Organocatalysis: Fundamentals and Comparisons to Metal and Enzyme Catalysis

Abstract

Catalysis fulfills the promise that high-yielding chemical transformations will require little energy and produce no toxic waste. This message is carried by the study of the evolution of molecular catalysis of some of the most important reactions in organic chemistry. After reviewing the conceptual underpinnings of catalysis, we discuss the applications of different catalysts according to the mechanism of the reactions that they catalyze, including acyl group transfers, nucleophilic additions and substitutions, and C-C bond forming reactions that employ umpolung by nucleophilic additions to C=O and C=C double bonds. We highlight the utility of a broad range of organocatalysts other than compounds based on proline, the cinchona alkaloids and binaphthyls, which have been abundantly reviewed elsewhere. The focus is on organocatalysts, although a few examples employing metal complexes and enzymes are also included due to their significance. Classical Brønsted acids have evolved into electrophilic hands, the fingers of which are hydrogen donors (like enzymes) or other electrophilic moieties. Classical Lewis base catalysts have evolved into tridimensional, chiral nucleophiles that are N-(e.g., tertiary amines), P-(e.g., tertiary phosphines) and C-nucleophiles (e.g., N-heterocyclic carbenes). Many efficient organocatalysts bear electrophilic and nucleophilic moieties that interact simultaneously or not with both the electrophilic and nucleophilic reactants. A detailed understanding of the reaction mechanisms permits the design of better catalysts. Their construction represents a molecular science in itself, suggesting that sooner or later chemists will not only imitate Nature but be able to catalyze a much wider range of reactions with high chemo-, regio-, stereo-and enantioselectivity. Man-made organocatalysts are much smaller, cheaper and more stable than enzymes.

Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst

“…Cinchona derivatives, Figure , are extensively employed as robust stereoselective catalysts and in addition were subject to many computational and experimental studies. − These are flexible compounds that in solution exist as a mixture of conformers. − Their function is directly related to their structure and their activity may be controlled via their conformational dynamics, this resembles enzymes function. , One way for the solvent to affect the reaction is by formation of a molecular complex with the catalyst, which may “select” one of the possible conformers of the asymmetric catalyst. − If this conformer produces the largest ee, the solvent enhances or even determines the enantioselectivity.…”

“…Hydrogen bond catalysis has been utilized as a powerful strategy in organic synthesis, particularly in enantioselective organocatalysis. Asymmetric catalysis by chiral hydrogen bond donors and the metal-free organocatalysis involving hydrogen bonding interactions benefit from formation of hydrogen bonds with substrates and clearly select the transition states that make stronger hydrogen bonds. − Hydrogen bonds are also involved in the reaction mechanisms in the enzyme-catalyzed chemistry. , Substitution of cinchona by a good hydrogen bond donor like the thiourea group (which by itself is also a well-known organic catalyst that includes asymmetric derivatives) at the 6′ position, plays an important role in the catalytic functionality of the cinchona molecule. − …”

“…11−14 Their function is directly related to their structure and their activity may be controlled via their conformational dynamics, this resembles enzymes function. 15,16 One way for the solvent to affect the reaction is by formation of a molecular complex with the catalyst, which may "select" one of the possible conformers of the asymmetric catalyst. 17−19 If this conformer produces the largest ee, the solvent enhances or even determines the enantioselectivity.…”

Efficient esterification of n-butanol with acetic acid catalyzed by the Brönsted acidic ionic liquids: influence of acidity

“…17,18 The esterication of alcohols with carboxylic acids in acidic chloroaluminate IL was investigated by Deng et al 19 Moreover, the esterication of alcohols with acid anhydrides in the presence of basic or acidic catalysts, such as 4-pyrrolidinopyridine and H 2 SO 4 , has been previously reported. 20,21 Lee et al 22 employed the metallic Lewis acids, such as Cu(OTf) 2 , Sc(OTf) 3 , Yb(OTf) 3 , and In(OTf) 3 , as catalysts in ILs to catalyze the ester-ication of alcohols with acetic anhydride. However, these catalysts suffer from some limitations such as long reaction time, low conversion rate, and lower yield.…”

Determination of Enantioselectivities by Means of Chiral Stationary Phase HPLC in Order to Identify Effective Proline-Derived Organocatalysts

“…53 Though the term organocatalysis was introduced by Ostwald in 1900, 54 it remained relatively forgotten until the 1970's when Hajos and Parrish (Hoffmann-La Roche), 55 and Eder et al (Schering) 55 independently reported the intramolecular aldol reaction catalyzed by (S)-proline, whose product was obtained in 99% yield and 93% enantiomeric excess. This asymmetric approach experienced a rebirth since 2000, when List et al 56 published their seminal work describing the employment of proline as organocatalyst in the enantioselective intermolecular aldol reaction between acetone and different aldehydes.…”