Mass Spectrometric Screening of Chiral Catalysts by Monitoring the Back Reaction of Quasienantiomeric Products: Palladium‐Catalyzed Allylic Substitution

Abstract

The enantioselectivity of a chiral catalyst is usually determined by measuring the enantiomeric excess of the reaction product. However, the ee value obtained from analysis of the product does not necessarily reflect the intrinsic enantioselectivity of the catalyst. A competing noncatalytic background reaction which produces a racemic product, catalytically active impurities, or dissociation of a chiral ligand from a metal catalyst can lead to low enantiomeric purity even though the catalyst itself is highly selective.We recently reported a method for determining the intrinsic enantioselectivity of chiral catalysts by using quasienantiomeric substrates and electrospray ionization mass spectrometry (ESI-MS) as the analytical tool. [1][2][3] In contrast to previously developed screening methods for enantioselective reactions which also make use of quasienantiomeric substrates, [4,5] our method relies on the quantification of catalytic intermediates rather than analysis of the product.As a first application, we studied the kinetic resolution of racemic allyl esters by using a palladium-catalyzed allylic substitution reaction (Scheme 1).[6] By starting with a 1:1 mixture of two mass-labeled, quasienantiomeric substrates (S)-4 a and (R)-4 b, the selectivity factor s = k a /k b of a catalyst can be deduced from the ratio of the corresponding allyl intermediates 5 a/5 b as determined by mass spectrometry (Scheme 2). As ESI-MS allows the selective detection of charged species in the presence of a large excess of neutral compounds, cationic intermediates such as 5 a and 5 b can be observed even at low catalyst loadings under conditions normally used for preparative catalytic reactions. The method is fast and reliable, does not require workup of the reaction mixture, and in contrast to methods based on product analysis allows the simultaneous screening of catalyst mixtures (if the catalysts have different molecular masses). The screening of a large number of catalysts showed that the selectivity of a catalyst in the kinetic resolution step did not correlate with the enantioselectivity of the nucleophilic addition to the allyl intermediate 2. It is this step that determines the enantioselectivity of the overall reaction leading from the racemic allyl ester 1 to the optically active substitution product 3 (Scheme 1). Many catalysts that gave high enantioselectivity in the overall reaction were inefficient in the kinetic resolution of allyl esters.Herein we report an extension of our screening method which allows the determination of the enantioselectivity in the nucleophilic addition step and can, therefore, be used to evaluate the intrinsic enantioselectivity of chiral catalysts for the overall allylic substitution process. Instead of screening the forward reaction, we monitored the back reaction of quasienantiomeric products that leads to the corresponding mass-labeled allyl-palladium complexes. According to the principle of microscopic reversibility, the transition states of Scheme 1. General mechanism of the palladium-ca...

Elusive Reaction Intermediates in Solution Explored by ESI‐MS: Reverse Periscope for Mechanistic Investigations

“…Chemie ESI-MS. [30] In fact, according to the principle of microscopic reversibility,t he forward and back reaction share the same transition state.T hus,i ti sp ossible to treat the quasienantiomeric final products with the same chiral catalyst used to prepare them, and detect the reaction intermediates of the back reaction. Theh igh sensitivity of ESI-MS allows detection of the intermediates in the back reaction, even if they are in low concentration.…”

Palladium Intermediates in Solution

“…In an ongoing study using water as a solvent in palladium chemistry, Muzart et al [49,50] described the substitution of allylic acetates 51 with different nucleophiles such as acetylacetone (52) and sodium para-toluenesulfinate (54) in aqueous media using a palladium complex and the hydrophilic ligand [(HOCH 2 CH 2 NH-COCH 2 ) 2 NCH 2 ] 2 (56). Scheme 7.27 shows the specific reactions studied by ESI-MS in order to further investigate mechanistic aspects of these reactions.…”

“…Pfaltz et al [51,52] applied ESI-MS to the study of the kinetic resolution of palladium-catalyzed enantioselective allylation of diethyl ethylmalonate with allylic esters (Scheme 7.30). However, in this particular case the authors used the ESI-MS technique for the high-throughput parallel screening of the chiral catalyst [53], suspecting that it might be possible to determine the catalysts capacity for enantiodiscrimination by examining catalyst-bound reactant complexes rather than by analyzing the final product.…”

“…Here as well it can be concluded that the most selective ligand in the kinetic resolution step, which is the sterically most demanding one, is 70 with naphthyl groups in the sulfonamide moieties. Another application of this screening method designed by the same authors [52] was to monitor the back reaction of quasienantiomeric final products in order to determine the enantioselectivity in the nucleophilic addition step. The authors explained the fact that the enantioselectivity determined from back-reaction screening was identical to that of the forward reaction in terms of the principle of microscopic reversibility, which states that transition states of forward and back reactions are identical.…”

Mass spectrometric and theoretical studies on dissociation of the CS bond in the benzenesulfonic acid and benzenesulfinic acid anion series: Homolytic cleavage vs heterolytic cleavage

“…MS/MS not only provides extensive structural information about organic molecules, but also can act as an important tool for mechanistic studies in gas-phase organic chemistry [23][24][25][26][27][28][29][30][31][32]. In this paper, benzenesulfonic acid and benzenesulfinic acid series have been selected as the target compounds to study the dissociation of pivotal bonds.…”