Ketals and Polyketals as Release Agents

Abstract

Disclosed herein are ketal compounds, oligomers, and polyketals that are obtained in both high purity and high yield. These ketals and polyketals are utilized for their ability to readily release small chemical molecules, preferably fragrance molecules. Also disclosed are the utility of ketals and polyketals as delivery vehicles for controlled release of fragrances over time and/or on demand.

Claims

1. A polyethylene glycol (PEG) linked ketal comprising a structure represented as: ##STR00026## wherein R.sub.1, R.sub.2 are either the same or different derivatives of molecules/macromolecules with alcohol functionality(ies)

2. The PEG linked ketal of claim 1, wherein R.sub.1, R.sub.2 are selected from one or more of alcohol derivatives from the group of alcohols consisting of; hydroxy cinnamyl alcohol; rhodinol; anisyl alcohol; alpha-terpinol; nerol; maltol; leaf alcohol; ebanol; dihydromercinol; hydroxycitronellal; lavender ketone; raspberry ketone; dimetol; phenyl ethyl alcohol; alpha-methylcinnamic alcohol; linalool oxide; acetoin; isopentyl alcohol; isoamyl alcohol; 2-phenyl methanol; 4-allyl-2-methoxyphenol (eugenol); 3-(2-bornyloxy)-2-methyl-1-propanol; 2-tert-butylcyclohexanol; 4-tert-butylcyclohexanol; benzyl alcohol; 1-decanol; 9-decen-1-ol; dihydroterpineol; 2,4-dimethyl-4-cyclohexen-1-yl methanol; 2,4-dimethylcyclohexyl methanol; 2,6-dimethyl-2-heptanol; 2,6-dimethyl-4-heptanol; 3a,4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano[1H] inden-5-ol; 3,7-dimethyl-1,6-nonadien-3-ol; 2,6-dimethyl-2,7-octadien-6-ol (linalool); cis-3,7-dimethyl-2,6-octadien-1-ol (nerol); trans-3,7-dimethyl-2,6-octadien-1-ol (geraniol; 3,7-dimethyl-1,7-octanediol; 3,7-dimethyl-1-octanol (tetrahydrogeraniol); 2,6-dimethyl-2-octanol (tetrahydromyrcenol); 3,7-dimethyl-3-octanol (tetrahydrolinalool); 2,6-dimethyl-7-octen-2-ol (dihydromyrcenol); 3,7-dimethyl-6-octen-1-ol (citronellol); 2,2-dimethyl-3-(3-methylphenyl)-1-propanol; 2,2-dimethyl-3-phenyl-1-propanol, 2-ethoxy-4-methoxymethylphenol; 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; cis-3-hexen-1-ol, 4-(4-hydroxy-3-methoxyphenyl)-2-butanone; 1-hydroxy-2-(1-methyl-1-hydroxyethyl)-5-methylcyclohexane; 3-(hydroxymethyl)-2-nonanone; 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-1-carboxaldehyde; isoborneol; 3-isocamphylcyclohexanol; 2-isopropenyl-5-methylcyclohexanol (isopulegol); 1-isopropyl-4-methylcyclohex-3-enol (terpinenol); 4-isopropylcyclohexanol, 1-(4-isopropylcyclohexyl) ethanol; 4-isopropylcyclohexylmethanol; 2-isopropyl-5-methylcyclohexanol (menthol); 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol); 2-(4-methyl-3-cyclohexenyl)-2-propanol (terpineol); 2-(4-methylcyclohexyl)-2-propanol (dihydroterpineol); 4-methoxybenzyl alcohol, 2-methoxy-4-methylphenol; 3-methoxy-5-methylphenol; 1-methoxy-4-propenylbenzene (anethol); 2-methoxy-4-propenylphenol (isoeugenol); 4-methyl-3-decen-5-ol; 2-methyl-6-methylene-7-octen-2-ol (myrcenol); 3-methyl-4-phenyl-2-butanol; 2-(2-methylphenyl) ethanol; 2-methyl-4-phenyl-1-pentanol; 3-methyl-5-phenyl-1-pentanol; 2-methyl-1-phenyl-2-propanol; (1-methyl-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl) cyclopropyl) methanol; 3-methyl-4-(2,2,6-trimethylcyclohexen-1-yl)-2-butanol; 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; (3-methyl-1-(2,2,3-trimethyl-3-cyclopentenyl)-3-cyclohexen-1-yl) methanol; 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol; 2-methyl-2-vinyl-5-(1-hydroxy-1-methylethyl) tetrahydrofuran; trans,cis-2,6-nonadienol; 1-nonanol; nopol; 1,2,3,4,4a,5,6,7-octahydro-2,5,5-trimethyl-2-naphthol; 1-octanol; 3,4,5,6,6-pentamethyl-2-heptanol; 2-phenylethanol; 2-phenylpropanol; 3-phenylpropanol (hydrocinnamic alcohol); 3-phenyl-2-propen-1-ol (cinnamic alcohol); 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl) cyclohexan-1-ol; 3,5,5-trimethylcyclohexanol; 2,4,6-trimethyl-4-cyclohexen-1-ylmethanol; 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol; 3,7,11-trimethyl-2,6,10-dodecatrien-1-ol (farnesol); 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol); 3,5,5-trimethyl-1-hexanol (isononanol); 1-undecanol; 10-undecen-1-ol; and vetiverol.

3. The PEG linked ketal of claim 1 or 2, wherein at least one of R.sub.1, R.sub.2 is a diol derivative.

4. The PEG linked ketal of claim 1 or 2, wherein at least one of R.sub.1, R.sub.2 is a polyol derivative.

5. The PEG linked ketal of any of claims 1-4, wherein each of the R.sub.1, R.sub.2 groups may be unique and different from any other or all of these groups within the PEG linked ketal molecule.

6. The PEG linked ketal of claim 1, wherein R.sub.1 and R.sub.2 are selected from the group consisting of one or more of: provitamins, vitamins, pain relief agents, and small molecule pharmaceuticals, which are as distinguished from mono-alcohol or poly-alcohol containing fragrance moieties.

7. The PEG linked ketal of claim 1, wherein R.sub.1, R.sub.2 are both substituted 2-phenylethanol derivatives within a substituted ketal structure represented as; ##STR00027##

8. The PEG linked ketal of claim 1, wherein R.sub.1, R.sub.2 are both substituted isoamyl alcohol derivatives within a substituted ketal structure represented as; ##STR00028##

9. A synthesis process for producing a polyethylene glycol (PEG) linked ketal of Structure I ##STR00029## comprising the steps of: (i) reacting a polyethylene glycol with a levulinic acid together with 1-ethyl, 3,(3-dimethylamino propyl) carbodiimide (EDC), 4-dimethyl amino pyridine (DMAP), and dichloromethane (DCM) to form a PEG linked ketal and (ii) reacting a fragrance molecule having one or more alcohol moieties with the PEG linked ketal in a presence of tetrabutylammonium tribromide (TBAB) and trimethyl orthoformate ##STR00030## wherein R.sub.1, R.sub.2 are either one or more of mono- or poly-alcohol derivatives.

10. The process of claim 9 wherein at least one of R.sub.1 and R.sub.2 are diols or polyols.

11. The process of claim 9, wherein R.sub.1 and R.sub.2 are selected from the group consisting of one or more of: provitamins, vitamins, pain relief agents, and small molecule pharmaceuticals which are as distinguished from mono-alcohol or poly-alcohol containing fragrance moieties.

12. The process of claim 9, wherein each of the R.sub.1, R.sub.2 groups may be unique and different from any other or all of these groups within the PEG linked ketal molecule.

13. A process for decomplexation of fragranced PEG linked ketal compounds and consequent release of one or more fragrance molecules having at least one alcohol moiety, via an acid hydrolysis process step, as shown below: ##STR00031## in which process, the PEG linkaged ketal is subjected to an environment where the conditions are acidic, or wherein the PEG linkaged ketal is contacted with an acid, whereby the PEG linkaged ketal structure undergoes an acid catalysis which releases the one or more fragrance molecules having at least one alcohol moiety and, in some cases, also acetone as a by-product.

14. A process for decomplexation of PEG-ketal compounds and consequent release of one or more fragrance molecules having at least one alcohol moiety, via an acid hydrolysis process step, as shown below: ##STR00032## in which process, the PEG linkaged ketal is subjected to an environment where the conditions are acidic, or wherein the PEG linkaged ketal is contacted with an acid, whereby the PEG linkaged ketal structure undergoes an acid catalysis which releases the one or more fragrance molecules having at least one alcohol moiety and, in some cases, also acetone as a by-product.

15. The process of claim 13 or 14, wherein PEG-ketal compounds by coming into contact with the epidermis of a mammalian body, or with saliva or other bodily fluid which has a pH of less than 7.

16. The process of claim 15, wherein the PEG-ketal compounds form part of a topically applied composition which is applied to the epidermis of mammalian body.

17. The process of claim 16, wherein the PEG-ketal compounds form part of an orally ingestible composition.

18. The process of claim 15, wherein the PEG-ketal compounds form part of a treatment composition for inanimate surfaces, or an aerosolizable composition.

19. A polyketal according to the structure II: ##STR00033## wherein R′ is a terminated independent hydrogen, or R′ is a C.sub.1-C.sub.10 alkyl, or C.sub.5-C.sub.10 cycloalkyl and wherein R′—OH is a C.sub.1-C.sub.10 alkyl alcohol or a C.sub.5-C.sub.10 cycloalkyl alcohol and R′ of R′—OH is not H that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups or combinations thereof; Z is a C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.6 cycloalkyl including cyclohexane, that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups such that O—Z—O is an ester group in that it is derived from an acid in which at least one —OH group is replaced by an —O-alkyl or —O-aryl group and where n is in a range between 1-200.

20. A polyketal of claim 18, wherein R′—OH are selected from one or more of a group of substituted alcohols consisting of; hydroxy cinnamyl alcohol; rhodinol; anisyl alcohol; alpha-terpinol; nerol; maltol; leaf alcohol; ebanol; dihydromercinol; hydroxycitronellal; lavender ketone; raspberry ketone; dimetol; phenyl ethyl alcohol; alpha-methylcinnamic alcohol; linalool oxide; acetoin; isopentyl alcohol; isoamyl alcohol; 2-phenyl methanol; 4-allyl-2-methoxyphenol (eugenol); 3-(2-bornyloxy)-2-methyl-1-propanol; 2-tert-butylcyclohexanol; 4-tert-butylcyclohexanol; benzyl alcohol; 1-decanol; 9-decen-1-ol; dihydroterpineol; 2,4-dimethyl-4-cyclohexen-1-yl methanol; 2,4-dimethylcyclohexyl methanol; 2,6-dimethyl-2-heptanol; 2,6-dimethyl-4-heptanol; 3a,4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano[1H] inden-5-ol; 3,7-dimethyl-1,6-nonadien-3-ol; 2,6-dimethyl-2,7-octadien-6-ol (linalool); cis-3,7-dimethyl-2,6-octadien-1-ol (nerol); trans-3,7-dimethyl-2,6-octadien-1-ol (geraniol; 3,7-dimethyl-1,7-octanediol; 3,7-dimethyl-1-octanol (tetrahydrogeraniol); 2,6-dimethyl-2-octanol (tetrahydromyrcenol); 3,7-dimethyl-3-octanol (tetrahydrolinalool); 2,6-dimethyl-7-octen-2-ol (dihydromyrcenol); 3,7-dimethyl-6-octen-1-ol (citronellol); 2,2-dimethyl-3-(3-methylphenyl)-1-propanol; 2,2-dimethyl-3-phenyl-1-propanol, 2-ethoxy-4-methoxymethylphenol; 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; cis-3-hexen-1-ol, 4-(4-hydroxy-3-methoxyphenyl)-2-butanone; 1-hydroxy-2-(1-methyl-1-hydroxyethyl)-5-methylcyclohexane; 3-(hydroxymethyl)-2-nonanone; 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-1-carboxaldehyde; isoborneol; 3-isocamphylcyclohexanol; 2-isopropenyl-5-methylcyclohexanol (isopulegol); 1-isopropyl-4-methylcyclohex-3-enol (terpinenol); 4-isopropylcyclohexanol, 1-(4-isopropylcyclohexyl) ethanol; 4-isopropylcyclohexylmethanol; 2-isopropyl-5-methylcyclohexanol (menthol); 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol); 2-(4-methyl-3-cyclohexenyl)-2-propanol (terpineol); 2-(4-methylcyclohexyl)-2-propanol (dihydroterpineol); 4-methoxybenzyl alcohol, 2-methoxy-4-methylphenol; 3-methoxy-5-methylphenol; 1-methoxy-4-propenylbenzene (anethol); 2-methoxy-4-propenylphenol (isoeugenol); 4-methyl-3-decen-5-ol; 2-methyl-6-methylene-7-octen-2-ol (myrcenol); 3-methyl-4-phenyl-2-butanol; 2-(2-methylphenyl) ethanol; 2-methyl-4-phenyl-1-pentanol; 3-methyl-5-phenyl-1-pentanol; 2-methyl-1-phenyl-2-propanol; (1-methyl-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl) cyclopropyl) methanol; 3-methyl-4-(2,2,6-trimethylcyclohexen-1-yl)-2-butanol; 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; (3-methyl-1-(2,2,3-trimethyl-3-cyclopentenyl)-3-cyclohexen-1-yl) methanol; 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol; 2-methyl-2-vinyl-5-(1-hydroxy-1-methylethyl) tetrahydrofuran; trans,cis-2,6-nonadienol; 1-nonanol; nopol; 1,2,3,4,4a,5,6,7-octahydro-2,5,5-trimethyl-2-naphthol; 1-octanol; 3,4,5,6,6-pentamethyl-2-heptanol; 2-phenylethanol; 2-phenylpropanol; 3-phenylpropanol (hydrocinnamic alcohol); 3-phenyl-2-propen-1-ol (cinnamic alcohol); 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl) cyclohexan-1-ol; 3,5,5-trimethylcyclohexanol; 2,4,6-trimethyl-4-cyclohexen-1-ylmethanol; 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol; 3,7,11-trimethyl-2,6,10-dodecatrien-1-ol (farnesol); 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol); 3,5,5-trimethyl-1-hexanol (isononanol); 1-undecanol; 10-undecen-1-ol; and vetiverol.

21. A process of producing fragrance functional polyketals of Structure II ##STR00034## according to the reaction scheme illustrated: ##STR00035## wherein a diol (B) is reacted with 2,2-dimethoxypropane (A), and a mono-alcohol fragrance (HO—R′) in p-toluene-sulfonic acid (C) to provide a polyketal of Structure II; wherein R′ is a terminated independent hydrogen, or R′ is a C.sub.1-C.sub.10 alkyl, or C.sub.5-C.sub.10 cycloalkyl and wherein R′—OH is a C.sub.1-C.sub.10 alkyl alcohol or a C.sub.5-C.sub.10 cycloalkyl alcohol and R′ of R′—OH is not H that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more phenyl groups; Z is a C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.6 cycloalkyl including cyclohexane, that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups such that O—Z—O is an ester group in that it is derived from an acid in which at least one —OH group is replaced by an —O-alkyl or —O-aryl group and where n is in a range between 1-200.

22. A process of acid catalysis of a polyketal with an acid at a pH of below 7 according to the following reaction scheme; ##STR00036## wherein R′ of said substituents are H, C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.10 cycloalkyl and wherein R′—OH is a C.sub.1-C.sub.10 alkyl alcohol or a C.sub.5-C.sub.10 cycloalkyl alcohol and R′ of R′—OH is not H that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups; and wherein; Z of said substituents is a C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.6 cycloalkyl including cyclohexane, that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups such that O—Z—O is an ester group in that it is derived from an acid in which at least one —OH group is replaced by an —O-alkyl or —O-aryl group.

23. The process of claim 21, wherein the polyketals reach a higher weight average molecular weight by reflux at 100 degrees Celsius to boil off methanol, addition of 2,2-dimethoxypropane and benzene every 2 hours for 12 hours, and use of a 5 A molecular sieve to capture excess methanol.

24. The process of claim 23, wherein said polyketals reach a weight average molecular weight of greater than 1000 g/mol and exhibit a polydispersity index (PDI) of less than 3.00.

25. The polyketal of claim 1, wherein the PEGs are substituted by polymers containing alcohol containing functionalities from one or more of a group consisting of: polysaccharides, starch, modified starch, cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, monosaccharides, lipids, polyester, polyamides, polyvinyl alcohol, polynucleotides, polyacetals, and polyurethanes.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0328] FIG. 1 is an NMR confirmation of the presence of methyl levulinate.

[0329] FIG. 2 is a Structure IB of Isoamyl alcohol (IAA) substituted PEG linked ketal.

[0330] FIG. 3 is a GPC chromatogram of polyketal (Mw=2900 g.Math.mol.sup.−1; 1.65) end-functionalized with 2-Phenylethanol.

[0331] FIG. 4 is a .sup.1H-NMR (400 MHz) spectra for polyketal end-functionalized with 2-Phenylethanol in CDCl.sub.3.

[0332] The present disclosure is further illustrated and described by the following Detailed Description and Examples.

DETAILED DESCRIPTION

[0333] Keto-functionlizable polymers useful in the present invention, include poly(ethylene glycol) (PEG), cellulose, and also include most polymer systems (preferably with hydroxyl (—OH) end groups) can be functionalized by using molecules containing ketone groups that are subsequently reacted with mono- or poly-alcohol containing fragrance molecules so to incorporate these fragrance molecules into these polymers, which form complexes, which may also be referred do as polymer-alcohol-based-fragrance conjugates, which may be subsequently decomplexed when exposed to appropriate conditions. Such polymers include oligomeric and polymeric chains exhibiting ketal linkages. The preferred polyethylene glycol (PEG) system described herein, demonstrates ketalization chemistry using ketones, and in this demonstration, a “two-armed” a ketone-polyethylene glycol-levulinic acid (PEG-LA) is formed via a one-step synthesis via carbodiimide by coupling of the PEG with levulinic acid resulting in a 98.9% recovery yield. A preferred PEG molecular weight range is about 1,000-25,000 g/mol. While a ketone-polyethylene glycol-levulinic acid (PEG-LA) is a preferred embodiment of the invention, it is a non-limiting example and it is understood that other functionalized PEG's may be used as well according to the present invention, i.e, including those known to the art and disclosed in US Patent Application 2017/0362380, the complete contents of which are hereby incorporated by reference.

[0334] To form the polymer-alcohol-based-fragrance conjugates the keto-functionalized ketone-polyethylene PEG-LA (levulinic acid) was further reacted with mono-alcohols, here, fragrances bearing 2-phenylethanol and isoamyl alcohol to produce PEG-ketals As previously noted, as well as described in more detail herein, the use of other fragrance molecules having one, two, three of more reactive alcohol moieties are clearly contemplated as forming part of the invention. In order to use the PEG-ketal product(s) as release agents (or as “delivery vehicle”), the PEG-ketals are reacted under a suitable environmental condition, i.e., exposed to an acidic pH, and the alcohol containing fragrances are released by degradation (or decomplexation of the polymer-alcohol-based-fragrance conjugate), which was validated by qualitative techniques including the detection by perception of the alcohol containing fragrance molecule by the human nose, which is effective in perceiving fragrances at parts per trillion levels or even lower.

[0335] A preferred synthesis, mechanism, and resulting structures scheme to form these PEG-ketal compounds (“polymer-alcohol-based-fragrance conjugate”) are provided in the two step fragrance incorporation process shown below;

##STR00012##

wherein:
DMAP is 4-dimethyl amino pyridine,
EDC is 1-ethyl, 3,(3-dimethylamino propyl) carbodiimide,
TNATB is tetrabutylammonium tribromide and TMOF is trimethyl orthoformate,
DCM is dichloromethane,
and R.sub.1, R.sub.2 are either identical or different derivatives of molecules/macromolecules with alcohol functionality(ies), which may be mono-alcohols, diols, triols or further higher order polyols. Each of the R.sub.1, R.sub.2 groups may be different from any other R.sub.1, R.sub.2 groups present in the resultant molecule, or more specifically each of these groups may be unique and different from any other or all of these groups within the resultant molecule; in certain preferred embodiments each of the R.sub.1, R.sub.2 present are one or more of alcohol derivatives from the group consisting of; [0336] hydroxy cinnamyl alcohol; [0337] rhodinol; [0338] anisyl alcohol; [0339] alpha-terpinol; [0340] nerol; [0341] maltol; [0342] leaf alcohol; [0343] ebanol; [0344] dihydromercinol; [0345] hydroxycitronellal; [0346] lavender ketone; [0347] raspberry ketone; [0348] dimetol; [0349] phenyl ethyl alcohol; [0350] alpha-methylcinnamic alcohol; [0351] linalool oxide; [0352] acetoin; [0353] isopentyl alcohol; [0354] isoamyl alcohol; [0355] 2-phenyl methanol; [0356] 4-allyl-2-methoxyphenol (eugenol); [0357] 3-(2-bornyloxy)-2-methyl-1-propanol; [0358] 2-tert-butylcyclohexanol; [0359] 4-tert-butylcyclohexanol; [0360] benzyl alcohol; [0361] 1-decanol; [0362] 9-decen-1-ol; [0363] dihydroterpineol; [0364] 2,4-dimethyl-4-cyclohexen-1-yl methanol; [0365] 2,4-dimethylcyclohexyl methanol; [0366] 2,6-dimethyl-2-heptanol; [0367] 2,6-dimethyl-4-heptanol; [0368] 3a,4,5,6,7,7a-hexahydro-2,4-dimethyl-4,7-methano[1H] inden-5-ol; [0369] 3,7-dimethyl-1,6-nonadien-3-ol; [0370] 2,6-dimethyl-2,7-octadien-6-ol (linalool); [0371] cis-3,7-dimethyl-2,6-octadien-1-ol (nerol); [0372] trans-3,7-dimethyl-2,6-octadien-1-ol (geraniol; [0373] 3,7-dimethyl-1,7-octanediol; [0374] 3,7-dimethyl-1-octanol (tetrahydrogeraniol); [0375] 2,6-dimethyl-2-octanol (tetrahydromyrcenol); [0376] 3,7-dimethyl-3-octanol (tetrahydrolinalool); [0377] 2,6-dimethyl-7-octen-2-ol (dihydromyrcenol); [0378] 3,7-dimethyl-6-octen-1-ol (citronellol); [0379] 2,2-dimethyl-3-(3-methylphenyl)-1-propanol; [0380] 2,2-dimethyl-3-phenyl-1-propanol, 2-ethoxy-4-methoxymethylphenol; [0381] 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; [0382] cis-3-hexen-1-ol, 4-(4-hydroxy-3-methoxyphenyl)-2-butanone; [0383] 1-hydroxy-2-(1-methyl-1-hydroxyethyl)-5-methylcyclohexane; [0384] 3-(hydroxymethyl)-2-nonanone; [0385] 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-1-carboxaldehyde; [0386] isoborneol; [0387] 3-isocamphylcyclohexanol; [0388] 2-isopropenyl-5-methylcyclohexanol (isopulegol); [0389] 1-isopropyl-4-methylcyclohex-3-enol (terpinenol); [0390] 4-isopropylcyclohexanol, 1-(4-isopropylcyclohexyl) ethanol; [0391] 4-isopropylcyclohexylmethanol; [0392] 2-isopropyl-5-methylcyclohexanol (menthol); [0393] 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol); [0394] 2-(4-methyl-3-cyclohexenyl)-2-propanol (terpineol); [0395] 2-(4-methylcyclohexyl)-2-propanol (dihydroterpineol); [0396] 4-methoxybenzyl alcohol, 2-methoxy-4-methylphenol; [0397] 3-methoxy-5-methylphenol; [0398] 1-methoxy-4-propenylbenzene (anethol); [0399] 2-methoxy-4-propenylphenol (isoeugenol); [0400] 4-methyl-3-decen-5-ol; [0401] 2-methyl-6-methylene-7-octen-2-ol (myrcenol); [0402] 3-methyl-4-phenyl-2-butanol; [0403] 2-(2-methylphenyl) ethanol; [0404] 2-methyl-4-phenyl-1-pentanol; [0405] 3-methyl-5-phenyl-1-pentanol; [0406] 2-methyl-1-phenyl-2-propanol; [0407] (1-methyl-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl) cyclopropyl) methanol; [0408] 3-methyl-4-(2,2,6-trimethylcyclohexen-1-yl)-2-butanol; [0409] 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol; [0410] (3-methyl-1-(2,2,3-trimethyl-3-cyclopentenyl)-3-cyclohexen-1-yl) methanol; [0411] 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol; [0412] 2-methyl-2-vinyl-5-(1-hydroxy-1-methylethyl) tetrahydrofuran; [0413] trans,cis-2,6-nonadienol; [0414] 1-nonanol; [0415] nopol; [0416] 1,2,3,4,4a,5,6,7-octahydro-2,5,5-trimethyl-2-naphthol; [0417] 1-octanol; [0418] 3,4,5,6,6-pentamethyl-2-heptanol; [0419] 2-phenylethanol; [0420] 2-phenylpropanol; [0421] 3-phenylpropanol (hydrocinnamic alcohol); [0422] 3-phenyl-2-propen-1-ol (cinnamic alcohol); [0423] 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl) cyclohexan-1-ol; [0424] 3,5,5-trimethylcyclohexanol; [0425] 2,4,6-trimethyl-4-cyclohexen-1-ylmethanol; [0426] 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol; [0427] 3,7,11-trimethyl-2,6,10-dodecatrien-1-ol (farnesol); [0428] 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol); [0429] 3,5,5-trimethyl-1-hexanol (isononanol); [0430] 1-undecanol; [0431] 10-undecen-1-ol; and [0432] vetiverol.

[0433] A further aspect of the invention is the process for decomplexation of the PEG-ketal compounds (viz., “polymer-alcohol-based-fragrance conjugates”) and consequent release of one or more fragrance molecules having at least one alcohol moiety, via an acid hydrolysis process step, as shown below:

##STR00013##

[0434] When the PEG linkaged ketal structure is subjected to an environment where the conditions are acidic, or when contacted with an acid, the PEG linkaged ketal structure undergoes an acid catalysis which releases the one or more fragrance molecules having at least one alcohol moiety and, in some cases, also acetone as a by-product. Here, while the foregoing illustration shows a reaction wherein two monohydric alcohol comprising fragrance molecules are released to the ambient environment, it is nonetheless to be understood that these alcohol containing fragrance molecules may also be polyhydric, and further that R.sub.1, R.sub.2 may be identical or different. The foregoing illustrative reaction also demonstrates a delivery system wherein a volatile fragrance molecule having at least one hydroxyl moiety is decomplexed and released to the ambient environment.

[0435] In separate embodiments, R.sub.1 and R.sub.2 are identical or different diols and/or polyols, preferably diols or polyols of fragrance molecules. The following Ketal Structure IA is the result of identical R.sub.1 and R.sub.2 substituents reacted with 2-phenylethanol.

##STR00014##

[0436] An alternative embodiment includes providing an alternate ketal structure, with IAA (isoamyl alcohol) as the mono-alcohol resulting in Structure IB;

##STR00015##

[0437] The resultant polyethylene glycol (PEG) linked ketals having a structure (I) (also referred to as a “polymer-alcohol-based-fragrance conjugate”) prior to acid hydrolysis is as given below;

##STR00016##

which is a ketal PEG linker structure, wherein R.sub.1, R.sub.2 are either the same or different monoalcohol containing fragrance molecules, and wherein these ketal structures, when acid catalyzed at a pH less than 7, releases the fragrance and acetone as by-products. As previously stated herein, each of the R.sub.1, R.sub.2 groups of structure (I) may be different from any other R.sub.1, R.sub.2 groups present in the molecule, or more specifically each of these groups may be unique and different from any other or all of these groups within the molecule. Also, as previously stated herein, in the foregoing molecule of structure (I), R.sub.1, R.sub.2 each independently may be selected from one or more of alcohol derivatives, particularly one or more alcohol moiety containing fragrance compounds.

[0438] To achieve the polyketal structure II (also referred to as a “polymer-alcohol-based-fragrance conjugate”) shown below, which is a fragrance comprising polyketal, the following reaction scheme was followed;

##STR00017##

wherein in this case, 1,4 cyclohexanedimethanol (B) is reacted with 2,2-dimethoxypropane and a mono-alcohol fragrance (HO—R′) (C) to provide the polyketal of Structure II;

##STR00018##

wherein R′ is a terminated independent hydrogen, or R′ is a C.sub.1-C.sub.10 alkyl alcohol, or C.sub.5-C.sub.10 cycloalkyl and wherein R′—OH is a C.sub.1-C.sub.10 alkyl alcohol or a C.sub.5-C.sub.10 cycloalkyl alcohol and R′ of R′—OH is not H that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more phenyl groups;
Z is a C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.6 cycloalkyl including cyclohexane, that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups such that O—Z—O is an ester group in that it is derived from an acid in which at least one —OH (hydroxyl) group is replaced by an —O-alkyl (alkoxy) or —O-aryl group and where n is in a range between 1-200.

[0439] When catalyzed with an acid at a pH below 7, the following acid catalyzed degradation substituents are released;

##STR00019##

again, wherein R′ is a terminated independent hydrogen, or R′ is a C.sub.1-C.sub.10 alkyl, or C.sub.5-C.sub.10 cycloalkyl and wherein R′—OH is a C.sub.1-C.sub.10 alkyl alcohol or a C.sub.5-C.sub.10 cycloalkyl alcohol and R′ of R′—OH is not H that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups;
Z is a C.sub.1-C.sub.10 alkyl, and/or a C.sub.5-C.sub.6 cycloalkyl including cyclohexane, that is optionally substituted with an oxygen in the ring and/or further optionally substituted with one or more aryl groups such that O—Z—O is an ester group in that it is derived from an acid in which at least one —OH (hydroxyl) group is replaced by an —O-alkyl (alkoxy) or —O-aryl group;
and where n is in a range between 1-100.

[0440] In this case the released substituents include a fragranced mono-alcohol and the other substituents are non-toxic GRAS by-products.

[0441] Although the reaction disclosed above refers to fragrance molecules comprising one or more reactive alcohol moieties, it is within the scope of this invention that these molecules comprising one or more reactive alcohol moieties may be molecules such as vitamin, provitamins, and pain relief medications and pharmaceuticals of small and moderate size, which are distinguishable from fragrance molecules comprising one or more reactive alcohol moieties.

[0442] The reaction yield for step (i) above resulted in in high (99+%) purity for the difunctional PEG using levulinic acid and the yield was determined to be 98.9%. Fragrance release, where R.sub.1 and R.sub.2 is 2-phenylethanol (2-PE) provided a lower yield of 93.1% of which at least 50% is the fragrance 2-phenylethanol (2-PE). Fragrance release, where R.sub.1 and R.sub.2 is isoamyl alcohol (IAA) resulted in a yield of 94.7% of which at least 50% is the fragrance functional isoamyl alcohol (IAA).

[0443] The structure for incorporation of a 2-phenylethanol fragranced alcohol (rose scent) into a polymer-alcohol-based-fragrance conjugate is illustrated by the ketal-linked PEG structure IA provided below;

##STR00020##

[0444] The structure for incorporation of a isoamyl alcohol (IAA) fragranced alcohol (banana scent) into a polymer-alcohol-based-fragrance conjugate is illustrated by in the ketal-linked PEG structure IB provided below;

##STR00021##

[0445] A qualifying small molecule step for the synthesis of both PEG Structures IA and IB was determined to proceed via a route that resulted in essentially 100% yields by utilizing methyl levulinate and levulinic acid. The highest yields along with the fastest kinetics and approx. 100% completion of the reactions utilized a reaction scheme in the presence of tetrabutylammonium tribromide (“TBATB”) and trimethyl orthoformate (“TMOF”) for both of the ketal structures IA and IB from small molecule as illustrated below;

##STR00022##

[0446] In another embodiment, it was shown that PEG-ketal small molecule conversion efficiency to form the ketal structures IA and IB during the reaction can be improved by lowering the number average molecular, weight, Mw, of the PEG from 6000 to less than 1000. In order to achieve the higher molecular weight polyketals of Structure II, it was necessary to slowly add 2,2-dimethoxypropane and benzene every 2 hours for 12 hours over the course of the reaction, reflux at 100 degrees Celsius to boil away the methanol and to utilize a 5 A molecular sieve to capture the excess methanol.

[0447] Certain embodiments of the invention are disclosed in more specific detail in one or more of the following examples. It is to be understood however that these examples are provided solely for the purposes of illustration and not limitation of any aspect of the invention, whose scope is only limited by the claims.

EXAMPLES

Example 1. NMR Characterization of the PEG-Ketal

[0448] ##STR00023##

[0449] .sup.1H NMR was used to study the conversion efficiency of the esterification of PEG-OH with levulinic acid. FIG. 1 presents NMR confirmation of the presence of methyl levulinate Characteristic peaks at positions δ 2.1, 2.6 and 2.72 shows the presence of levulinic acid. Furthermore, the integration shows the presence for 3H, 2H and 2H which correspond to the theoretical number of protons for each respective peak. The ketone functionality in levulinic acid was used to determine the purity of the product below.

[0450] .sup.1H NMR was used to characterize the attachment of isoamyl alcohol (IAA) via ketal linkage as provided in FIG. 2, Structure IB of IAA substituted PEG linked ketal. IAA is an aromatic mono-alcohol that has a fruity fragrance, and is the chemical that constitutes the fragrance in banana. NMR spectrum shows partial disappearance of δ 2.1 and the appearance of peak at δ 1.27. Peak δ 2.1 represents the terminal 3H peak adjacent to the ketone. Upon commencement of reaction, the partial disappearance of peak δ 2.1 indicates ketone is converted to ketal. Appearance of peak 81.27 further confirms this result.

Example 2. Synthesis of Polyketal

[0451] 1,4-cyclohexanedimethanol, 2,2-dimethoxypropane, benzene, triethylamine, N,N-dimethylformamide, and deuterated chloroform, tetrahydrofuran, ethyl acetate, and methanol were purchased from commercial suppliers and used as supplied. Additionally, p-Toluene-sulfonic acid was purchased from a commercial supplied but was dried using 5 A molecular sieve in ethyl acetate prior to its use.

[0452] The polymer's molecular weight distributions were measured using a Shimadzu LC-10AT Size Exclusion Chromatography (SEC) system equipped with an Agilent guard column and three SEC columns; Shimadzu ultraviolet light (254 nm) and refractive index (RID) detectors; and a Wyatt static light scattering detector. The columns were maintained at 40° C. in a Shimadzu column oven and calibrated using Agilent polystyrene standards in the range of Mp=162-483, 400 g mol.sup.−1. THF was used as the mobile phase with the flow rate maintained at 1 mL/min. Proton nuclear magnetic resonance (.sup.1H-NMR) spectra were recorded on a Bruker 400 MHz spectrometer in CDCl.sub.3 with chemical shifts expressed relative to the tetramethylsilane (TMS) standard at δ=0.00.

[0453] The scheme below was followed in synthesis of the polyketals;

##STR00024##

[0454] Polyketal copolymers were synthesized in a 100 mL two-necked round bottom flask, connected to a distilling head. The diol, 1,4-cyclohexanedimethanol (12.98 g, 90 mmol) was dissolved in 30 mL of anhydrous benzene and kept at 100° C. Dried 6.82 mL p-toluene-sulfonic acid solution dissolved in ethyl acetate (1.35 mg/mL) was added to the benzene solution. 10 mg activated 5 A molecular sieve was additionally added. The ethyl acetate was distilled off, and the polymerization reaction was initiated by the addition of 2,2-dimethoxypropane (10.94 mL). The reaction was stirred at 100° C. Additional doses of 2,2-dimethoxy-propane (5 mL) and benzene (25 mL) were added slowly to the reaction, every hour for six hours, to compensate for 2,2-dimethoxypropane and benzene that had distilled off. After 1.5 days, 0.5 mL of the fragrance molecule, 2-2-phenylethanol, was added and the reaction solution was stirred additionally at 100° C. for 12 hours. The reaction was stopped with triethylamine (2 mL). The copolymers were purified by under vacuum at 60° C. for 3 days and analyzed by .sup.1H NMR and GPC as shown in FIG. 3 and FIG. 4.

Example 3. Polyketal Degradation

[0455] The scheme below was utilized in the degradation (“decomplexation”) of the polyketals leading to fragrance release;

##STR00025##

[0456] The side chain functionalized polyketal polymers were dissolved in 5 mL THF and added dropwise to 15 mL cold Phosphate Buffer Solution (0.1 M) of pH 7.4 and pH 5.5 (final polymer conc. is 5 g.Math.L.sup.−1). The solutions temperature was raised to 37° C. (equivalent to t=0). At various later times, 0.5 ml of each sample was collected, and the degradation was stopped by the addition of excess Et.sub.3N. The solution was immediately injected into a GPC to monitor the molecular weight distribution.

[0457] As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. “Or” means “and/or.” The endpoints of all ranges directed to the same component or property are inclusive of the endpoint and independently combinable, except when the modifier “between” is used. The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). A “combination” is inclusive of blends, mixtures, alloys, reaction products, and the like.

[0458] In general, the compositions or methods can alternatively comprise, consist of, or consist essentially of, any appropriate components or steps disclosed. The invention can additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any components, materials, ingredients, adjuvants, or species, or steps used in the prior art compositions or that are otherwise not necessary to the achievement of the function and/or objectives of the present claims.

[0459] Unless otherwise defined, all terms (including technical and scientific terms) used have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Compounds are described using standard nomenclature. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, CHO is attached through carbon of the carbonyl group. “Alkyl” means a straight or branched chain saturated aliphatic hydrocarbon having the specified number of carbon atoms. “Alkylene” means a straight or branched divalent aliphatic hydrocarbon group having the specified number of carbon atoms. “Aryl” means a cyclic moiety in which all ring members are carbon and a ring is aromatic. More than one ring can be present, and any additional rings can be independently aromatic, saturated or partially unsaturated, and can be fused, pendant, spirocyclic or a combination thereof. “Hetero” means a group or compound including at least one heteroatom (e.g., 1-4 heteroatoms) each independently N, O, S, Si, or P.

[0460] A “hydrocarbon group” means a group having the specified number of carbon atoms and the appropriate valence in view of the number of substitutions shown in the structure. Hydrocarbon groups contain at least carbon and hydrogen, and can optionally contain 1 or more (e.g., 1-8, or 1-6, or 1-3) heteroatoms selected from N, O, S, Si, P, or a combination comprising at least one of the foregoing. Hydrocarbon groups can be unsubstituted or substituted with one or more substituent groups up to the valence allowed by the hydrocarbyl group independently selected from a C.sub.1-30 alkyl, C.sub.2-30 alkenyl, C.sub.2-30 alkynyl, C.sub.6-30 aryl, C.sub.7-30 arylalkyl, C.sub.1-12alkoxy, C.sub.1-30 heteroalkyl, C.sub.3-30 heteroarylalkyl, C.sub.3-30 cycloalkyl, C.sub.3-15 cycloalkenyl, C.sub.6-30 cycloalkynyl, C.sub.2-30 heterocycloalkyl, halide (F, Cl, Br, or I), hydroxy, nitro, cyano, amino, azido, amidino, hydrazino, hydrazono, carbonyl, carbamyl, thiol, carboxy (C.sub.1-6 alkyl) ester, carboxylic acid, carboxylic acid salt, sulfonic acid or a salt thereof, and phosphoric acid or a salt thereof. While stereochemistry of the various compounds is not explicitly shown, it is to be understood that this disclosure encompasses all isomers.

[0461] All cited patents, patent applications, and other references are incorporated by reference in their entirety.

[0462] While the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes can be made and equivalents can be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the mode described and contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.