dissolved in a 1:1 CH.sub.3CN/DMSO mixture (56 mL total volume) in a 250 mL round-bottomed flask. Next, a solution of NaH.sub.2PO.sub.4 (1.2 g, 10 mmol) and NaClO.sub.2 (0.9 g, 10 mmol) in 13 mL deionized water was added to the reaction mixture. After stirring at room temperature for 48 hours, the CH.sub.3CN was evaporated under reduced pressure and the reaction mixture was quenched by adding 30 mL of a 1 N aqueous HCl solution. Next, the water layer was extracted with CH.sub.2Cl.sub.2 (4 × 20 mL) and the combined organic phases were washed with brine (4 × 100 mL). After drying over anhydrous MgSO.sub.4, the solvent was removed in vacuo and syn-5 (1.03 g, 0.810 mmol) was obtained as a yellow oil in 81% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 7.87 (s, 3H), 6.58 (s, 3H), 4.31 (t, J= 6.5 Hz, 6H), 3.83 (s, 9H), 3.67 - 3.52 (m, 42H), 3.37 (s, 9H), 2.04 (m, J = 8.5, 6.6 Hz, 6H), 1.82 (m, J = 8.9, 6.2 Hz, 6H), 1.64 (s, 9H)..sup.13C-NMR (125 MHz, CDCl.sub.3) δ 165.2, 161.9, 158.5, 136.7, 135.0, 134.3, 124.7, 110.5, 96.1, 72.0, 70.7, 70.7, 70.6, 70.6, 70.5, 70.2, 70.2, 59.1, 56.0, 26.2, 26.1, 18.8. HRMS (ESI) calcd. for C.sub.66H.sub.97O.sub.24: m/z = 1273.6370 [M + H].sup.+; found: 1273.6377.
Synthesis of Syn-dimethyl (1′s,5′r)-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate (Syn-dimethyl-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate)(Syn-6)
[0293] MeOH (40 mL) was added to syn-5 (1.030 g, 0.810 mmol) in a 100 mL round-bottomed flask, followed by the dropwise addition of concentrated H.sub.2SO.sub.4 (1.0 mL). The reaction mixture was stirred under reflux for 24 hours. After evaporation of MeOH under reduced pressure, 1 N aqueous NaOH (10 mL) was added and the product was extracted from the aqueous layer using CH.sub.2Cl.sub.2 (2 × 20 mL). Next, the combined organic layers were dried over anhydrous MgSO.sub.4, filtered, and the solvent was removed in vacuo. The resulting brown oil was purified by column chromatography over silica gel (eluent: 15 vol-% MeOH in CH.sub.2Cl.sub.2) to afford syn-6 (0.745 g, 0.567 mmol) as a yellow oil in 70% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 7.60 (s, 3H), 6.53 (s, 3H), 4.11 (t, J= 6.3 Hz, 6H), 3.83 (s, 9H), 3.80 (s, 9H), 3.67 - 3.52 (m, 42H), 3.37 (s, 9H), 1.96 (m, 6H), 1.85 (m, 6H), 1.66 (s, 9H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 166.2, 161.2, 160.3, 135.3, 135.2, 134.8, 122.8, 112.0, 97.0, 72.0, 71.0, 70.7, 70.7, 70.6, 70.1, 68.9, 59.1, 55.7, 51.6, 26.3, 26.2, 18.8. HRMS (ESI) calcd. for C.sub.69H.sub.106NO.sub.24: m/z = 1332.7128 [M + NH.sub.4].sup.+; found: 1332.7105.
Synthesis of Syn-(1′r,3′s)-4,4″-bis((2,5,8,11-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)~5~(hydrazinecarbonyl)~2-methoxyphenyi)~6,6″-dimethoxy-2’,4’,6′-trimethyl-[1,1′:3′,1′-terphenyl]-3,3″-dicarbohydrazide(Syn-4,4″-bis((2,5,8,1-1-tetraoxapentadecan-15-yl)oxy)-5′-(4-((2,5,8.11-tetraoxapentadecan-15-yl)oxy)-5-(hydrazinecarbonyl)-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbohydrazide)(Syn-7)
[0294] Syn-6 (0.745 g, 0.567 mmol) was dissolved in 45 mL of a 1:2 THF/MeOH mixture in a 250 mL sealed heavy-wall glass reaction vessel. Next, the solution was degassed with argon and hydrazine monohydrate (9.0 mL) was added. After heating at 65° C. for 48 hours under argon atmosphere, the solvent was evaporated under reduced pressure (under a nitrogen atmosphere) and the resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with water (3 × 60 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure, and dried in vacuo to afford syn-7 (0.567 g, 0.431 mmol) as a yellow oil in 76% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 8.79 (s, 3H), 7.92 (s, 3H), 6.52 (s, 3H), 4.19 (t, J= 6.6 Hz, 6H), 3.77 (s, 9H), 3.68 - 3.52 (m, 42H), 3.36 (s, 10H), 2.04 - 1.96 (m, 6H), 1.80 (m, 6H), 1.65 (s, 9H). .sup.13C-NMR (125 MHz, CDCl3) δ 166.0, 160.0, 157.0, 134.5, 134.2, 123.4, 112.3, 95.8, 71.5, 70.2, 70.2, 70.2, 70.1, 69.8, 68.7, 58.6, 55.5, 25.9, 25.8, 18.4. HRMS (ESI) calcd. for C.sub.66H.sub.103N.sub.6O.sub.21: m/z = 1315.7176 [M + H].sup.+; found: 1315.7200.
Example 4 - Synthesis of Tet-1
[0295] Syn-7 (0.274 g, 0.208 mmol) was dissolved in 350 mL of anhydrous CH.sub.2Cl.sub.2, and the solution was degassed with argon. Next, terephthalaldehyde (0.0419 g, 0.312 mmol) and HPLC grade TFA (24 .Math.L, 0.313 mmol) were added consecutively, and the reaction mixture was stirred at room temperature under an argon atmosphere. After 48 hours, the acid was neutralized with a saturated aqueous sodium bicarbonate solution (10 mL), the organic layer was separated, and the aqueous phase extracted with additional CH.sub.2Cl.sub.2 (30 mL). Finally, the combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by size exclusion chromatography over polystyrene beads (200-400 mesh) with CH.sub.2Cl.sub.2 as the eluent to afford Tet-1 (0.242 g, 0.0416 mmol) as an orange-yellow solid in 80% yield. .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 11.08 (s, 12H), 8.26 (s, 12H), 7.99 (s, 12H), 7.84 (s, 24H), 6.64 (s, 12H), 4.33 (t, J = 6.6 Hz, 24H), 3.89 (s, 36H), 3.63 - 3.44 (m, 168H), 3.29 (s, 36H), 2.16 - 2.08 (m, 24H), 1.88 (m, 24H), 1.67 (s, 36H)..sup.13C-NMR (125 MHz, CD.sub.2Cl.sub.2) δ 162.0, 161.2, 157.9, 146.6, 136.5, 135.7, 135.5, 135.1, 128.3, 124.6, 113.7, 96.4, 72.4, 71.1, 71.0, 71.0, 71.0, 70.9, 70.8, 70.1, 59.1, 56.3, 26.9, 26.9, 19.0. HRMS (ESI) calcd. for C.sub.312H.sub.425N.sub.24O.sub.84Na: m/z = 1170.9964 [M + 5H].sup.5+; found: 1170.9982.
Example 5 - Synthesis of Amine-Functionalized Poly(isobutylene-alt-n-octyl Maleamide) (NH.SUB.2.-POA)
[0296] Poly(isobutylene-alt-maleic anhydride) (
Example 6 - Isolation of Short and Long Amine-Functionalized Poly(isobutylene-alt-n-octyl Maleamide) (Short-NH.SUB.2.-POA and Long-NH2-POA)
[0297] Analytical samples of the shortest (Short-NH.sub.2-POA,
[0298] Characterization data for Short-NH.sub.2-POA. .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 3.70-2.30 (broad m, ~46H), 2.20-0.50 (broad m, ~220H). DOSY-.sup.1H-NMR (500 MHz, CDCl.sub.3, polystyrene standard, see
[0299] Characterization data for Long-NH.sub.2-POA. .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 3.60 -2.20 (broad m, ~162H), 1.70-0.70 (broad m, ~854H). DOSY-.sup.1H-NMR (500 MHz, CDCl.sub.3, polystyrene standard, see
Example 7 - Synthesis of N′-benzylidene-2,4-bis(hexyloxy)Benzohydrazide (Control)
[0300] ##STR00054##
Synthesis of 2,4-bis(hexyloxy)Benzohydrazide (S4)
[0301] Methyl 2,4-dihydroxybenzoate (S3, 10.00 g, 59.50 mmol), K.sub.2CO.sub.3 (25.00 g, 181.0 mmol), and 25.5 mL bromohexane (30.00 g, 178.0 mmol) were dissolved in a mixture of DMF and MeOH (12:1 volume ratio, 13 mL total volume) in a round-bottomed flask and the resulting solution was heated to 100° C. for 36 hours. Afterwards, the reaction mixture was cooled to room temperature and hexanes (300 mL) as well as a 1 N aqueous NaOH solution (100 mL) were added. The hexane layer was washed with 1 N aqueous NaOH (4 × 30 mL) and the combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced pressure to afford a colorless oil.
[0302] The obtained colorless oil (0.20 g, 0.590 mmol) was dissolved in a mixture of THF and MeOH (1:2 volume ratio, 7.5 mL total volume) in a 12 mL sealed reaction vial. The reaction mixture was degassed with argon and hydrazine monohydrate (2 mL) was added. After heating to 63° C. for 48 hours, the solvent was evaporated under reduced pressure under a N.sub.2 atmosphere. The resulting solid was purified with preparative TLC over silica gel (eluent: 25 vol-% EtOAc in CH.sub.2Cl.sub.2), to afford S4 (68 mg, 0.20 mmol) as a yellow solid in 34% yield over two steps. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 8.87 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 6.58 (dd, J = 8.8, 2.2 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.99 (t, J= 6.5 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 2H), 1.64 - 1.31 (m, 12H), 0.91 (td, J = 6.9, 3.6 Hz, 6H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 167.0, 163.4, 158.6, 133.9, 113.0, 106.2, 100.2, 100.0, 69.4, 68.6, 31.9, 31.7, 29.4, 29.3, 26.1, 26.0, 22.9, 14.3. HRMS (ESI) calcd. for C.sub.19H.sub.32N.sub.2O.sub.3: m/z = 337.2491 [M + H].sup.+; found: 337.2495.
Synthesis of Control
[0303] S4 (24.3 mg, 0.072 mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2 (6 mL) in a 12 mL sealed reaction vial. The solution was degassed with argon and excess benzaldehyde (5.85 mg, 0.144 mmol) was added. Next, HPLC grade TFA (3 .Math.L, 0.015 mmol) was pipetted into the reaction mixture, which was then stirred at room temperature for 5 hours. Afterwards, the acid was neutralized with a saturated sodium bicarbonate solution and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified with preparative TLC over silica gel (eluent: 10 vol-% EtOAc in CH.sub.2Cl.sub.2) to afford Control (18.37 mg, 0.043 mmol) as a white solid in 60% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.97 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.84 - 7.71 (m, 2H), 7.45 -7.35 (m, 3H), 6.62 (dd, J = 8.9, 2.2 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 4.17 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.5 Hz, 2H), 2.04 - 1.93 (m, 2H), 1.85 - 1.73 (m, 2H), 1.65 - 1.28 (m, 12H), 0.92 (td, J = 7.0, 3.6 Hz, 6H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 163.6, 162.2, 158.2, 146.8, 134.6, 134.2, 130.3, 128.7, 127.7, 113.2, 106.4, 99.9, 69.5, 68.5, 31.7, 31.7, 29.4, 29.2, 26.2, 25.8, 22.8, 22.7, 14.2, 14.1. HRMS (ESI) calcd. for C.sub.26H.sub.36N.sub.2O.sub.3: m/z = 425.2804 [M + H].sup.+; found: 425.2813.
Example 8 - Synthesis of Nitrophenyl-3,5-dinitrobenzoate (NDB)
[0304] ##STR00055##
[0305] To a solution of p-nitrophenol (S5, 50 mg, 0.359 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) was added 4-(dimethylamino)pyridine (DMAP, 44 mg, 0.359 mmol) and the resulting mixture was stirred under an argon atmosphere at 0° C. for 30 minutes. Next, a solution of 3,5-dinitrobenzoyl chloride (S6, 82.86 mg, 0.359 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) was added slowly at 0° C. and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with a 10% aqueous HCl solution, extracted with CH.sub.2Cl.sub.2, and the combined organic phases were washed with brine (3 × 5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced pressure to yield NDB. The crude product was purified with flash chromatography over silica gel (eluent: 20 vol-% hexanes in CH.sub.2Cl.sub.2) in to afford NDB (145 mg, 0.345 mmol) in 96% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 9.39 - 9.30 (m, 3H), 8.43 - 8.31 (m, 2H), 7.52 - 7.47 (m, 2H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 160.5, 154.577560, 149.1, 146.3, 132.4, 130.1, 125.8, 123.60, 122.4. NDB was unstable in the mass spectrometer. For this reason, NDB was derivatized to obtain a high-resolution mass spectrum, by reacting it with n-octylamine to form 3,5-dinitro-N-octylbenzamide.
[0306] Characterization data for 3,5-dinitro-N-octylbenzamide: .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 9.18 (t, J = 2.1 Hz, 1H), 8.97 (d, J = 2.1 Hz, 2H), 3.52 (m, J = 7.4, 5.8 Hz, 2H), 1.71 - 1.61 (m, 2H), 1.42 - 1.23 (m, 10H), 0.89 - 0.83 (m, 3H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 162.9, 148.7, 138.3, 127.3, 121.0, 41.02, 31.9, 29.5, 29.36, 29.3, 27.1, 22.7, 14.2. HRMS (ESI) calcd. for C.sub.69H.sub.73N.sub.6O.sub.12: m/z = 322.1403 [M - H].sup.-; found: 322.1407.
Example 9 - Synthesis of Edge-Model
[0307] ##STR00056##
Synthesis of 2-((2,5,8,11-Tetraoxapentadecan-15-yl)oxy)benzaldehyde (S8)
[0308] In a round-bottomed flask, 2-hydroxybenzaldehyde (S7, 500 mg, 4.09 mmol), K.sub.2CO.sub.3 (1.24 g, 9.01 mmol), and S2 (2.7 g, 9.01 mmol) were dissolved in 25 mL of CH.sub.3CN and the resulting solution was heated to 40° C. for 24 hours. Afterwards, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The concentrated product was dissolved in CH.sub.2Cl.sub.2 and washed with water. The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced pressure to afford crude S8 as a colorless oil. The resulting crude product was purified with flash chromatography over silica gel (eluent: 20 vol-% EtOAc in hexanes), to afford S8 (1.39 g, 4.09 mmol) as a yellow oil in 40% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.52 (s, 1H), 7.84 (m, 1H), 7.54 (m, 1H), 7.09 - 6.90 (m, 2H), 4.12 (t, J = 6.4 Hz, 2H), 3.69 - 3.54 (m, 14H), 3.38 (s, 3H), 2.01 - 1.89 (m, 2H), 1.87 - 1.75 (m, 2H). .sup.13C-NMR (126 MHz, CDCl.sub.3) δ 189.9, 161.5, 136.0, 128.4, 125.0, 120.6, 112.6, 72.0, 70.9, 70.7, 70.7, 70.7, 70.3, 68.4, 59.1, 26.3, 26.1. HRMS (ESI) calcd. for C.sub.18H.sub.28O.sub.6: m/z = 341.1964 [M + H].sup.+; found: 341.1967.
Synthesis of 2-((2,5,8,11-Tetraoxapentadecan-15-yl)oxy)benzoic Acid (S9)
[0309] S8 (540 mg, 1.59 mmol) was dissolved in a 1:1 CH.sub.3CN/DMSO mixture (10 mL total volume) in a 250 mL round-bottomed flask. Next, a solution of NaH.sub.2PO.sub.4 (729 mg, 5.28 mmol) and NaClO.sub.2 (478 mg, 5.28 mmol) in 13 mL of deionized water was added to the reaction mixture. After stirring at room temperature for 24 hours, the CH.sub.3CN was evaporated under reduced pressure and the reaction mixture was quenched by adding 5 mL of a 1 N aqueous HCl solution. Next, the water layer was extracted with CH.sub.2Cl.sub.2 (4 × 20 mL) and the combined organic phases were washed with brine (4 × 100 mL). After drying over anhydrous MgSO.sub.4, the solvent was removed in vacuo and S9 (565 mg, 1.59 mmol) was obtained as a yellow oil in quantitative yield. The crude product was used directly without further purification for the next step. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.97 (s, 1H), 8.15 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 (ddd, J = 8.8, 7.3, 1.8 Hz, 1H), 7.10 (td, J = 7.6, 1.0 Hz, 1H), 7.04 (dd, J = 8.5, 0.9 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 3.72 - 3.44 (m, 14H), 3.36 (s, 3H), 2.11 - 1.87 (m, 2H), 1.83 - 1.64 (m, 2H)..sup.13C-NMR (126 MHz, CDCl.sub.3) δ 189.3, 161.2, 135.7, 127.8, 124.6, 120.2, 112.3, 71.7, 71.7, 70.5, 70.3, 70.3, 70.2, 70.2, 69.9, 69.9, 69.9, 68.0, 58.7, 58.7, 33.5, 29.4, 28.0, 26.0, 25.8. HRMS (ESI) calcd. for C.sub.13H.sub.28O.sub.7: m/z = 357.1913 [M + H].sup.+; found: 357.1922.
Synthesis of 2-((2,5,8,11-tetraoxapentadecan-15-yl)oxy)benzohydrazide (S10)
[0310] MeOH (20 mL) was added to S9 (577 mg, 1.62 mmol) in a 50 mL round-bottomed flask, followed by the dropwise addition of concentrated H.sub.2SO.sub.4 (0.2 mL). Next, the reaction mixture was stirred under reflux for 4 hours. After evaporation of all the MeOH under reduced pressure, a 0.5 M aqueous solution of NaOH (10 mL) was added and the product was extracted from the aqueous layer using CH.sub.2Cl.sub.2 (2 × 20 mL). Next, the combined organic layers were dried over anhydrous MgSO.sub.4, filtered, and the solvent was removed in vacuo to afford the crude methyl ester of S9 as a yellow oil. Part of the obtained oil (0.49 g, 1.32 mmol) was dissolved in a mixture of THF and MeOH (1:2 volume ratio, 25 mL total volume) in a 100 ml 3-neck flask. The reaction mixture was degassed with argon and hydrazine monohydrate (2 mL) was added. After heating to 65° C. for 72 hours, the solvent was evaporated under reduced pressure under a N.sub.2 atmosphere. The resulting product was dissolved in CH.sub.2Cl.sub.2 and washed with brine (3 × 20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford S10 (356.9 mg, 0.963 mmol) as a yellow oil in 60% yield over two steps. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 8.96 (s, 1H), 8.14 (dd, J = 7.8, 1.8 Hz, 1H), 7.39 (dddd, J = 8.2, 7.3, 1.9, 0.6 Hz, 1H), 7.08 - 6.98 (m, 1H), 6.92 (dd, J = 8.3, 0.9 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.66 - 3.46 (m, 15H), 3.33 (s, 3H), 2.01 - 1.86 (m, 2H), 1.82 - 1.67 (m, 2H). .sup.13C-NMR (126 MHz, CDCl.sub.3) δ 166.5, 156.9, 133.0, 132.1, 121.3, 120.1, 112.3, 72.0, 70.7, 70.7, 70.7, 70.6, 70.6, 70.3, 69.0, 59.1, 26.2, 26.2. HRMS (ESI) calcd. for C.sub.18H.sub.30N.sub.2O.sub.6: m/z = 371.2182 [M + H].sup.+; found: 371.2186.
Synthesis of Edge-Model
[0311] S10 (36 mg, 0.0972 mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2 (10 mL) in a 12 mL sealed reaction vial. The solution was degassed with argon and terephthalaldehyde (6.36 mg, 0.0474 mmol) was added. Next, HPLC grade TFA (1.45 .Math.L, 0.019 mmol) was pipetted into the reaction mixture, which was then stirred at room temperature for 5 hours. Afterwards, the acid was neutralized with a saturated sodium bicarbonate solution and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (2 × 10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified with preparative TLC over silica gel (eluent: 3.0 vol-% MeOH in CH.sub.2Cl.sub.2) to afford Edge-model (32 mg, 0.0380 mmol) as a white solid in 40% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 11.06 (s, 2H), 8.32 - 8.24 (m, 2H), 8.19 (s, 2H), 7.84 (s, 4H), 7.47 (t, 2H), 7.11 (t, J = 7.5 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 4.24 (t, J = 6.4 Hz, 4H), 3.65 - 3.49 (m, 28H), 3.35 (s, 6H), 2.07 (m, 4H), 1.95 - 1.71 (m, 4H)..sup.13C-NMR (126 MHz, CDCl.sub.3) δ 162.3, 156.7, 146.8, 135.7, 133.4, 132.7, 127.9, 121.6, 120.62, 112.4, 71.9, 70.6, 70.6, 70.5, 70.3, 69.1, 59.0, 26.4, 26.3. HRMS (ESI) calcd. for C.sub.44H.sub.62N.sub.4O.sub.12: m/z = 839.4442 [M + H].sup.+; found: 839.4464.
Example 10 - Synthesis of Syn-(1′s,5′r)-4,4″-dibutoxy-5′-(4-butoxy-5-(2-((E)-4-formylbenzylidene)hydrazine-1-carbonyl)-2-methoxyphenyl)-N′.SUP.3.,N⁗′.SUP.3″ -bis((E)-4-formylbenzylidene)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbohydrazide (Syn-4,4″-dibutoxy-5′-(4-butoxy-5-(2-((E)-4-formylbenzylidene)hydrazine-1-carbonyl)-2-methoxyphenyl)-N′3.,N⁗′.SUP.3″.-bis((E)-4-formylbenzylidene)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbohydrazide)(Syn-12)
##STR00057##
Synthesis of Syn-(1′r,3′s)-4,4″-dibutoxy-5′-(4-butoxy-5-formyl-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde (Syn-4,4″-dibutoxy-5′-(4-butoxy-5-formyl-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbaldehyde)(Syn-S9)
[0312] Syn-3 (0.500 g, 0.876 mmol), bromobutane (0.67 ml, 6.3 mmol), and K.sub.2CO.sub.3 (1.21 g, 8.76 mmol) were added to a round-bottomed flask containing dry DMF (10 mL) and the reaction mixture was stirred at 60° C. for 48 hours. Afterwards, the solution was added dropwise into 30 mL of a 1 N aqueous HCl solution and the formed precipitate was filtered to afford syn-S9 (0.580 g, 0.788 mmol) as a colorless solid in 90% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 10.36 (s, 3H), 7.55 (s, 3H), 6.50 (s, 3H), 4.12 (t, J= 6.3 Hz, 6H), 3.84 (s, 9H), 1.87 (m, 6H), 1.64 (s, 9H), 1.59 - 1.53 (m, 9H), 1.01 (t, J = 7.4 Hz, 9H). .sup.13C-NMR (126 MHz, CDCl.sub.3) δ 188.2, 163.2, 162.8, 135.0, 134.5, 131.9, 123.6, 118.8, 95.5, 68.4, 55.9, 31.3, 19.4, 18.8, 13.9. HRMS (ESI) calc. for C.sub.45H.sub.55O.sub.9: m/z = 739.3846 [M + H].sup.+; found: 739.3859.
Synthesis of Syn-dimethyl (1′s,5′r)-4,4″-dibutoxy-5′-(4-butoxy-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate (Syn-dimethyl-4,4″-dibutoxy-5′-(4-butoxy-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate)(Syn-S10)
[0313] Syn-S9 (0.580 g, 0.788 mmol) was dissolved in 30 ml of a 2:1 (vol-%) CH.sub.3CN/DMSO mixture in a 200 ml round-bottomed flask. Next, a solution of NaH.sub.2PO.sub.4 (0.96 g, 8.0 mmol) and NaClO.sub.2 (0.870 g, 9.61 mmol) in deionized water (8 ml) was added and the reaction mixture was stirred at room temperature. After 72 hours, the CH.sub.3CN was evaporated under reduced pressure, and 30 ml of a 1 N aqueous HCl solution were added at 0° C. The precipitate which formed was filtered and — to esterify all the acid functional groups — dissolved in MeOH (16 ml) in a 100 ml round-bottomed flask. Concentrated H.sub.2SO.sub.4 (1.0 ml) was added dropwise and the reaction was left stirring under reflux for 48 hours. Finally, the MeOH was evaporated under reduced pressure and the acid neutralized with 10 ml of a 1 N aqueous NaOH solution. The product was extracted from the resulting aqueous solution with CH.sub.2Cl.sub.2 (2 × 20 mL) and the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and evaporated to dryness under reduced pressure. The resulting crude product was purified with chromatography over silica gel (eluent: 10 vol-% EtOAc in CH.sub.2Cl.sub.2) and recrystallized from hexanes to afford syn-S10 (0.320 g, 0.386 mmol) as a colorless solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 7.60 (s, 3H), 6.54 (s, 3H), 4.09 (t, J = 6.5 Hz, 6H), 3.84 (s, 9H), 3.80 (s, 9H), 1.87 (dq, J = 8.7, 6.6 Hz, 6H), 1.67 (s, 10H), 1.63 - 1.53 (m, 6H), 1.00 (t, J = 7.4 Hz, 9H)..sup.13C-NMR (126 MHz, CDCl.sub.3) δ 166.3, 161.2, 160.4, 135.3, 135.2, 134.8, 122.7, 112.1, 97.0, 69.0, 55.7, 51.6, 31.5, 19.4, 18.8, 14.0. HRMS (ESI) calcd. for C.sub.48H.sub.61O.sub.12: m/z = 829.4163 [M + H].sup.+; found: 829.4185.
Synthesis of Syn-(1′r,3′s)-4,4″-dibutoxy-5′-(4-butoxy-5-(hydrazinecarbonyl)-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarbohydrazide (Syn-4,4″-dibutoxy-5′-(4-butoxy-5-(hydrazinecarbonyl)-2-methoxyphenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′2,1″-terphenyl]-3,3″-dicarbohydrazide)(Syn-S11)
[0314] Syn-S10 (0.320 g, 0.386 mmol) was dissolved in 30 ml of a 1:2 vol-% THF/MeOH mixture in a 250 ml sealed heavy-wall glass reaction vessel. The reaction mixture was degassed with argon and hydrazine monohydrate (1.6 ml) was added. After heating to 60° C. for 48 hours, most of the solvent was evaporated under reduced pressure under a N.sub.2 atmosphere. The resulting solid was filtered, washed with water (3 × 10 ml), and dried in vacuo to afford syn-S11 (0.256 g, 0.308 mmol) as a colorless solid in 80% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 8.83 (s, 3H), 7.93 (s, 3H), 6.52 (s, 3H), 4.16 (t, J = 6.6 Hz, 6H), 3.77 (s, 9H), 1.90 (dq, J = 8.8, 6.6 Hz, 6H), 1.66 (s, 9H), 1.58 - 1.51 (m, 6H), 1.02 (t, J = 7.4 Hz, 9H)..sup.13C-NMR (126 MHz, CDCl.sub.3) δ 166.7, 160.4, 157.5, 135.1, 135.0, 134.6, 124.0, 112.8, 96.2, 69.1, 55.9, 31.3, 19.5, 18.8, 13.9. HRMS (ESI) calcd. for C.sub.45H.sub.61N.sub.6O.sub.9: m/z = 829.4500 [M + H].sup.+; found: 829.4492.
Synthesis of Syn-12
[0315] Syn-S11 (0.079 g, 0.096 mmol) was dissolved in dry CH.sub.2Cl.sub.2 (10 mL) in a 50 mL round-bottomed flask. The solution was degassed with argon and terephthalaldehyde (1.430 mmol, 0.192 g) was added. Next, HPLC grade TFA (19 .Math.L, 0.096 mmol) was pipetted into the reaction mixture, which was stirred at room temperature for 48 hours. Afterwards, the acid was neutralized with saturated sodium bicarbonate solution and the aqueous layer extracted with CH.sub.2Cl.sub.2. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by size exclusion chromatography over polystyrene beads (200-400 mesh) with CH.sub.2Cl.sub.2 as the eluent to afford syn-12 (0.096 g, 0.081 mmol) as a light-yellow solid in 85% yield. .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 11.14 (s, 3H), 10.02 (s, 3H), 8.23 (s, 3H), 8.00 - 7.88 (m, 15H), 6.64 (s, 3H), 4.31 (t, J = 6.5 Hz, 6H), 3.92 (s, 9H), 2.08 - 1.96 (m, 6H), 1.71 - 1.61 (m, 15H), 1.09 (t, J = 7.4 Hz, 9H). .sup.13C-NMR (126 MHz, CD.sub.2Cl.sub.2) δ 192.1, 162.3, 161.5, 158.2, 145.2, 140.6, 137.6, 135.9, 135.5, 135.2, 130.4, 128.3, 124.5, 113.1, 96.2, 70.0, 56.3, 31.9, 20.0, 19.0, 14.1. HRMS (ESI) calcd. for C.sub.69H.sub.73N.sub.6O.sub.12: m/z = 1177.5286 [M + H].sup.+; found: 1177.5309.
Example 11- Synthesis of Additional Verteces Syn-Dimethyl (1′r,3′s)-5′-(2,4-dimethoxy-5-(methoxycarbonyl)phenyl)-4,4″,6,6″-tetramethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate (Syn-dimethyl-5′-(2,4-dimethoxy-5-(methoxycarbonyl)phenyl)-4,4″,6,6″-tetramethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate)(Syn-S20) and Syn-Dimethyl (1′r,5′s)-4,4″-bis((2-ethylhexyl)oxy)-5′-(4-((2-ethylhexyl)oxy)-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2’,4’,6′-trimethyl-[1,1′:3′1″-terphenyl]-3,3″-dicarboxylate (Syn-Dimethyl-4,4″-bis((2-ethylhexyl)oxy)-5′-(4-((2-ethylhexyl)oxy)-2-methoxy-5-(methoxycarbonyl)phenyl)-6,6″-dimethoxy-2′,4′,6′-trimethyl-[1,1′:3′,1″-terphenyl]-3,3″-dicarboxylate)(Syn-S21)
Synthesis of Syn-S20
[0316] Syn-2 (1.010 mmol) was dissolved in a 1:1 CH.sub.3CN/DMSO mixture (56 mL total volume) in a 250 mL round-bottomed flask. Next, a solution of NaH.sub.2PO.sub.4 (1.2 g, 10 mmol) and NaClO.sub.2 (0.9 g, 10 mmol) in 13 mL deionized water was added to the reaction mixture. After stirring at room temperature for 48 hours, the CH.sub.3CN was evaporated under reduced pressure and the reaction mixture was quenched by adding 30 mL of a 1 N aqueous HCl solution. Next, the water layer was extracted with CH.sub.2Cl.sub.2 (4 × 20 mL) and the combined organic phases were washed with brine (4 × 100 mL). After drying over anhydrous MgSO.sub.4, the solvent was removed in vacuo. Finally, MeOH (40 mL) was added to the resulting oxidized product (0.810 mmol) in a 100 mL round-bottomed flask, followed by the dropwise addition of concentrated H.sub.2SO.sub.4 (1.0 mL). The reaction mixture was stirred under reflux for 24 hours. After evaporation of MeOH under reduced pressure, 1 N aqueous NaOH (10 mL) was added and the product was extracted from the aqueous layer using CH.sub.2Cl.sub.2 (2 × 20 mL). Next, the combined organic layers were dried over anhydrous MgSO.sub.4, filtered, and the solvent was removed in vacuo. The crude product was purified by recrystallization to afford the methyl ester syn-S20 in 74% yield as a colorless solid. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 7.64 (s, 3H), 6.58 (s, 3H), 4.00 (s, 9H), 3.87 (s, 9H), 3.85 (s, 9H), 1.69 (s, 9H). HRMS characterization data was obtained after derivatization with hydrazine: HRMS (ESI) calcd. for C.sub.36H.sub.43N.sub.6O.sub.9: m/z = 703.3092 [M + H].sup.+; found: 703.3086.
Synthesis of Syn-S21
[0317] Syn-3 (0.68 g, 1.190 mmol), 7.140 mmol of the corresponding alkylating agent (2-ethylhexyl bromide), as well as K.sub.2CO.sub.3 (1.38 g, 10.0 mmol) were added to a round-bottomed flask containing anhydrous DMF (15 mL) and the reaction mixture was stirred at 40° C. for 72 hours. Then, the reaction mixture was quenched by adding 50 mL of a 1 M aqueous HCl solution. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3 × 30 mL) and the combined organic layers were washed with brine (4 × 75 mL), dried over anhydrous MgSO.sub.4, filtered, and evaporated under reduced pressure. If necessary, excess alkylating agent was removed by column chromatography. The resulting alkylated product (1.010 mmol) was dissolved in a 1:1 CH.sub.3CN/DMSO mixture (56 mL total volume) in a 250 mL round-bottomed flask. Next, a solution of NaH.sub.2PO.sub.4 (1.2 g, 10 mmol) and NaClO.sub.2 (0.9 g, 10 mmol) in 13 mL deionized water was added to the reaction mixture. After stirring at room temperature for 48 hours, the CH.sub.3CN was evaporated under reduced pressure and the reaction mixture was quenched by adding 30 mL of a 1 N aqueous HCl solution. Next, the water layer was extracted with CH.sub.2Cl.sub.2 (4 × 20 mL) and the combined organic phases were washed with brine (4 × 100 mL). After drying over anhydrous MgSO.sub.4, the solvent was removed in vacuo. Finally, MeOH (40 mL) was added to the resulting oxidized product (0.810 mmol) in a 100 mL round-bottomed flask, followed by the dropwise addition of concentrated H.sub.2SO.sub.4 (1.0 mL). The reaction mixture was stirred under reflux for 24 hours. After evaporation of MeOH under reduced pressure, 1 N aqueous NaOH (10 mL) was added and the product was extracted from the aqueous layer using CH.sub.2Cl.sub.2 (2 × 20 mL). Next, the combined organic layers were dried over anhydrous MgSO.sub.4, filtered, and the solvent was removed in vacuo. The resulting brown oil was purified by column chromatography over silica gel to afford the methyl esters syn-S21 in 60% yield. .sup.1H-NMR (500 MHz, CDCl.sub.3) δ 7.62 (s, 3H), 6.55 (s, 3H), 3.99 (dd, J = 5.6, 4.5 Hz, 6H), 3.86 (s, 9H), 3.83 (s, 9H), 1.92 - 1.28 (m, 42H), 0.98 (t, J = 7.4 Hz, 9H), 0.96 - 0.90 (m, 9H). .sup.13C-NMR (125 MHz, CDCl.sub.3) δ 166.39, 160.98, 160.35, 135.18, 135.16, 134.64, 122.46, 112.09, 96.58, 71.25, 55.67, 51.52, 39.59, 30.49, 29.17, 23.81, 23.06, 18.72, 14.12, 11.20. LC-MS: MH.sup.+ at m/z 997.6.
Example 12 - Synthesis of Additional Tetrahedra Tet-2, Tet-3, Tet-4, Tet-5, and Tet-6
General Procedure for the Conversion of the Methyl Ester Verteces Into Tetrahedra
[0318] Methyl ester verteces syn-4, syn-SlO, syn-S20, or syn-S21 (0.567 mmol) were dissolved in 45 mL of a 1:2 THF/MeOH mixture in a 250 mL sealed heavy-wall glass reaction vessel. Next, the solutions was degassed with argon and hydrazine monohydrate (9.0 mL) was added. After heating at 65° C. for 48 hours under argon atmosphere, the solvents were evaporated under reduced pressure (under a nitrogen atmosphere) and the resulting mixtures were extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with water (3 × 60 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure, and dried in vacuo. The resulting crude hydrazides (0.208 mmol) were dissolved in 350 mL of anhydrous CH.sub.2Cl.sub.2, and the solutions were degassed with argon. Next, the corresponding dialdehydes (0.312 mmol) and HPLC grade TFA (0.313 mmol) were added consecutively, and the reaction mixtures were stirred at room temperature under an argon atmosphere. After 48 hours, the acid was neutralized with a saturated aqueous sodium bicarbonate solution (10 mL), the organic layers were separated, and the aqueous phases extracted with additional CH.sub.2Cl.sub.2 (30 mL). Finally, the combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude products were purified by size exclusion chromatography over polystyrene beads (200-400 mesh) with CH.sub.2Cl.sub.2 as the eluent to afford the hydrazone-linked organic tetrahedra Tet-2 - Tet-6 as orange-yellow solids in 45-72% yield.
[0319] Tet-2: .sup.1H-NMR (500 MHz, DMSO-d.sub.6) δ 11.30 (s, 3H), 8.28 (s, 3H), 7.67 (d, J = 125.0 Hz, 9H), 6.85 (s, 3H), 4.31 (br, 6H), 3.89 (s, 9H), 1.95 - 1.40 (m, 21H), 1.25 (s, 9H). LC-MS: MH.sub.2.sup.2+ at m/z 1954.2.
[0320] Tet-3: .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 8.92 - 8.47 (m, 3H), 8.22 - 7.64 (m, 9H), 7.12 - 6.58 (m, 3H), 4.77 - 3.84 (m, 18H), 1.95 - 1.65 (m, 9H). LC-MS: MH.sub.4.sup.4+ at m/z 1701.
[0321] Tet-4: .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 11.10 (s, 3H), 8.27 (s, 1H), 8.04 (s, 3H), 7.87 (s, 3H), 7.60 (s, 2H), 6.69 (s, 3H), 4.24 (m, 6H), 3.95 (s, 9H), 2.08 - 1.55 (m, 27H), 1.30 (s, 9H), 1.15 - 0.85 (m, 18H). LC-MS: MH.sub.3.sup.3+ at m/z 1527.
[0322] Tet-5: .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 11.21 (s, 3H), 8.39 (s, 3H), 8.00 (d, J= 30.5 Hz, 6H), 6.69 (s, 3H), 4.38 (s, 6H), 4.10 - 3.83 (m, 18H),3.80 - 3.47 (m, 42H), 3.38 - 3.02 (m, 9H), 2.57 - 2.06 (m, 6H), 1.95 (m, 6H), 1.79 - 1.65 (m, 9H). LC-MS: MH.sub.3.sup.3+ at m/z 2071.6.
[0323] Tet-6: .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) δ 11.22 (s, 3H), 8.44 (s, 3H), 8.06 (s, 3H), 8.04 (s, 3H), 6.68 (s, 3H), 4.86 (s, 6H), 4.39 - 4.35 (m, 6H), 3.92 (s, 9H), 3.74 - 3.41 (m, 42H), 3.33 (s, 9H), 2.28 - 2.07 (m, 6H), 1.94 (m, 6H), 1.29 (s, 9). .sup.13C-NMR (125 MHz, CD.sub.2Cl.sub.2) δ 161.1, 160.6, 157.5, 149.6, 134.9, 134.5, 130.9, 124.1, 122.5, 113.1, 78.3, 76.9, 71.9, 70.5, 70.5, 70.4, 70.3, 70.2, 69.5, 61.3, 58.6, 55.8, 31.9, 29.7, 29.3, 26.3, 26.3, 22.7, 18.4, 13.9, 0.7, -0.4. HRMS (ESI) calcd. for C.sub.348H.sub.448N.sub.24O.sub.96: m/z = 1624.7728 [M + 4H].sup.4+; found: 1624.7725.
Example 13 - Sample Preparation and Measurements of Rate Constants
[0324] For all kinetic measurements, stock solutions of all reagents in CD.sub.2Cl.sub.2 were prepared in advance and used promptly. The stock solutions were stored at -10° C. in sealed vials under an argon atmosphere. All volumetric measurements were performed with Rainin Positive Displacement (MR-10, -100, -1000) micropipettes, which are optimized for organic solvents with low vapor pressures like CD.sub.2Cl.sub.2. The concentrations of reagents in the stock solutions were calibrated by .sup.1H-NMR integration and comparison of the integrals with the integral of 1,2,4,5-tetrabromobenzene as the internal standard. For each time-dependent .sup.1H-NMR experiment, the active ester (NDB) was added last to the reaction mixtures and the addition time of NDB is reported as the start time of the experiments. The progress of the aminolysis reactions was monitored by integrating (
Example 14 - DOSY Size-Selectivity Experiments
[0325] For the DOSY .sup.1H-NMR size-selectivity experiments, two NMR reaction mixtures were prepared and reaction progress was monitored by following the .sup.1H-NMR integrations of the p-nitrophenol resonances at 6.9 ppm. Both reactions were equalized as described in detail in
Example 15 - Molecular Dynamics (MD) Simulations of the NH.SUB.2.-POA Polymers on Their Own and in Complex With a Prototypical Nanocage (Tet-1)
[0326] In order to verify proposed model for the observed kinetic behavior of Tet-1, 800-ns MD simulations with the OPLS3e force field in explicit CH.sub.2Cl.sub.2 solvent were employed. The MD simulations (i) explained the outcome of the DOSY .sup.1H-NMR spectra shown in
Model Preparation
[0327] All models were constructed using the Maestro program (Schrödinger Release 2018-2: Maestro, Schrödinger, LLC, New York, NY). Tet-1 and [NH.sub.2-POA@Tet-1] (complex formed between POA and Tet-1)(the symbol @ between a two components is used to indicate formation of the complex between the two components) systems were simulated in periodic simulation boxes of ~121 × 121 × 121 Å.sup.3 and ~67 × 67 × 67 Å.sup.3, respectively, with CH.sub.2Cl.sub.2 molecules as the solvent. Each construct went through minimization, equilibration, and either 100-ns, 250-ns, or 800-ns MD production stages, depending on convergence speed. At least two replicas with differing random seeds were run for all simulations.
Simulation Setup and Analysis
[0328] Each model was simulated in the NPT ensemble (300 K, 1 atm, Martyna-Tuckerman-Klein coupling scheme) using the OPLS3 or the OPLS3e force field. All simulations were performed in the Maestro-Desmond program (GPU version 5.4) with a time step of 2 fs. The Ewald technique was used for the electrostatic calculations. The Van der Waals and short-range electrostatics were cut off at 9 Å. Hydrogen atoms were constrained using the SHAKE algorithm. MD trajectories were analyzed using in-house python scripts and the Schrödinger (2018-2 release) API.
Example 16 - Testing the Stability of Tet-1 Upon Heating in the Presence of Water
[0329] To investigate the hydrolytic stability of Tet-1, Tet-1 (2.3 mg, 3.93 × 10.sup.-4 mmol) was dissolved in a 90:10 vol-% mixture (440 .Math.L) of DMSO-d6 and D.sub.2O. The .sup.1H-NMR of the solution was then recorded and the mixture heated at 80° C. for five hours. No changes were observed (
Example 17 - Diffusion Ordered Spectroscopy (DOSY)
[0330] The NMR samples for DOSY .sup.1H-NMR spectroscopy were prepared in CD.sub.2Cl.sub.2 at room temperature, with TMS as the internal reference. The DOSY .sup.1H-NMR spectra were acquired on a Varian Unity Inova 500 spectrometer, equipped with a HCN probe with Z-axis gradients, and a Highland Technologies L700 gradient amplifier. The standard DOSY Varian pulse program. ‘Dbppste’ was used, with a stimulated echo sequence and bipolar gradient pulse pairs. All experiments were acquired at 25° C. and DOSY spectra were processed using Agilent’s VnmrJ 4.2 software, employing the discrete approach for the inverse Laplace transform in the diffusion dimension.
DOSY .SUP.1.H-NMR Spectrum of Tet-1
[0331] Based on the DOSY .sup.1H-NMR spectrum (
Full DOSY .SUP.1.H-NMR Spectra of NH.SUB.2.-POA, [NH.SUB.2.-POA@Tet-1], and Tet-1
[0332] The full DOSY 1H-NMR spectra shown in
Example 18 - Molecular Weight Measurements of NH.SUB.2.-POA With DOSY .SUP.1.H-NMR
[0333] NH.sub.2-POA kept getting stuck on GPC columns. Therefore, the molecular weight of the NH.sub.2-POA samples was determined with an alternative, well-established (Li et al., “Application of .sup.1H DOSY for Facile Measurement of Polymer Molecular Weights,” Macromolecules 45:9595-9603 (2012), which is hereby incorporated by reference in its entirety), DOSY .sup.1H-NMR-based technique. Specifically, four dilute (0.4 mg in 0.75 mL of CDCl.sub.3) polystyrene (PS) standard samples with different molecular weights (
TABLE-US-00001 Diffusion Constants (D) Obtained from the DOSY .sup.1H-NMR Analysis of the PS Standards Standard D (x10.sup.-10 m.sup.2 s.sup.-1) log D log
[0334] Finally, a calibration curve was obtained by plotting log D for the different standards vs. log
Equation S4 was then used to determine the molecular weights (
TABLE-US-00002 Diffusion Constants (D) and Corresponding Molecular Weights (
[0335] Next, NMR samples of NH.sub.2-POA, Short-NH.sub.2-POA, and Long-NH.sub.2-POA in CDCl.sub.3 were prepared by dissolving 0.4 mg of each polymer in 0.75 mL CDCl.sub.3. Finally, the DOSY .sup.1H-NMR spectra (
Example 19 -.SUP.1.H-.SUP.1.H-NOESY NMR Spectrum of the [Long-NH.SUB.2.-POA@Tet-1] Complex
[0336] The .sup.1H-.sup.1H-NOESY NMR spectra for the [Short-NH.sub.2-POA@Tet-1] (
Example 20 - .SUP.1.H-NMR Titration Experiments
Measurements of the Complex Association Constants and Complex Dissociation Rates for the [Short-NH.SUB.2.-POA@Tet-1] and [Long-NH.SUB.2.-POA@Tet-1] Complexes
[0337] Tet-1 (1.1 mg, 1.88 × 10.sup.-4 mmol) was dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and transferred to an NMR tube. In separate vials, Short- and Long-NH.sub.2-POA (8.4 mg) were dissolved in 300 .Math.L CD.sub.2Cl.sub.2 and the resulting solutions were titrated into the NMR samples containing Tet-1 in up to 10 steps. Upon titration, significant broadening of peaks corresponding to Tet-1 especially with long polymers was observed (
[0338] To investigate whether hydrogen bonding is important for the binding of NH.sub.2-POA with Tet-1, DMSO-d6 (60 .Math.L) was added to an NMR sample containing Short-NH.sub.2-POA (1.2 mM) and Tet-1 (0.23 mM) in CD.sub.2Cl.sub.2 (740 .Math.L). Immediately after the addition of the DMSO-d6 (which is a well-known hydrogen bond disruptor), the .sup.1H-NMR resonances corresponding to Tet-1 sharpened (
Titration of Tet-1 With Itself
[0339] 1 mg of Tet-1 (1.709 × 10.sup.-4 mmol) was dissolved in 600 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and the solution was transferred into an NMR tube. In a separate scintillation vial, 3 additional equivalents of Tet-1 (5.1273 × 10.sup.-4 mmol) were dissolved in 240 .Math.L CD.sub.2Cl.sub.2 and the resulting solution was titrated (
Titration of NH.SUB.2.-POA With Itself
[0340] 1 mg of NH.sub.2-POA (0.166 × 10.sup.-3 mmol) was dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and the solution was transferred into an NMR tube. In a separate scintillation vial, 4 additional equivalents of NH.sub.2-POA (0.664 × 10.sup.-3 mmol) were dissolved in 480 .Math.L CD.sub.2Cl.sub.2 and the resulting solution was titrated into the NMR tube in 5 steps. No significant shifts of any .sup.1H-NMR resonances corresponding to NH.sub.2-POA were observed upon increasing the concentration of NH.sub.2-POA.
Example 21 - .SUP.1.H-NMR Rate Measurements With NH.SUB.2.-POA
[0341] .sup.1H-NMR rate measurements were performed as described above. All .sup.1H-NMR spectra (with integrals of the key p-nitrophenol resonance used to monitor the progress of the reactions) are shown in
[0342] .sup.1H-NMR Rate Measurements with Short-NH.sub.2-POA are shown in
[0343] .sup.1H-NMR Rate Measurements with Long-NH.sub.2-POA are shown in
Example 22 - .SUP.1.H-NMR Rate Measurements With NH.SUB.2.-POA in the Presence of DMSO-d6
[0344] The .sup.1H-NMR rate measurements were performed as described above, except that they were executed in a 90:10 vol% mixture of a CD.sub.2Cl.sub.2:DMSO-d.sub.6 (instead of in pure CD.sub.2Cl.sub.2) with 1.5 mg of NH.sub.2-POA polymer, which corresponds to an initial amine concentration ([amine].sub.0) of approximately 1.5 mM. All .sup.1H-NMR spectra (with integrals of the key p-nitrophenol resonance used to monitor the progress of the reactions) are shown in
Example 23 - Derivation of Rate Equations
[0345] The kinetic data showed that plots of [amine].sup.-1 vs. reaction time (
[0346] In Equation S1, [amine] is the total concentration of amino groups on all the polymer chains, k.sub.cat/K.sub.M is the catalytic efficiency, [cat].sub.0 is the initial concentration of the organocatalyst, and [NDB] is the concentration of the active ester. For all the experiments an excess of active ester was used and the same initial amount of active ester was added to all experiments. Therefore, the NDB concentration can be approximated to remain constant during the aminolysis reactions, and, with [NDB].sub.0 defined as the initial concentration of the active ester, the rate law can be further simplified as:
[0347] Finally, the observed rate constant k.sub.obs was defined as:
[0348] Which led to the following simplified rate equation:
[0349] For the control reaction without any catalyst added, the rate constant k.sub.obs of the reaction was defined in an analogous manner:
Example 24 - Custom Python Script Used to Fit the Association Equilibrium Constant and De-Threading Rate Constant for the Complexes
[0350] Upon addition of the NH.sub.2-POA polymers, the Tet-1 .sup.1H-NMR resonances likely broadened (
Example 25 - Results of Examples 1-24
Synthesis of a Hydrazone-Linked Molecular Tetrahedron
[0351] To achieve activity and selectivity, a PSPM catalyst has to recognize the polymeric substrates to initiate catalysis (
[0352] For an efficient synthesis of hydrazone-tetrahedra (
[0353] The synthesis (Scheme 1) of syn-7 started with a trifold formylation of syn-1, which was created on a large scale with a solid state-driven amplification of the syn-atropoisomer of 1 (Sharafi et al., “Crystal Packing-Driven Enrichment of Atropoisomers,” Angew. Chem. Int. Ed. 56:7097-7101 (2017)), which is hereby incorporated by reference in its entirety).
Scheme 1. Synthesis of the Hydrazone-Linked Molecular Tetrahedron Tet-1
[0354] ##STR00058##
[0355] Reagents and conditions: (i) BCl.sub.3, CH.sub.2Cl.sub.2; (ii) Br-(CH.sub.2).sub.4(OCH.sub.2CH.sub.2).sub.3OCH.sub.3, K.sub.2CO.sub.3, DMF, Δ; (iii) MeOH, H.sub.2SO.sub.4, Δ; (iv) H.sub.2NNH.sub.2, MeOH, H.sub.2O, Δ.
[0356] The methoxyl groups ortho to the aldehydes of the resulting syn-2 were then removed selectively with BCl.sub.3 to afford the tris-phenol syn-3. Finally, syn-3 was converted into the vertex syn-7 through (i) alkylation of the phenolic —OH groups, (ii) Pinnick oxidation (Dalcanale et al., “Selective Oxidation of Aldehydes to Carboxylic Acids with Sodium Chlorite-Hydrogen Peroxide,” J. Org. Chem. 51:567-569 (1986), which is hereby incorporated by reference in its entirety) of the aldehydes to carboxylic acids, (iii) esterification, and (iv) hydrazinolysis of the resulting methyl esters. To form the tetrahedron Tet-1, two equivalents of the vertex syn-7 were mixed with three equivalents of terephtalaldehyde and trifluoroacetic acid (TFA) as the catalyst in CH.sub.2Cl.sub.2. After 48 hours of stirring at room temperature, Tet-1 was formed in 80% yield, as confirmed by high-resolution ESI mass spectrometry as well as .sup.1H-, .sup.13C- and DOSY .sup.1H-NMR spectroscopy.
[0357] The .sup.1H-NMR spectrum of Tet-1 illustrated its T.sub.d symmetry with only five resonances (all singlets) appearing in the region between 6 and 12 ppm. Based on a minimized molecular model (
Synthesis of Additional Hydrazone-Linked Molecular Tetrahedra
[0358] Additional hydrazone-linked tetrahedra Tet-2, Tet-3, Tet-4, Tet-5, and Tet-6 were synthesized analogous to the synthesis of Tet-1 (Scheme 2).
Scheme 2. Synthesis of the Hydrazone-Linked Molecular Tetrahedra Tet-2, Tet-3, Tet-4, Tet-5, and Tet-6
[0359] ##STR00059##
Polymer Recognition With Tet-1
[0360] After Tet-1 was isolated, the molecular tetrahedron’s ability to recognize amine-functionalized polymers with side chains was investigated, since binding to such macromolecules is a prerequisite for the catalytic polymer functionalization described below. To create amine-functionalized polymers, n-octylamine (90 mol %) was first condensed with commercial poly(isobutylene-alt-maleic) anhydride, and then the remaining anhydride units were reacted with 1,6-diaminohexane (Scheme 3). As shown by (i) elemental analysis, (ii) by Fourier-transform infrared (FTIR) spectroscopy, and (iii) by measuring the percentage of free amino groups through complete acylation at elevated temperature, this procedure led to full and partial amidation of the maleic anhydride units to afford a polydisperse mixture of amine-functionalized poly(isobutylene-alt-n-octyl maleamide) (NH.sub.2-POA) polymers with a molecular weight
Scheme 3. Synthesis of an Amine-Functionalized Polymeric Substrate for Size-Selective Catalysis
[0361] ##STR00060##
[0362] Reagents and conditions: (i) H.sub.2N-n-C.sub.8H1.sub.7, DMF, Δ; (ii) H.sub.2N-n-C.sub.6H.sub.12-NH.sub.2, DMF, Δ. Based on elemental analysis and the
[0363] Next, binding between Tet-1 and the polymeric NH.sub.2-POA substrate was confirmed with (i) DOSY .sup.1H-NMR spectroscopy (
[0364] In the threaded binding geometry, the solvodynamic diameter of NH.sub.2-POA increased by ca. 50%, compared to the solvodynamic diameter of the NH.sub.2-POA polymer on its own (
[0365] To gain further insight into the nature of the polymer recognition abilities of Tet-1, the shortest (Short-NH.sub.2-POA,
[0366] Analysis of the NMR titration data (
Organocatalytic Polymer Functionalization With Tet-1
[0367] Triglyme functional groups act (Basilio et al., “A New Reaction Pathway in the Ester Aminolysis Catalyzed by Glymes and Crown Ethers,” J. Org. Chem. 71:4280-4285 (2006), which is hereby incorporated by reference in its entirety) as organocatalysts to accelerate aminolysis reactions. Since Tet-1 possesses 12 peripheral triglyme chains and binds to amine-functionalized NH.sub.2-POA polymers, Tet-1 can engage in size-selective catalytic (
[0368] The progress of the reactions was followed by integrating (
[0369] On the other hand, with cat = Tet-1, the rate law can be written as:
[0370] Finally, for the control reaction without any catalyst added, the rate constant k.sub.obs of the reaction was defined in an analogous manner:
k.sub.obs in equations 1-3 are observed rate constant (defined in equation S3), [amine] is the total concentration of amino groups on all the polymer chains, and [cat].sub.0 is the initial concentration of the organocatalyst.
[0371] The rate constants k.sub.obs (
Size-Selectivity of the Organocatalytic Polymer Functionalization Process
[0372] The present application demonstrates that the Tet-1 catalyst can distinguish between different chain-lengths of the NH.sub.2-POA substrates directly in the complex mixture of all the polymer chains and partially reverse the intrinsic size selectivity for the catalytic polymer functionalization process. Evidence for the size selectivity includes: [0373] (i) A distinct difference (
(I) Evidence of Size-Selectivity Based on Solvodynamic Diameters
[0376] To investigate the size selectivity in the presence of all polymer chains, PSPM reactions were first ran with different catalysts and NDB as the acylation reagent to the same conversion (24%). For the first catalytic system, Tet-1 (0.28 mM) was used as the catalyst, while a combination of Triglyme + Control (3.4 mM each) was used as the control. To be able to directly compare the different reaction systems, they were equalized before analysis with the following protocol: (i) for the functionalization reaction catalyzed by Tet-1 (0.28 mM), Triglyme (3.4 mM) and Control (3.4 mM) were added just before analysis. (ii) For the control reaction catalyzed by Triglyme (3.4 mM equivalents) + Control (3.4 mM), Tet-1 (0.28 mM) was added again just before analysis. All measurements were executed with volumetric additions from identical stock solutions. In this manner it was ensured that, besides the differently-functionalized polymers, all other components and amounts thereof were exactly the same for all the samples in the end. As a result, different properties of the equalized reaction mixtures were expected to directly correlate with differences in the functionalization patterns of the polydisperse NH.sub.2-POA substrates.
[0377] DOSY .sup.1H-NMR spectra of all reaction mixtures were recorded immediately after equalization. From these spectra, the average solvodynamic diameters of the polymers were determined. Significant differences in the solvodynamic diameters of the polymers were observed between the control reaction and the Tet-1-catalyzed variant. These differences indicate (
[0378] The NH.sub.2-POA polymers contain (Scheme 3) both NH.sub.2 and COOH functional groups. In the non-polar CD.sub.2Cl.sub.2 solvent used for the acylation reactions, these functionalities formed strong hydrogen bonds, that are required (
(II) Comparing the Diffusion Constants of the Functionalized to the Unfunctionalized Polymers Provides Direct Evidence for Size Selectivity in the Polydisperse Mixture
[0379] To obtain additional evidence for the size-selectivity in the polymer mixture, the average size of the functionalized polymer chains was compared (
(III) Measurements of the Relative Rate Constants for the Acylation of Short and Long Polymers Separately Confirm the Selectivity of the Tet-1 Catalyst for Shorter Polymers
[0380] Some of the shortest (Short-NH.sub.2-POA;
[0381] The results shown in
[0382] Overall, based on the evidence shown in
Example 26 - Discussion of Examples 1-25
Mechanism of the Size-Selective Catalytic Polymer Functionalization
[0383] The control reactions executed with simple Triglyme and the Edge-model demonstrated that not only the triglyme functions of Tet-1, but also the cavity of the tetrahedron are important for catalysis. For instance, the slope (= k.sub.obs[cat].sub.0) of the rate plot with the NH.sub.2-POA substrate increased (
[0384] Furthermore, from the measured second-order rate dependence on the Tet-1 concentration, it was concluded that two tetrahedra must be interacting (Yamashina et al., “Cramming Versus Threading of Long Amphiphilic Oligomers into a Polyaromatic Capsule,” Nat. Commun. 9:4227 (2018), which is hereby incorporated by reference in its entirety) with the polymeric substrate in the rate-determining transition state of the reaction. Thus, based on (i) the kinetic data and (ii) the fact that the solvodynamic diameter of the polymers increased very significantly upon binding to Tet-1 (
The Role of Tet-1′s Cavity During Catalysis
[0385]
Origin of the Observed Size Selectivity
[0386] It is likely that a nanosized catalyst like Tet-1 can distinguish polymeric substrates of different sizes due to complex, large-section contacts, resembling interactions between biological macromolecules. Such non-local supramolecular recognition is difficult to achieve with small-molecule catalysts like Triglyme, since a small molecule catalyst interacts with reactive groups on the polymers (e.g. amines in this case) mostly in a local fashion. Although a small-molecule catalyst can also form multivalent contacts with its polymeric substrates, it will, in most instances, simply not be able to reach far away sections of a polymeric substrate to enable size-selective functionalization of such large substrates.
[0387] As suggested by MD simulations (
Conclusions
[0393] In conclusion, the concept of post-synthetic selective polymer modification operating in complex mixtures of polymeric substrates was demonstrated. The reaction proceeds with size selectivity in the presence of a hydrazone-linked tetrahedron with wide openings as the catalyst, in sharp contrast to the results observed with small-molecule catalysts. This conclusion is supported by (i) distinct differences in the overall solvodynamic radii of the of the polymeric products, (ii) by a significant alteration in the relative diffusion constants for the functionalized polymers compared to the unfunctionalized ones, as well as (iii) by rate constants measured separately for the shorter and longer polymer chains. These findings extend the scope of catalyst-controlled size selectivity to large substrates for post-synthetic polymer-functionalization reactions, applied to polydisperse polymer mixtures. This size-selective, catalytic approach represents a promising avenue to create new polymers.
Example 27 - Synthesis of Poly(isobutylene-alt-n-octyl Maleimide) (POI)
[0394] ##STR00061##
Poly(isobutylene-alt-maleic anhydride) (
Example 28 - Binding Studies
Materials and Instruments
[0395] Deuterated solvents were purchased from Cambridge Isotope Laboratory and used without further purification. Tetramethylsilane (TMS), which was applied as the internal standard in all .sup.1H-NMR binding studies, was purchased from Sigma Aldrich and used as received. All volumetric measurements were performed with Rainin Positive Displacement (MR-10, -100, -1000) micropipettes. The picrocrocin for the binding studies was isolated from the dry stigma of crocus sativus (Persian Saffron), which was received from the Skinner Laboratory at the University of Vermont’s Department of Agricultural Sciences. For extraction and purification of the picrocrocin, dehydrated stigma of crocus sativus was grinded with mortar and pestle in CH.sub.3CN. Next, the solution was filtered and the solvent evaporated under reduced pressure. The crude picrocrocin was purified with preparative thin-layer chromatography (TLC) over silica gel (eluent: CH.sub.3CN, R.sub.f = 0.15). The .sup.1H-NMR (500 MHz, CD.sub.3OD) spectrum of the picrocrocin obtained with applicants’ purification method matched the characterization data reported (Sobolev et al, “Saffron Samples of Different Origin: An NMR Study of Microwave-Assisted Extracts,” Foods 3:403-419 (2014), which is hereby incorporated by reference in its entirety) previously in the literature.
Sample Preparation and Measurements of Host-Guest Binding Constants
[0396] For all titration experiments with Tet-1, solutions of Tet-1 in CD.sub.2Cl.sub.2 were prepared first. The guests were then dissolved in the same solvent separately and titrated into the host solutions. For each titration, a series with approximately 10 .sup.1H-NMR spectra was recorded. For the fitting of the association constants, the concentrations of both the host and guest were listed (i.e. the dilution effect for each experiment was considered) together with the corresponding .sup.1H-NMR chemical shifts of representative protons. Next, those listings were entered into DynaFit (Kuzmic, P. “Program DYNAFIT for the Analysis of Enzyme Kinetic Data: Application to HIV Proteinase,”Anal. Biochem. 237:260-273 (1996), which is hereby incorporated by reference in its entirety), which was used to obtain association constants and corresponding standard errors by fitting to all representative .sup.1H-NMR resonances at the same time. To ensure that the fitted binding models are not distorted by the host and/or guests binding with themselves, a series of .sup.1H-NMR spectra (CD.sub.2Cl.sub.2, 298 K) was also recorded for varying concentrations of just Tet-1 as well as all the guests alone. No significant self-binding was observed (vide infra) for Tet-1 or any of the guest.
Measurement of the Complex Association Constant for [PVP@Tet-1] (Complex Formed Between PVP and Tet-1)
[0397] Tet-1 (1.1 mg, 1.88 × 10.sup.-4 mmol) was dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and then transferred to an NMR tube. In a separate vial, 5.0 equivalents of the guest polymer polyvinylpyrrolidone (PVP, 9.47 × 10.sup.-4 mmol) were dissolved in 340 .Math.L of CD.sub.2Cl.sub.2 and the resulting solution was titrated into the NMR tube in 11 steps. The best fit (
Measurement of the Complex Association Constants for [POI@Tet-1] (Complex Formed Between POI and Tet-1)
[0398] Tet-1 (1.1 mg, 1.88 × 10.sup.-4 mmol) was dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and transferred to an NMR tube. In a separate vial, 5.0 equivalents of the guest polymer polyvinylpyrrolidone (POI, 9.47 × 10.sup.-4 mmol) were dissolved in 340 .Math.L CD.sub.2Cl.sub.2 and the resulting solution was titrated into the NMR tube in 11 steps. Upon titration, very significant broadening of peaks corresponding to Tet-1 was observed (
[0399] To investigate whether hydrogen bonding is important for the binding of POI with Tet-1, DMSO-d6 (10 .Math.L) was added to an NMR sample containing POI (1.13 mM) and Tet-1 (0.22 mM) in CD.sub.2Cl.sub.2. Immediately after the addition of the DMSO-d6 (which is a well-known hydrogen bond disruptor), the .sup.1H-NMR resonances corresponding to Tet-1 sharpened (
Measurement of the Complex Association Constant for [PS@Tet-1] (Complex Formed Between PS and Tet-1)
[0400] In a vial, Tet-1 (2.83 mg, 4.83 × 10.sup.-4 mmol) was dissolved in 600 .Math.L of CD.sub.2Cl.sub.2 and the solution was transferred to an NMR tube. In a separate vial, 5.0 equivalents of polystyrene (PS,
Measurement of the Complex Association Constant for [Picrocrocin.SUB.3.@Tet-1] (Complex Formed Between 3 Molecules of Picrocrocin and Tet-1)
[0401] Tet-1 (1.1 mg, 1.88 × 10.sup.-4 mmol) was dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and transferred to an NMR tube. In a separate vial, picrocrocin (6.0 mg, 6.16 × 10.sup.-3 mmol) was dissolved in 640 .Math.L CD.sub.2Cl.sub.2 and the resulting solution was titrated into the NMR tube in 20 steps. Additional points for the titration were obtained by (i) evaporating all the NMR solvent and (ii) redissolving the picrocrocin/Tet-1 mixture in 500 .Math.L of CD.sub.2Cl.sub.2. The resulting more concentrated sample was then diluted back to a total volume of 900 .Math.L in four titration steps. The exact concentration of the picrocrocin in the titration samples was determined by integration of its .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) resonance at 10.06 ppm, with Tet-1′s .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2) resonance at 6.64 ppm serving as the internal standard. The best fit (
Titration of Tet-1 With Itself
[0402] 1 mg of Tet-1 (1.709 × 10.sup.-4 mmol) was dissolved in 600 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and the solution was transferred into an NMR tube. In a separate scintillation vial, 3 additional equivalents of Tet-1 (5.1273 × 10.sup.-4 mmol) were dissolved in 240 .Math.L CD.sub.2Cl.sub.2 and the resulting solution was titrated (
Titration of PVP With Itself
[0403] 7.5 mg of PVP (9.375 × 10.sup.-4 mmol) were dissolved in 200 .Math.L CD.sub.2Cl.sub.2 in a scintillation vial. Next, 20 .Math.L of the solution were added to an NMR tube and diluted by adding 500 .Math.L of CD.sub.2Cl.sub.2. The 180 .Math.L of solution remaining in the vial were then titrated (
Titration of POI With Itself
[0404] 7.1 mg of POI (6.867 × 10.sup.-4 mmol) were dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and the resulting solution was transferred into an NMR tube. An additional 5.0 equivalents (35.5 mg) of POI was dissolved in 340 .Math.L of CD.sub.2Cl.sub.2 in a separate scintillation vial and the solution was titrated (
Titration of Picrocrocin With Itself
[0405] 2.5 mg of picrocrocin (3.32 mmol) were dissolved in 200 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial. Next, 20 .Math.L of the solution were transferred to an NMR tube and diluted by adding 500 .Math.L of CD.sub.2Cl.sub.2. The 180 .Math.L of solution remaining in the vial were then titrated (
Example 29 - Molecular Dynamics (MD) Simulations of Picrocrocin and/or Polyvinylpyrrolidone (PVP) in Complex With a Prototypical Nanocage (Tet-1)
Model Preparation
[0406] All models were constructed using the program Maestro (Maestro, Schrödinger, LLC, New York, NY, 2018). The tetrahedron cage Tet-1 and picrocrocin models were built according to Scheme 1 and
Simulation Setup
[0407] Each model was simulated in the NPT ensemble (300 K, 1 atm, Martyna-Tuckerman-Klein coupling scheme) using the OPLS3 (Harder et al., “OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins,” J. Chem. Theory Comput. 12: 281-296 (2016), which is hereby incorporated by reference in its entirety) force field. All simulations were performed in the Maestro-Desmond program (Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, 2018) (GPU version) with a time step of 2 fs, except for the tetrahedron/picrocrocin system which was simulated with a time step of 1 fs. The Ewald technique was used for the electrostatic calculations. The Van der Waals and short-range electrostatics were cut off at 9 Å. Hydrogen atoms were constrained using the SHAKE algorithm.
Visualization and Analysis
[0408] Using in-house Tcl and Python scripts, the distance between the center of mass (COM) of Tet-1 and the COM of each picrocrocin molecule was measured. A picrocrocin molecule was considered inside the cage when the picrocrocin—Tet-1 COM distance was within a 10 Å cutoff, the approximate radius of the cage. The snapshots of the last frame of each simulation as well as the three trajectory movies (displayed as web enhanced objects) were made using Pymol (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC) and Maestro, respectively.
Example 30 - Results and Discussion of Examples 27-29
[0409] Polymer recognition with the cage was performed. First, a .sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2, 298 K) titration of Tet-1 with commercial polyvinylpyrrolidone (PVP,
[0410] If the side chains attached to the polymer are elongated further, however, host-guest exchange was expected to slow down. To test this hypothesis, poly(isobutylene-alt-n-octyl maleimide) (POI,
[0411] Upon addition of POI, the Tet-1 .sup.1H-NMR resonances likely broaden for a variety of reasons, including (i) slowed host-guest exchange, (ii) desymmetrization of the protons in the cage upon POI binding, as well as (iii) different polymer-cage binding modes coexisting with the polydisperse polymer sample. For these reasons, a detailed .sup.1H-NMR line-shape analysis for the [POI@Tet-1] system was impractical. Nevertheless, the sigmoidal character of the titration curve shown in
[0412] The hydrazone-linked tetrahedron also displayed utility in binding to glycoside natural products. For instance, while working toward selective sensors to gage the quality of saffron, it was discovered with a .sup.1H-NMR titration (500 MHz, CD.sub.2Cl.sub.2, 298 K,
[0413] 100 ns-long MD simulations of Tet-1 in a 5 mol% solution of picrocrocin in CH.sub.2Cl.sub.2 qualitatively reproduced the observed cooperativity. At ~8 ns of simulation time, three of the picrocrocins start to bind cooperatively to Tet-1 in a stable binding conformation with a fourth one more loosely associated with the side of the cage. Overall, a statistical analysis of the trajectory revealed (see the histogram displayed in
[0414] In summary, the hydrazone-linked molecular tetrahedron binds not only to polymers with side-chains, but also to the natural product picrocrocin — a key component of saffron. Experimental and computational evidence both manifested that picrocrocin binding is cooperative, providing a rare (Yoshizawa et al., “Discrete Stacking of Large Aromatic Molecules Within Organic-Pillared Coordination Cages,” Angew. Chem., Int. Ed. 44:1810-1813 (2005), which is hereby incorporated by reference in its entirety) example of cooperativity with a 3:1 binding stoichiometry inside a synthetic molecular host.
Example 31 - Measurement of the Complex Association Constant for [Curcumin.SUB.2.@Tet-1] (Complex Formed Between 2 Molecules of Curcumin and Tet-1)
[0415] Other spices were also extracted in an analogous manner and the resulting extracts titrated into solutions of a prototypical nanocage (Tet-1) to determine the recognition abilities of Tet-1. In one example, turmeric was extracted and when the extract was mixed with a CD.sub.2Cl.sub.2 solution of Tet-1, significant shifts of prominent Tet-1 .sup.1H NMR resonances were observed. Careful analysis of the .sup.1H NMR shifts observed during the addition of the turmeric extract indicated that it is likely the curcumin component in turmeric, which binds selectively to the nanocage Tet-1. Molecular docking studies (
[0416] Next, to confirm recognition of curcumin by Tet-1, a commercial sample of purified curcumin was obtained from Sigma Aldrich and the purified curcumin was titrated into a solution of Tet-1. Specifically, Tet-1 (2.0 mg, 3.41 × 10.sup.-4 mmol) was first dissolved in 500 .Math.L of CD.sub.2Cl.sub.2 in a scintillation vial and then transferred the Tet-1 solution to an NMR tube. In a separate vial, curcumin (1.0 mg, 2.7 × 10.sup.-3 mmol) was dissolved in 450 .Math.L of CD.sub.2Cl.sub.2 and the resulting solution was titrated into the NMR tube containing the Tet-1 solution in 8 steps. The .sup.1H NMR (CD.sub.2Cl.sub.2, 500 MHz, 298 K) spectrum was then recorded for each titration point, and the chemical shifts plotted (
[0417] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.