Acylation of Chiral Alcohols: A Simple Procedure for Chiral GC Analysis

Hindawi Publishing Corporation Journal of Analytical Methods in Chemistry Volume 2012, Article ID 452949, 10 pages doi:10.1155/2012/452949 Research Article Acylation of Chiral Alcohols: A Simple Procedure for Chiral GC Analysis Mireia Oromı́-Farrús,1 Mercè Torres,2 and Ramon Canela1 1 Chemistry Department, University of Lleida, 25198 Lleida, Spain 2 Food Technology Department, University of Lleida, 25198 Lleida, Spain Correspondence should be addressed to Mireia Oromı́-Farrús, Received 30 November 2011; Revised 4 February 2012; Accepted 15 February 2012 Academic Editor: Boryana M. Nikolova-Damyanova Copyright © 2012 Mireia Oromı́-Farrús et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The use of iodine as a catalyst and either acetic or trifluoroacetic acid as a derivatizing reagent for determining the enantiomeric composition of acyclic and cyclic aliphatic chiral alcohols was investigated. Optimal conditions were selected according to the molar ratio of alcohol to acid, the reaction time, and the reaction temperature. Afterwards, chiral stability of chiral carbons was studied. Although no isomerization was observed when acetic acid was used, partial isomerization was detected with the trifluoroacetic acid. A series of chiral alcohols of a widely varying structural type were then derivatized with acetic acid using the optimal conditions. The resolution of the enantiomeric esters and the free chiral alcohols was measured using a capillary gas chromatograph equipped with a CP Chirasil-DEX CB column. The best resolutions were obtained with 2-pentyl acetates (α = 3.00) and 2-hexyl acetates (α = 1.95). This method provides a very simple and efficient experimental workup procedure for analyzing chiral alcohols by chiral-phase GC. 1. Introduction Chiral alcohols occur as natural products and frequently as intermediates in the synthesis of chiral molecules, most of them in the field of synthetic pharmaceuticals possessing chiral centres [1–3]. In pharmacy the use of enantiopure new drugs will certainly increase due to the often welldocumented different biological activities of enantiomers. Moreover, the pharmacokinetics or toxicology of each enantiomer with regard to the drug dosage or side effects is significantly different and consequently so are the resulting regulatory requirements [4, 5]. The determination of the enantiomeric excess (% ee) is therefore critical to the progress of these fields, so many methods have been developed for determining the degree of enantiomeric purity of chiral alcohols in the yield of chromatography and electrophoresis [6–12]. Nowadays, gas-liquid chromatography on chiral stationary phases, especially per-0-modified cyclodextrins, plays the dominant role for the chiral separation of a wide range of volatile compounds due to its ease of use and the commercial availability of columns [13]. However, many of these methods for determining the degree of enantiomeric purity of chiral alcohols are improved when these compounds are converted into volatile esters, such as acetate or trifluoroacetate. Acylation reduces polarity and enhances the separation of chiral compounds in the chromatographic column, as well as conferring better volatility. Typically, only derivatization with acetyl groups or with fluorinated acyl groups up to heptafluorobutyryl improves volatility [14]. Acylation of alcohols is among the most frequently used processes in organic synthesis. Although different methods are described in the literature [15–20], some of them are less effective or ineffective for secondary and tertiary alcohols, others are moisture sensitive or highly expensive, and they may even be potentially explosive (e.g., perchlorates or perchloric acid). Various acylation reactions using iodine as catalyst have been reported [21–26]. Ramalinga and coworkers described iodine as a Lewis catalyst for the esterification and transesterification of acids using an excess of alcohol under reflux conditions [27]. Chavan and coworkers described the transesterification in toluene of β-ketoesters with some 2 Journal of Analytical Methods in Chemistry R R1 R OH + OH R R I2 , Na 2 SO4 100◦ C O R1 + H2 O O O R1 : CH3 ; CF3 Scheme 1: Acylation reaction. primary, secondary alcohols and phenols using iodine as a catalyser in the presence of zinc as a mediator [28]. Afterwards, they described that even iodine acts as an efficient catalysts for transesterification reactions; however, phenols did not undergo transesterification [29]. A procedure for the acetylation of alcohols, amines and phenols with isopropenyl acetate and iodine as a catalyser under solventfree conditions were described by Ahmed and van Lier [30]. This procedure gave acetone as a by-product. Recently, Jereb and coworkers have demonstrated that iodine is an efficient catalyst for esterification under solventfree conditions for several alcohols [31]. We describe herein a simple and convenient procedure for acylation of chiral alcohols under solvent-free conditions in the presence of a catalytic amount of iodine with no byproducts formation and using near equimolar amounts of alcohol and carboxylic acid (Scheme 1). Initially, a systematic study was carried out for catalytic evaluation of iodine in the acetylation of 2-heptanol. Further, the optimized method was applied to (R)-2-heptanol and cis-1,3-cyclohexanediol to determine that no isomerization occurred with acetylation or trifluoroacetylation. Finally, it was applied to a variety of chiral alcohols. All the esters were analyzed by gas chromatography on a CP Chirasil-DEX CB column in order to provide optimum resolution for a chiral alcohol of a particular structural type. 2. Experimental 2.1. Reagents. 3-Hexanol (4), 4-methyl-2-pentanol (5), 3methylcyclopentanol (9), 3-methylcyclohexanol (10), 2tert-butylcyclohexanol (11), 2-methylcyclopentanol (12), 4methylcyclohexanol (13), 2-chlorocyclohexanol (14), 2,6dimethylcyclohexanol (15), 4-tert-butylcyclohexanol (16), 3, 3,5-trimethylcyclohexanol (17), 2-phenylcyclohexanol (18), DL-menthol (19), 1,2-cyclohexanediol (20), 1,3-cyclohexanediol (21), iodine, and acetic acid were all from Acros Organics, Barcelona, Spain. 2-Butanol (1), S-2-butanol, 2hexanol (3), S-2-hexanol, trans-S,S-1,2-cyclohexanediol, trans-R,R-1,2-cyclohexanediol, 2-heptanol (6), R-2-heptanol, (+)-menthol, and tert-butanol were purchased from Fluka, Madrid, Spain. 2-Octanol (7), 3-octanol (8), and cis-1,2-cyclohexanediol were from Sigma-Aldrich, Madrid, Spain. 2-Pentanol (2) was acquired from Merck, Barcelona, Spain. 1-Methylhexyl acetate was obtained by stirring at 100◦ C for 48 h in a screw-cap vial a mixture of 2-heptanol (20 mmol), acetic acid (200 mmol), iodine (0.6 mmol) and anh. Na2 SO4 (0.2 mmol). Afterwards, 25 mL of hexane were added and the mixture was filt (...truncated)