Mandelic Acid


[17199-29-0]  · C8H8O3  · Mandelic Acid  · (MW 152.16) (R)-(-)


(useful reagent for the resolution of enantiomeric amines1 and alcohols;5 serves as a chiral nonracemic template for asymmetric reductions,11-14 aldol condensations,15-17 and Diels-Alder reactions;18,19 chiral nonracemic starting material22)

Alternate Names: phenylglycolic acid; a-hydroxyphenylacetic acid.

Physical Data: (S)-(+): mp 134-135 °C; [a]20D + 156.6° (H2O, c = 2.9). (R)-(-): mp 133-135 °C; [a]20D - 158.0° (H2O, c = 2.5). (±): mp 121-123 °C; d 1.341 g cm-3; Ka 4.3 × 10-4 (25 °C).

Solubility: sol water (1 g/6.3 mL), ethanol (1 g/mL), acetic acid, chloroform; very sol ether.

Form Supplied in: white crystalline solid; widely available.

Handling, Storage, and Precautions: darkens and decomposes upon prolonged exposure to light.

Resolving Reagent.

Due to the ready availability of both enantiomers of this compound in high enantiomeric purity, mandelic acid is widely used as a reagent for enantiomeric resolutions.1 It is used in resolving racemic mixtures of amines1 or diamines2 as the diastereomeric ammonium salts. Amino esters3 or amino lactams4 are resolved by formation of the amides or ammonium salts,4b and alcohols5 are resolved by formation of the corresponding diastereomeric esters5a,b or ethers.5c Generally, the derivatives are crystalline solids easily purified by recrystallization. In a related application, enantiomeric purity determinations of chiral nonracemic amines by 1H NMR are obtained using mandelic acid as a solvating agent.6 As well, absolute configuration determinations of enantiomers can be undertaken using either isomer of mandelic acid in conjunction with CD-ORD,7 X-ray,8 and mass spectral analyses.9 Mandelic acid can also be utilized in enantiomeric chromatography10 as a chiral nonracemic mobile phase additive10a or as a solid support component.10b

Asymmetric Reductions.

Acyloxy-alkoxy borohydrides, produced from the reaction of mandelic acid enantiomers and Sodium Borohydride,11 and aluminum hydride reagents modified with ligands derived from mandelic acid,12 will reduce ketones with poor stereoselectivity. Reactions of nitriles with a mixture of NaBH4 and mandelic acid followed by alkylation of the intermediate N-boryl imine with organometallic reagents provide the corresponding primary amines in good yield but with low stereoselectivity (eq 1).13 However, catalytic hydrogenations with chiral nonracemic phosphino ligands (1),14b-d easily derived from mandelic acid (eq 2), with rhodium have given the corresponding products (e.g. amino acids) with high enantiomeric purity (eq 3).14

Aldol Condensations.

Mandelic acid and a variety of easily prepared derivatives serve as excellent chiral nonracemic auxiliaries for aldol condensations, giving products in high diastereoselectivity. Lewis acid mediated condensation of silyl enol ethers or allylsilanes with 1,3-dioxolan-4-ones (2), produced from the reaction of mandelic acid with various aldehydes and ketones, gives the corresponding products in up to 86% de (eq 4).15 The diastereomers are easily separated and the chiral nonracemic auxiliaries are readily removed with Lead(IV) Acetate without racemization, giving enantiomerically pure aldols or homoallylic alcohols.

Chiral nonracemic silyl ketene acetals produced from mandelic acid derived amino alcohols successfully undergo asymmetric Mukaiyama aldol condensations,16 and the magnesium enolates of acetoxy-1,1,2-triphenylethanols (3) derived from mandelic acid (eq 5) condense with aldehydes with high stereoselectivity (eq 6).17

Diels-Alder Reactions.

Hydroxamic acids of the mandelic acid enantiomers serve as precursors to chiral nonracemic acylnitroso dienophiles (4) (eq 7).18 In most examples the stereoselectivity of the cycloaddition is relatively low. However, in some cases (with double asymmetric induction),19 significant diastereoselectivities can be achieved (eq 8).

Asymmetric Organometallic Reagents.

Amino derivatives (5) of mandelic acid serve as ligands for copper reagents, facilitating conjugate additions to enones with high enantioselectivity (eqs 9 and 10).20 Lithio benzylmandelate enantioselectively cleaves tricyclic anhydrides to give enantiomers of bicyclic dicarboxylic acids.21

Chiral Nonracemic Starting Material.

Both (S)-(+)- and (R)-(-)-mandelic acid are used extensively for enantiomeric syntheses.22 It is a convenient starting material for enantiomerically pure phenylethanediol and styrene oxide (eq 11).23 These methodologies are useful in preparing enantiomerically enriched deuterated compounds.24 Enantiomerically pure benzoins produced from mandelic acid serve as templates for preparing enantiomerically enriched [16O, 17O, 18O] phosphate esters25 and sulfate esters.26 The alcohol, acid, or aromatic ring functional groups can be interconverted in a variety of ways, so mandelic acid serves as an excellent chiral nonracemic starting material for numerous categories of compounds, including such complex molecules as macrolide antibiotics.27

1. (a) Wilen, S. H. Tables of Resolving Agents and Optical Resolutions; Eliel, E. L., Ed.; University of Notre Dame: Notre Dame, 1972. (b) Newman, P. Optical Resolution Procedures for Chemical Compounds; Optical Resolution Information Center: Riverdale, New York, 1978; Vol. 1.
2. (a) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M. BCJ 1986, 59, 931. (b) Saigo, K.; Tanaka, J.; Nohira, H. BCJ 1982, 55, 2299.
3. Baldwin, J. E.; Adlington, R. M.; Rawlings, B. J.; Jones, R. H. TL 1985, 26, 485.
4. (a) Colon, D. F.; Pickard, S. T.; Smith, H. E. JOC 1991, 56, 2322. (b) Fitzi, R.; Seeback, D. T 1988, 44, 5277.
5. (a) Schmidlin, T.; Wallach, D.; Tamm, C. HCA 1984, 67, 1998. (b) Whitesell, J. K.; Reynolds, D. JOC 1983, 48, 3548. (c) Bihovsky, R.; Bodepudi, V. T 1990, 46, 7667.
6. Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.; Snyder, J. K. JOC 1988, 53, 5335.
7. (a) Barth, G.; Voelter, W.; Mosher, H. S.; Bunnenberg, E.; Djerassi, C. JACS 1970, 92, 875. (b) Whitman, C. P.; Craig, J. C.; Kenyon, G. L. T 1985, 41, 1183.
8. (a) Patil, A. O.; Pennington, W. T.; Paul, I. C.; Curtin, D. Y.; Dykstra, C. E. JACS 1987, 109, 1529. (b) Lamm, B.; Simonsson, R.; Sundell, S. TL 1989, 30, 6423.
9. (a) Yang, H. J.; Chen, Y. Z. Org. Mass Spectrom. 1992, 27, 736. (b) Chen, Y. Z.; Li, H.; Yang, H. J.; Hua, S. M.; Li, H. Q.; Zhao, F. Z.; Chen, N. Y. Org. Mass Spectrom. 1988, 23, 821.
10. (a) Duprat, F.; Coyard, V. Chromatographia 1992, 34, 31. (b) Choulis, N. H. JPS 1972, 61, 1325.
11. (a) Nasipuri, D.; Sarkar, A.; Konar, S. K.; Ghosh, A. IJC(B) 1982, 21, 212. (b) Polyak, F. D.; Solodin, I. V.; Dorofeeva, T. V. SC 1991, 21, 1137.
12. Garry, S. W.; Neilson, D. G. JCS(P1) 1987, 601.
13. Itsuno, S.; Hachisuka, C.; Ushijima, Y.; Ito, K. SC 1992, 22, 3229.
14. (a) Harada, T. BCJ 1975, 48, 3236. (b) Brown, J. M.; Murrer, B. A. JCS(P2) 1982, 489. (c) Riley, D. P.; Shumate, R. E. JOC 1980, 45, 5187. (d) King, R. B.; Bakos, J.; Hoff, C. D.; Marko, L. JOC 1979, 44, 1729.
15. Mashraqui, S. H.; Kellogg, R. M. JOC 1984, 49, 2513.
16. Gennari, C.; Molinari, F.; Cozzi, P. G.; Oliva, A. TL 1989, 30, 5163.
17. (a) Devant, R.; Mahler, U.; Braun, M. CB 1988, 121, 397. (b) Braun, M.; Devant, R. TL 1984, 25, 5031. (c) Millar, A.; Mulder, L. W.; Mennen, K. E.; Palmer, C. W. OPP 1991, 23, 173.
18. (a) Defoin, A.; Brouillard-Poichet, A.; Streith, J. HCA 1992, 75, 109. (b) Kirby, G. W.; Nazeer, M. TL 1988, 29, 6173. (c) Snider, B. B.; Phillips, G. B.; Cordova, R. JOC 1983, 48, 3003.
19. Defoin, A.; Pires, J.; Tissot, I.; Tschamber, T.; Bur, D.; Zehnder, M.; Streith, J. TA 1991, 2, 1209.
20. Corey, E. J.; Naef, R.; Hannon, F. J. JACS 1986, 108, 7114.
21. (a) Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. JOC 1991, 56, 2122. (b) Ohtani, M.; Matsuura, T.; Watanabe, F.; Narisada, M. JOC 1991, 56, 4120.
22. Szabo, W. A.; Lee, H. T. Aldrichim. Acta 1980, 13, 13.
23. Eliel, E. L.; Delmonte, D. W. JOC 1956, 21, 596.
24. (a) Elsenbaumer, R. L.; Mosher, H. S. JOC 1979, 44, 600. (b) Sankawa, U.; Sato, T. TL 1978, 981. (c) Hill, R. K.; Prakash, S. R.; Zydowsky, T. M. JOC 1984, 49, 1666. (d) Morrison, J. D.; Tomaszewski, J. E.; Mosher, H. S.; Dale, J.; Miller, D.; Elsenbaumer, R. L. JACS 1977, 99, 3167.
25. Cullis, P. M.; Lowe, G. JCS(P1) 1981, 2317.
26. Lowe, G.; Salamone, S. J. CC 1984, 466.
27. Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. JACS 1981, 103, 1566.

Bruce D. Harris

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.