Synthesis of Secondary Ethers Derived from Meadowfoamoil Terry A

Home , Oleyl alcohol

Synthesis of Secondary Ethers Derived from MeadowfoamOil Terry A. Isbell* and Melissa S. Mund New Crops Research, NCAUR, ARS, USDA, Peoria, Illinois 61604

ABSTRACT: Secondary ethers can be obtained from meadow cationic reaction pathways (4). The facile ring opening of the foam-derived delta lactones or 5-hydroxy fatty acids by using o-Iactone has potential for the development of a whole new Lewis or Bronsted acid catalysts in good yield (70-90%). The class of novel hydroxylated fatty acid derivatives. conversion of 8-lactone or 5-hydroxy fatty acid to 5-ethers is In the course of examining the ring opening of the o-Iac performed under atmospheric pressure between 67 and 125°e tone with methanol to form methyl 5-hydroxy eicosanoate with 0.5-6.4 mole equivalents of acid catalyst in the presence (Scheme 2), we noted the formation of a 5-alkoxy ester in of 2-40 equivalents of alcohol and a reaction time of 1-140 h. moderate yield (62%). Typically, secondary (2°) ethers are Acid catalysts include mineral acids, such as perchloric and sul furic; Lewis acids, such as boron trifluoride; and heterogeneous difficult to synthesize in good yield. The development of sec catalysts, such as clays and ion-exchange resins. Primary alco ondary ethers from fats is usually achieved from halo (5) or hols, such as methanol, butanol, decanol, and oleyl alcohol, or epoxy lipids (6). Madrigal et al. (7) have described a synthe branched-chain alcohols, such as 2-ethylhexanol, can be used sis of ether fatty acids derived from unsaturated fatty acids. to make secondary ether fatty esters. The 5-ether fatty esters and This reaction provided low yields 0-34%) of the ~9-~ 15 the process for their formation have not been previously known alkoxy adducts from a sulfuric acid-catalyzed reaction with and appear to be limited to structures where stabilized cations C I to C6 alkyl alcohols. Ballantine et at. (8,9), with the use of can be formed. The novel ethers were fully characterized by nu small-chain alkyl alcohols, were able to synthesize 2° ethers clear magnetic resonance and gas chromatography-mass spec in low yields with cation-exchanged sheet silicates in con trometry. junction with large quantities of the undesirable alkene dehy JADeS 75,1021-1029 (1998). dration product 05-88%). Good ether yields (34-88%) were KEY WORDS: 5-Alkoxy, branched-chain alcohols, 5 only achieved when a 3° stabilized benzyl cation was con eicosenoic acid, esters, fatty acids, Lewis acids, meadowfoam, densed with an alcohol (10). mineral acids, montmorillonite, secondary ethers, stabilized This investigation will examine the role of a proximally cations. located carboxylic acid functionality on the stability of a de veloping cation and its impact on the formation of 2° ethers. 0- and y-Iactones, derived in a single-step reaction from un saturated meadowfoam fatty acids, will serve as starting ma Meadowfoam is a developing new crop that is currently terials for this ether synthesis. grown on a commercial scale in the Willamette Valley of Ore gon. The meadowfoam triglycerides are composed of long EXPERIMENTAL PROCEDURES chain fatty acids, with 5-eicosenoic acid (63%) as the major fatty acid. The other main components are 5.13-docosa Materials. o-Lactone and 5-hydroxy fatty acids were obtained dienoic acid (17%), 5-docosenoic acid (4%), and 13-do from meadowfoam fatty acids by the method of Isbell and cosenoic acid (12%). This unique combination of monoenoic Plattner (3). Meadowfoam oil was supplied by The Fanning fatty acids makes for an oxidatively stable oil with an oxida Corp. (Chicago, IL). Methanol, butanol, acetone, and sulfuric tive stability index (OSI) time of 246.9 h. Other vegetable acid were purchased from Fisher Scientific Co. (Fairlawn, oils, such as soybean oil and high-oleic sunflower oiL have NJ). Acetonitrile was obtained from EM Science (Gibbstown, OSI times of 19.9 and 49.8 h, respectively (I). NJ). Decyl alcohol, 2-ethylhexyl alcohol, perchloric acid Meadowfoam's unique fatty acid composition, particularly 70%, montmorillonite K-I 0 clay, boron trifluoride gas, Am the ~5 unsaturated fatty acids, has been exploited for the pro berlyst XN-I0 I0 strongly acidic resin, Dowex strongly acidic duction of novel estolides (2) and o-Iactones (3) (Scheme I). resin, and silica gel 60-A were purchased from Aldrich Because of the unique chemistry of the ~5-position on the Chemical Co. (Milwaukee, WI). Saturated fatty acid methyl fatty acid backbone, unusual oxidative stabilization of the ester (FAME) standards and BF/methanol (14% wt/vol) were fatty acid is imparted (I), as well as enhanced reactivities in obtained from Alltech Associates (Deerfield, IL). Instrumentation. Gas chromatography (GC) was per *To whom correspondence should be addressed at USDA. ARS. NCAUR. New Crops. 1815 N. University St.. Peoria. IL 61604. formed with a Hewlett-Packard 5890 Series II gas chromato E-mail: [email protected] graph (Palo Alto, CAl, equipped with a flame-ionization de-

o OH Meadowfoam Fatty Acids

HCI04. CH2Cl2 350C

6-Eicosanolactone 92% Yield

0] n 0 OH

Estolide 67% Yield SCHEME 1 tector and an autosampler/injector. Analyses were conducted SP 2380 analysis: column flow 1.2 mLimin with a helium on an SP 2380, 30 m x 0.25 mm i.d. (Supelco, Bellefonte, head pressure of 15 psi; split ratio 40: I; programmed ramp

PA). Saturated CS-C30 FAME provided standards for calcu 180 to 250°C at 3°C/min, hold 2 min at 250°C; injector and lating equivalent chainlength (ECL) values, which were used detector temperatures set at 250°C. Retention times for eluted to make FAME assignments. peaks with ECL values in parentheses: methyl 5-eicosenoate

Methanol BF3 Reflux

Methyl 5-hydroxyeicosanoate +

Methyl 5-methoxyeicosanoate 62% SCHEME 2

JAOCS, Vol. 75, no. 8 (1998) SECONDARY ETHER SYNTHESIS 1023

3.3 min (20.34), butyl5-eicosenoate 5.2 min (22.41), methyl IH NMR of methyl 5-methoxyeicosanoate: <5 3.65 (s, 5-methoxyeicosanoate 5.5 min (22.79), butyl 5-butoxye O=C-O-CH3, 3H), 3.29 [s, H3C-O-CH-(CH2)r, 3H], icosanoate 9.4 min (26.25), y-Iactone 15.7 min (30.94), and 3.12 [p, H3C-O-CH-(CH2)2-' IHL 2.31 [t, -CH2C(O)-O-, <5-lactone l7.1 min (3\.94). 2H], \.50-1.35 (m, 4H), 1.35-\.20 (Ill, 28H), and 0.86 ppm High-pelformance liquid chromatography (HPLC). HPLC (t, J = 6.7 Hz, -CH3' 3H). 13C NMR of methyl 5-methoxy analyses were performed on a Thermo Separation Products eicosanoate: <5 174. I (s, -C=O), 80.5 [d, H3C-O-CH (Fremont CA) instrument with a P2000 binary pump and an (CHz)z-L 56.4 [q, H3C-O-CH-(CH2)z-L 5\.4 (q, AS2000 autosampler/injector, coupled to an evaporative light O=C-O-CH3), 34.1 (t), 33.3 (t), 32.8 (t), 31.9 (t), 29.8 (t), scattering Varex Mark III detector (ELSD III, Alltech Associ 29.7 (t), 29.3 (t), 25.2 (t), 22.7 (t), 20.8 (t), and 14.1 ppm [q, ates). A Dynamax C (Rainin Instrument Co., Woburn, MA) s -(CH2)lrCH3]' column (250 mm x 4.6 mm, 60 A., 811m) was used to sepa IH NMR of methyl 5-eicosenoate: <55.36 (m, -HC=CH-, rate the decyl reaction mixtures. Components were eluted 2H), 3.65 (s, O=C-O-CH3, 3H), 2.28 [t, J = 7.5 Hz, from the column with a gradient elution at a flow rate of I -CHlC(O)-O-, 2H], 2.08-1.92 (Ill, -CHl-CH=CH-CHl-, mUmin. Acetonitrile/acetone gradient: 0 min, 70:30; 8 min, 4H), -1.35-\.20 (111, 28H) and 0.86 ppm (t, J = 6.6 Hz, -CH3' 40:60; 12 min, 40:60: 12.1 min, 70:30, and 15 min, 70:30. Re 3H). 13C NMR of methyl 5-eicosenoate: <5 174.2 (s, -C=O), tention times for eluted peaks were: <5-lactone 4.0 min, decyl 131.7 (d, -CH=CH-), 128.7 (d, -CH=CH-), 5\.4 (q, 5-hydroxyeicosanoate 4.6 min, decyl 5-eicosenoate 5.2 min, O=C-O-CH,), 33.3 (t), 32.6 (t), 3\.9 (t), 29.7 (t), 29.6 (t), and decyl 5-decoxyeicosanoate 6.9 min. 29.5 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.3(t), 29.2 (t), 24.9 (t), HPLC of2-ethylhexyl ethers. A Dynamax Cs column (250 24.7 (t), 22.7 (t) 22.7 (t), and 14. I ppm [q, -(CHz)lrCH3]' mm x 4.6 mm, 60 A., 811m) was used to separate the 2-ethyl IH NMR of butyl 5-butoxyeicosanoate: <54.05 (t, J = 6.7 hexyl ether reaction mixtures. Components were eluted from Hz, 2H, -CHlCOlCHlCHl-), 3.38 [Ill, 2H, -CHlCHl-O the column under isocratic conditions of acetonitrile/acetone CH(CH,),-], 3. I8-[1Il, lH, '::'CH7CH,-O-CH(CH7)~-)L-2.29 95:5 at a flow rate of 1 mUmin. Retention times for eluted (t, J = 7~4- Hz, 2H, -CH?COlCHlCH7-), 1.65-1.2 (Ill, 40H), peaks were: 5-hydroxyeicosanoic acid 4.2 min, <5-lactone 4.2 (Ill, ). - 13 0.86 ppm 9H, -CH3 C- NMR of butyl 5-butoxy min, 2-ethylhexyl 5-hydroxyeicosanoate 4.6 min, 2-ethyl eicosanoate: <5 173.8 (s. C=O), 79.0 [d, -CHzCHz-O hexyl 5-eicosenoate 6.1 min, 2-ethylhexyl 5-(2-ethylhexoxy) CH(CH7 ),-L 68.7 [t, -CH,CHl-O-CH(CHl),-L 64. I (t, eicosanoate 8.9 min. -d-I?C07CH7CH~-), -CH,C07-CH?CH 7 -), 34.4 (t, 33.9 (t), GC-mass spectrometry (GC-MS). GC-MS was performed 33.4(t), 32.3 (t), 3\.9 (t), 30.7 (t), 29.8 (t), 29.7,-(t), 29.6 (t), with a Hewlett-Packard 5890A GC with a 30 m x 0.25 mm i.d 25.3 (t), 22.6 (t), 21.0 (t), 19.4 (t), 19. I (t), 14.1 (q), 13.9 (q), DB-I column (J&W Scientific, Folsom, CA) and a Hewlett and 13.7 ppm (q). Packard 5970 mass-selective detector. GC conditions: helium IH NMR of butyl 5-eicosenoate: <55.36 (Ill, -HC=CH-, head pressure 5 psi: split ratio 50: I; injector temperature set at 2H), 4.05 (s, O=C-O-CHrCHz-, 2H), 2.27 [t, J = 7.6 Hz, 250°C; transfer line temperature set at 250°C; programmed -CH7C(O)-O-, 2H], 2.08-\.92 (Ill, -CH,-CH=CH-CH7-, ramp from 170 to 250°C at 5°C/min. MS conditions: mass (Ill, 4H),- 1.67 -OCHzCHZCHZCH3' - 2H), 1.59 Dn, range 50 to 550 amu; electron multiplier 200 volts relative. -OCHzCHzCHzCH3, 2H), 1.35-\.20 (Ill, 28H), 0.92 [t, J = MS spectra of methyl 5-methoxyeicosanoate: m/e 255 7.4 Hz, -(CH)),CH,], and 0.86 ppm [t, J = 6.6 Hz, (C H O, 5.5%), 145 (C H 0 . 100%), 113 (32.0%), and 71 I7 3S 7 13 3 -(CHz)14CH3' 3Hi 13C NMR of butyl 5-eicosenoate: <5 173.9 (32.9%). (s, -C=O), 131.7 (d, -CH=CH-), 128.8 (d, -CH=CH-), 64. I MS spectra of butyl 5-butoxyeicosanoate: m/e 439 (t, O=C-O-CH)-), 34.4 (t), 33.7 (t), 32.6 (t), 32.5 (t), 3\.9 [(M - Ht, carbon probe (400 MHZ H/IOO.61 MHZ ~C) IH NMR of decyl 5-decoxyeicosanoate: <54.04 [t, J = 6.75 with CDCI as the solvent in all experiments. 3 Hz, -OCHz(CH2)zCH3, 2H], 3.37 [to J = 6.73 Hz, -CHzCHr

JAOCS, Vol. 75, no. 8 (1998) 1024 T.A. ISBELL AND M.s. MUND

OCH(CH2-)2' 2H], 3.18 [p, -CH2CHr OCH(CHr )2' lH], at 160-180°C at 0.2 mm Hg to remove unsaturated byprod 2.31 (t, J =7.5 Hz, -CH?CO,CHn 2H), 1.72-1.20 (Ill, 64H) ucts and excess alcohol. Hz~ and 0.86 ppm (t, J = 7. r -CH3, 9H). 13C NMR of decyl After the reaction of 8-lactone and BF/alcohol had 5-decoxyeicosanoate: 8 173.8 (s, C=O), 79.0 [d, -CH2CH2-G reached completion, the crude reaction mixture was poured CH(CH,)?-], 68.9 [t, -CH?CH7-O-CH(CH7 ),-], 64.4 (t, into a separatory funnel and diluted with 50 mL hexane,

-CH7 C6;CH?CH?-), 34.4 (t, -cB?C07 CH?ci-C-), 33.9 (t), washed 2 x 10 mLwith saturated NaCI solution. dried over 33.4(t), 33.4 (t), 31.9 (t), 30.2 (t), 29.8-(t), 29.7-(t), 29.6 (t), Na2S04, and gravity-filtered through a #1 Whatman (Maid 29.5 (t), 29.3 (t), 29.2 (t), 28.6 (t), 26.3 (t), 25.9 (t), 25.4 (t), stone, England) filter paper. 22.7 (t), 21.0 (t), and 14.1 ppm (q). After the reaction with montmorillonite K-IO clay reached IH NMR of oleyl 5-0Ieyloxyeicosanoate: 8 5.33 (Ill, completion, the crude reaction mixture was diluted in 50 mL -CH=CH-, 2H), 4.04 [t, J = 6.7 Hz, -OCH2(CH2)s-, 2H], of hexane and filtered through #1 Whatman filter paper in a 3.37 [t, J = 6.7 Hz, -CH2CH2-OCH(CHr )2' 2H], 3.24 [p, Buchner funnel and vacuum filtration flask. -CH2CH2-OCH(CHr )2' IH], 2.30 (Ill, -CH2C02CH2-, 2H), After the reaction with mineral acids reached completion, 2.05 (Ill, 2H), 1.77-1.20 (Ill, 92H) and 0.87 ppm (t, J = 4.0 Hz, the crude reaction mixture was poured into a separatory fun -CH3,9H). nel and diluted with 50 mL of hexane. washed 2 x 10 mL with Methods. A series of reactions was conducted to examine 0.5 M Na2HP04 solution, dried over Na2S04, and gravity-fil the production of 5-alkoxy eicosanoates from 8-lactones, y tered through a #1 Whatman filter paper. lactones, or 5-hydroxy fatty acid. 8-Lactone, y-Iactone, or 5 SF] a/coho/ates. BF/methanol was purchased from All hydroxy fatty acid (0.5 g) was dissolved in the appropriate al tech as a 14% wt/vol solution; all other BF3 solutions were cohol (5 mL) and reacted under the conditions listed in Ta made as described below. Solutions of BF3 were made by bles I and 2. Mixing was maintained throughout the course placing 100 g of the desired alcohol in a flask, fitted with a of the reaction by magnetic stirring. The reaction vessels were fritted-glass bubbler. The flask was then cooled in an ice-bath fitted with reflux condensers to recycle volatile alcohols back and placed on a top-loading balance. BF3 gas was passed into the reaction mixture. Temperature was maintained at through the solution until the appropriate weight gain was ob

±loC of the desired set point via a temperature controller and served. Extreme care must be taken when using BF3 gas be a thermocouple that was immersed in the reaction mixture, cause the gas is poisonous and draw-back of the alcohol into except for those reactions that were conducted at the alcohol's the gas cylinder could result in an explosion. An appropriate boiling point where reflux maintained the temperature. Isola dry trap must be placed between the cylinder and the flask tion and workup of the reaction are listed below, based on the that contains the alcohol to prevent pull-back of the alcohol catalyst employed. All reaction mixtures, subsequent to the into the cylinder. In addition, the effluent gas above the alco workup, were concentrated ill vacuo, then kugelrohr-distilled hol should be passed through a dry trap (prevents water pull-

TABLE 1 Etherification Reactions of &-lactone and .~-t1vnlrOl'V Acid Acid Acid Temperature Time Ether Alkene 5-0H o-Lactone Entry Substrate Alcohol catalyst equiv:' I'Ci (hi (%!', (''l'o)b (°It,/' (%/'

A o-LactoneC CH]OH 5% BF/ 2.3 67 46 59 7 o 30 B o-Lactone CH]OH 10% BF] 4.5 67 23 71 10 o 19 C o-Lactone CH]OH 10% BF] 4.5 67 44 79 9 o 11 Do-Lactone CH]OH 14% BF) 6.4 67 24 86 10 o 3 E o-Lactone CH]OH Fe~] Clave 0.1 g 67 23 1 14 1 84 F o-Lactone CH]OH H,SO/ ' 17.0 67 21 26 39 1 34 Go-Lactone CH]OH HCIO} 0.35 67 4 5 91 o H o-Lactone Decanol Fe+] Clav 0.1 g 100 96 91 6 3 o 7 .. I o-Lactone Decanol Fe+] Clay 0.1 g 1~:J 24 84 12 1 o J o-Lactone Decanol 5% BF] 2.3 85 5 80 8 o o K o-Lactone Decanol 10% BF] 4.5 85 24 93 7 o o L o-Lactone 2-Ethylhexyl Fe+] Clay 0.1 g 120 22 84 11 5 o M 5-Hydroxyb 2-Ethylhexyl 5% BF] 0.4 110 3 75 22 o o N 5-Hydroxy 2-Ethylhexyl 5% BF] 1.0 120 18 80 14 5 o o 5-Hydroxy 2-Ethylhexyl HCI04 0.3 80 28 78 7 15 o P o-Lactone Oleyli Fe+] clay 0.1 g 150 20 -50 NA NA -50 "Moles of acid catalyst with respect to moles of substrate. b,\iormalized mass percentage, gas chromatography analysis for methyl. 2-ethyl hexyl, high-performance liquid chromatography for oleyl.

,\-laterials: Co-Lactone. a mixture of C20 and C22 o-Iactones. derived from meadowfoam fatty acids: dSF y boron trifluoride complex as weight of SF 3 per vol , 4 ume (wt!voi) of butanol: cFe] clay, an iron (1111 cation-exchanged K-10 clay; 'H 2 S04 concentrated sulfuric acid: gHCIO is 70% perchloric acid: h5-hydroxy fatty acid. a mixture of C20 and Cn 5-hydroxy fatty acids, derived from meadowfoam o-Iactones. 'Reaction followed by thin-layer chromatography only. Products isolated by flash column chromatography.

JAOCS, Vol. 75. no. 8 (19981 SECONDARY ETHER SYNTHESIS 1025

TABLE 2 Etherification Reactions with Butanol Acid Acid Temperature Time Ether Alkene 5-Hydroxy Lactone Substrate (0C) (h) (%)b (%)b (%r (%Ib

A Ii-LactoneC SF/ 4.5 85 19 84 13 o 3 S 5-Hydroxye SF) 4.5 85 22 82 14 o 3 C y-Lactone' SF) 4.5 85 22 21 1 o 78 D y-Lactone SF) 4.5 85 94 76 8 o 15 E MFN SF) 4.5 85 17 o 100 o o F Ii-Lactone SF) 4.5 20 120 2 2 o 96 G Ii-Lactone SF) 4.5 60 141 28 4 o 66 H Ii-Lactone SF) 4.5 70 66 43 8 o 49 I Ii-Lactone SF) 4.5 80 45 83 12 o 4 J li-Lactone SF) 4.5 90 20 83 14 o 3 K Ii-Lactone SF) 4.5 117 1 75 o o L y-Lactone SF .1 4.5 117 23 74 13 o 12 M Ii-Lactone K-l0 Clay" 0.1 g 117 24 64 21 o 13 N Ii-Lactone Fe-;-.1 Cla/ 0.1 g 117 21 70 17 2 10 ° Ii-Lactone Amberlvst i 0.1 g 117 22 53 45 o 1 P Ii-Lactone Dowe/ 0.1 g 117 22 40 32 7 20 1 Q 5-Hydroxy H J S04 2 110 18 67 33 o o R 5-Hydroxy p-TSAil1 1 90 1 52 26 12 6 S 5-Hydroxy HCIO/ 1 90 44 72 20 5 2 T 5-Hydroxy HCIOjHO 0.5 92 5 64 24 12 o U 5-Hydroxy HCIOIfP 0.5 98 2 48 41 11 o V 5-Hydroxy HCIOjDq 0.5 92 4 18 27 55 o ",'''loles of acid catalyst with respect to moles of substrate. b,'\Jormalized mass percentage by gas chromatography. C 3' 3 l'vlaterials: CIi-Lactone, a mixture of C20 and n Ii-Iactones, derived from meadowfoam fatty acids; clBF boron trifluoride complex as weight of BF per vol ume (wtJvol) of butanol; e5-hydroxy fatty acid, a mixture of C20 and Cn 5-hydroxy fatty acids, derived from meadowfoam Ii-Iactones.; 'y-Iactone, a mixture of C20 and Cn y-Iactones, derived from meadowfoam fatty acids; 8MFA, meadowfoam fatty acids; "K-10 clay, montmorillonite K-10 acid activated clay, ob tained from Aldri~h Chemical Co. (Milwaukee, WI); iFe3 clay, an iron (III) cation-exchanged K-lO clay; iAmberlyst, a strongly acidic sulfonic acid-based ion

, n1 exchange resin; 'Dowex (Aldrich Chemical Co.), a strongly acidic sulfonic acid-based ion exchange resin; IH2 S04 concentrated sulfuric acid; p-TSA, p-toluenesulfonic acid; nHCI04 is 70'\"0 perchloric acid. ''This is a reaction performed in 10 mL heptane, Ptoluene, or qdioxane. back into the alcohol) and then through a water solution to vided good yields of ethers. However, attempts to synthesize prevent escape of excess BFy ethers with 2° alcohols as the nucleophile provided only 5 hydroxy esters. Etherification reactions with methanol proved to be the most challenging. Etherifications in methanol were RESULTS AND DISCUSSION temperature-restricted by its low boiling point and the re The facile rate of ring opening of b-Iactones with nucleophiles duced solubility of the b-Iactone in methanoL However, the (4) prompted us to react a variety of alcohols to form 5-hy methanol series (entries A-D, Table I) demonstrated that acid droxy esters (Isbell, T.A., unpublished results), as depicted in concentration plays a significant role in the formation of Scheme I. During the course of this study, we noted the for ethers. with stronger acid concentrations providing higher mation of a secondary ether as a minor by-product in some in yields of ether during shorter reaction times. Other catalysts stances and as the major product in others. The synthesis of a failed to provide significant yields of ether with methanoL 2° ether from an alcohol is typically fraught with the problem The montmorillonite-cation exchanged clays gave good to of dehydration to the alkene as the major pathway (7-10) un excellent yields (70 to 91 %) for all alcohols except methanoL less a stabilized cation transition state can be obtained. The but generally required higher temperatures to achieve cat unique stability of the .65 fatty acid in oxidative stability tests alytic activity. All clay catalysts, however, failed to provide (I) and its unusual reactivity to form b-Iactone, the kinetic reproducible yields in larger-scale reactions. product (3), over the thermodynamically favored y-Iactone A thorough examination of the factors that influence the (10.11) indicate that unique cationic stabilization is possible at etherification of b-eicosanolactone or its corresponding 5-hy the .65 position by the proximally located carboxylic acid droxy acid is reported in Table 2. Initially, etherification of b functionality. Utilization of this stability provided good yields lactone was compared to 5-hydroxy fatty acid, meadowfoam of a variety of 2° ethers, which are reported in Tables I and 2. fatty acids, and y-Iactone (entries A-E, Table 2). b-Lactone The etherification reaction is general for primary alcohols and 5-hydroxy fatty acid gave nearly identical results under and demonstrates that b-Iactones have good reactivity with the same reaction conditions. Rate. yield, and degree of dehy alcohoL from methanol through oleyl alcohol. Alcohols dration are experimentally equivalent. These data suggest that branched at the ~-position, such as 2-ethylhexyL also pro- both b-Iactone and 5-hydroxy fatty acid pass through the

JAOCS. Vol. 75, no. 8 (1998) 1026 T.A. ISBELL AND M.S. MUND same transition state during the course of the reaction. y-Lac ture (100 to 125°C) to achieve good rates (entries H and I, tone provided good yields of ether (entries C, D, and L, Table Table I, and entry N, Table 2). 2), even though at a much slower rate. The y-Iactone's slow The iron (III) cation-exchanged clay was significantly rate of conversion to ether is in good agreement with Brown more catalytic than its parent montmorillonite K-IO clay. The and colleagues' predictions (12) on the stability of the five other heterogenous solid catalysts, Amberlyst and Dowex membered ring and the demonstrated rates of ring opening of strongly acidic ion exchange resins, severely dehydrated the lactones with nucleophiles (4). Interestingly, meadowfoam b-Iactone, which is typical of sulfonic acid-based materials. fatty acids with L15 unsaturation could not be converted to Sulfonic acid dehydration was further exemplified by sulfuric ethers and remained unchanged during the reaction. This in and p-toluene sulfonic acids, where 26 to 45% olefin was ob dicates that the catalyst is coordinated to the oxygen at the L15 tained with these catalysts (entries M-R, Table 2). position, developing a b+ charge at this site, but a full carbo Perchloric acid provided good conversion to ether (72%) cation appears not to have developed. Furthermore, the ether from the 5-hydroxy fatty acid, with 20% dehydration to the remains solely at the L15 position with no evidence of migra alkene. Co-solvents in the HCl04 reaction diminished the tion from this position, as determined by GC-MS of the iso yield of ether but appeared to enhance the rate. The more lated ethers (see below), further decreasing the probability polar the solvent the greater the tendency to dehydrate (en that a full carbocation was developed. tries T- V. Table 2). Heptane gave the best yield in this series, Temperature enhances the rate of etherification (entries and the more polar toluene and dioxane provided dehydration F-L, Table 2). Higher temperatures induce faster rates of re as the major pathway. Increased solvent polarity would create action but at the cost of secondary reaction mechanisms that a dipolar environment in the solution. Consequently, the dipo lead to dehydration. Even y-Iactone has a good rate at 117°C, lar environment would allow a greater degree of charge sepa but the amouOi. of dehydration at this temperature is nearly ration and a more carbocation-like transition state. Therefore. double the dehydration in the same reaction carried out at as the transition state becomes carbocation-like, loss of adja 85°C. The optimum reaction temperature for etherification of cent protons into the carbocation center becomes likely. b-Iactone appears to be 90°C, where rate and dehydration are Mechanism ofetherification reaction. The mechanism of at reasonable values for production of ether. Weaker catalysts, the etherification reaction is depicted in Scheme 3. In the such as the iron (III) clay, however, require higher tempera- mechanism shown, H+ will represent the acid catalyst pres-

H ~o H+ ~~ 1 3 P-R H H+ H+ HO- H+

OH 0 OH 0 ~OH -H+ ~OR 2 4 fa ~o-...... _R__~r--()0-R

8 7

III H R H...... / e 0/ 0 o - ~OR Y1Cf~R 10 R-O 9 0- \ J R H H SCHEME 3

JAOCS, Vol. 75, no. 8 (1998) SECONDARY ETHER SYNTHESIS 1027 ent, whether that be Br0sted or Lewis acid, because both cohol in path B will provide ester interchange with no net types of catalyst will act to activate the carboxylate function effect. ality. The 8-lactone and the 5-hydroxy fatty acid must pass The ester functionality, R, most likely will release electron through a similar transition state because their reaction pa density into the cation as well, further diminishing its charge. rameters are nearly identical. Furthermore, we found that the All these factors taken into consideration will provide a sta intramolecular cyclization of 5-hydroxy fatty acid to 8-lac ble transition state that minimizes cationic charge and reduce tone is fast, even at room temperature and under low acid con the probability of elimination to form the dehydrated alkene centrations. Scheme 3 depicts a probable mechanistic path fatty acid, which is the major mechanistic pathway in other way for the etherification reaction. Intramolecular conversion 2° alcohol/ether syntheses. between 8-lactone 1 and 5-hydroxy acid 2 is a fast process, The Br0nsted acids, perchloric and sulfuric, have lower with the acid-catalyzed reaction favoring the 8-lactone and conversion to ether and higher olefin products, compared to the base-catalyzed reaction providing the 5-hydroxy fatty the Lewis acid catalysts. The reduced yield of ether with acid. In the presence of an acid catalyst, a near instantaneous Br0nsted acids is most likely a result of deprotonation of the conversion of 1 to 5-hydroxy ester 4 is observed (4). Conse developing cation by the stronger conjugate bases, i.e., quently, 2 could be converted to its ester under normal ester HSO;, as compared to the conjugate bases of the Lewis acids, mechanistic pathways, but the rapid conversion of 2 to 4 such as boron trifluoride and iron clay. The stronger the con suggests that 8-lactone 1, even though 8-lactone was not de jugate base, the more likely proton abstraction will occur in tected initially in our reactions with 2, served as an interme the transition state. Consequently, proton abstraction leads to diate to ester 4. Over the period of several hours at low tem olefin production. peratures «60°C), 5-hydroxy ester 4 will ring-close back to Characterization ofethers. GC-MS cleavages are distinct 8-lactone. for the ethers and provide strong evidence for their structural Protonation of ester 4 will yield cation 5, which has three configuration. Figure I shows GC-MS spectra of the two po other stabilized forms 6, 7, and 8. In effect, the cation is sitional ethers, 5-butoxy from 8-lactone and 4-butoxy from y dissipated over 5 atoms as depicted in the hybrid resonance lactone. The base peak in both spectra shows cleavage around form 9. Capture of cation 9 by the alcohol in path A will the ether functionality toward the carboxylate terminus to yield ether 10. Conversely, capture of cation 9 by the al- provide the oxonium stabilized radical cation 229 amu for the

(f 229 99/ 7 367 ~ S7 0 ~~~ + MW= 440 229 H-o 0 H~~ ! 173 I 21S 439 /Il!:••) SO 100 ISO 200 2S0 300 350 400

21S

311 229 255 269 36i m

/Il!:••) SO 100 ISO 200 300 350 400 FIG. 1. Mass spectrum of 5- and 4-butoxy ethers.

JAOCS, Vol. 75, no. 8 (1998) 1028 T.A. ISBELL AND M.S. MUND

1' O~ 2

}' ; 2 ~~II

I' O~

5 and 6 .)f,~~~,

I • i I i i I I• i • I I •• iii i • i i j i • iii i • iii' iii I• i I 'I • I ppm 5.5 i I• 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0

FIG. 2. Comparison of 1H nuclear magnetic resonance of 5-butoxy ether and unsaturated butyl ester.

5"butoxy and 215 amu for the 4-butoxy ethers. The other would be produced from the etherification reaction to result ether fragment, resulting from cleavage at the ether toward in MS fragments at 187 and 243 amu; neither of these frag the alkyl terminus, is much weaker, and yields fragments 297 ments is present in these spectra. and 311 amu from 5- and 4-butoxy, respectively. Other key NMR analysis ofthe ethers is shown in Figure 2, where the fragments are the cyclized oxonium fragments at 99 and 85 5-butoxy ester is compared to the major by-product, the unsat amu, which are the major fragments for .16 and .15 oxy urated ester. The NMR assignments were derived from the lH, genated fatty acids and/or 0- and y-Iactones, respectively. The l3C, DEPT (indicates the number of hydrogens attached to a MS spectra provide evidence (no 159 amu and few 215 amu carbon), COSY (determines the coupling between adjacent fragments in the 5-butoxy spectrum) that the etherification re protons) and HETCOR (determines which hydrogens are at action yields only one regioisomer. Because other regioiso tached to each carbon) spectra. The prominent recurring fea mers are absent, this indicates that the cation is held at the po ture of the ethers is the 1H NMR methine signal of the ether at sition of generation, and migration from this site does not 3.15 ppm, labeled as resonance 5. The methylene of the ether occur due to the stability of the .15 position. The minor frag (3.35 ppm) also has a significantly different chemical shift ment at 215 amu in the 5-butoxy spectrum is most likely due than the corresponding ester methylene (4.05 ppm). In addi to the small amount of y-Iactone (-I %) in the starting O-lac tion, the ester contains unsaturated signals at 5.4 ppm. tone. Similarly, the 229 amu peak in the 4-butoxy spectrum is from a small amount of o-Iactone present in the starting y-lac ACKNOWLEDGMENTS tone. If cation migration had occurred, it would have pro The authors express their sincere gratitude to Dr. David Weisleder ceeded in both directions (13), and .16 ethers would have re for his valuable assistance in providing NMR spectra. We also thank sulted. Therefore, a nearly equal amount of .14 and .16 ethers The Fanning Corporation (Chicago, IL) for samples of meadowfoam

JAOCS, Vol. 75, no. 8 (1998) SECONDARY ETHER SYNTHESIS 1029 oil, which provided the material for the synthesis of o-Iactones and alyzed Addition of Alkoxy Groups to the Olefinic Double Bonds hydroxy fatty acids. of Soybean Oil, 1. Am. Oil Chem. Soc. 65: 1508-1510 (1988). 8. Ballantine, J.A., M. Davies, J.H. Purnell, M. Rayanakorn, J.M. Thomas, and K.J. Williams, Chemical Conversions Using Sheet REFERENCES Silicates: Novel Intermolecular Dehydration of Alcohols to I. Isbell, T.A., Development ofMeadowfoam as an Industrial Crop Ethers and Polymers. J. Chem. Soc. Chem. Comm.:427-428 Through Novel Fatty Acid Derivatives, Lipid Tech. 9: 140-144 (1981). (1997). 9. Ballantine, J.A., M. Davies, 1. Patel, J.H. Purnell, M. 2. Isbell, T.A., and R. Kleiman, Mineral Acid Catalyzed Conden Rayanakorn, K.J. Williams. and J.M. Thomas, Organic Reac sation of Meadowfoam Fatty Acids into Estolides, J. Am. Oil tions Catalysed by Sheet Silicates: Ether Formatio~ by the In Chem. Soc. 73:1097-1107 (1996). termolecular Dehydration of Alcohols and by Addition of Alco 3. Isbell, T.A., and B.A. Plattner, A Highly Regioselective Synthe hols to Alkenes. J. Mol. Catl. 26:37-56 (1984). sis of o-Lactones from Meadowfoam Fatty Acids, Ibid. 10. Okuda, Y., M. Yoshihara, T. Maeshima, M. Fujii, and T. Aida, 74:153-158 (1997). Reaction of I-Phenylethanol with Chiral Alcohols in the Pres 4. Isbell, T.A., and B.A. Plattner, The Rate of Ring Opening of r ence of Montmorillonite, Chem. Express 4: 17-20 (1989). and o-Lactones from Meadowfoam Oil, Ibid. 75:63-66 (1998). II. Showell, J.S., D. Swern, and W. Noble, Perchloric Acid Isomer 5. Gunstone, F.P., Chemical Properties, in The Lipid Handbook, ization of Oleic Acid, J. Org.Chem. 88:2697-2704 (1968). 2nd edn., edited by F.D. Gunstone, J.L. Harwood, and F.B. 12. Brown, H.C.. J.H. Brewster. and H. Shecter, An Interpretation Padley, Chapman & Hall, London, 1994, pp. 581-582. of the Chemical Behavior of Five- and Six-Membered Riner 6. Gunstone, F.P., and H.R. Schuler, Fatty Acids, Part 47. The Compounds, J. Am. Chem. Soc. 76:467-474 (1954). e Mass Spectra of Bis (Trimethylsilyloxy) and Methoxy 13. Isbell, T.A., and R. Kleiman, Characterization of Estolides Pro Trimethylsilyloxy Ethers Derived from a Series of Methyl duced from the Acid-Catalyzed Condensation of Oleic Acid, Epoxyoctadecenoates and Methyl Epoxyoctadecynoates, Chem. Ibid. 71:379-383 (1994). Phys. Lipids 15: 198-208 (1975). 7. Madrigal, R.V., M.O. Bagby, and E.H. Pryde, The Acid-Cat- [Received November 14, 1997; accepted February 25, 1998]

JAOCS, Vol. 75, no. 8 (1998)