Henry reaction mechanism

Hammar, R Marcelli, T. Hiemstra, H. Himo, R Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry Reaction Mechanism and Enantioselectivity. Adv. Synth. Catal. 2007, 349, 2537-2548. 

The interaction between experiment and theory is very important in the field of chemical transformations. In 1981 Kenichi Fukui and Roald Hoffmann received a Nobel Prize for their theoretical work on the electronic basis of reaction mechanisms for a number of important reaction types. Theory has also been influential in guiding experimental work toward demonstrating the mechanisms of one of the simplest classes of reactions, electron transfer (movement of an electron from one place to another). Henry Taube received a Nobel prize in 1983 for his studies of electron transfer in inorganic chemistry, and Rudolf Marcus received a Nobel Prize in 1992 for his theoretical work in this area. The state of development of chemical reaction theory is now sufficiently advanced that it can begin to guide the invention of new transformations by synthetic chemists. 

Few of these studies (460, 462) dealt with the Michael reaction one study (461) with the Henry reaction. The efficiency, stereoselectivity, and enantiose-lectivity of this process are rather high. The mechanism of the transformations is poorly known. Presumably, the chiral cation should shield the Si surface of nitronate, thus providing the Re approach of the substrate. In addition, the approach of the reagents, resulting in generation of syn isomers, is considered less favorable than the approach yielding anti isomers. 

Scheme 6.75 Proposed mechanism of the enantio- and diastereoselective aza-Henry reaction between N-Boc-protected aldimines and nitroalkanes in the presence of biflinctional catalyst 12 and catalyzed epimerization of the syn-adduct at increased temperature.

Cyclohexanediamine-derived amine thiourea 70, which provided high enantio-selectivities for the Michael addition [77] and aza-Henry reactions [78], showed poor activity in the MBH reaction. This fact is not surprising when one considers that a chiral urea catalyst functions by fundamentally different stereoinduction mechanisms in the MBH reaction, and in the activation of related imine substrates in Mannich or Streclcer reactions [80]. In contrast, the binaph-thylamine thiourea 71 mediated the addition of dihydrocinnamaldehyde 74 to cyclohexenone 75 in high yield (83%) and enantioselectivity (71% ee) (Table 5.6, entry 2) [79]. The more bulky diethyl analogue 72 displayed similar enantioselectivity (73% ee) while affording a lower yield (56%, entry 3). Catalyst 73 showed only low catalytic activity in the MBH reaction (18%, entry 4). 

No detailed reaction mechanism for the formation of vinyl acetate from ethylene was found in the literature surveyed. Some aspects of this reaction were discussed recently by Henry (16), who formulates the reaction in the following way ... 

Reaction Mechanism. Any mechanism proposed for the vinylation of acetic acid by the hexenes must be able to account for the production of the high boiling products, 1,2-hexandiol mono- and diacetates (VIII, IX and X), and possibly hexylidene diacetate, as well as the hexenyl acetates. The currently accepted mechanism for synthesizing vinyl acetate from ethylene and acetic acid is derived from that postulated by Henry (i, 19), based on studies of the Wacker acetaldehyde synthesis. The key step in this mechanism is an insertion reaction (18). 

All the steps in the Henry reaction are completely reversible. The first step of the mechanism is the deprotonation of the nitroalkane by the base at the a-position to form the corresponding resonance stabilized anion. Next, an aldol reaction (C-alkylation of the nitroalkane) takes place with the carbonyl compound to form diastereomeric P-nitro alkoxides. Finally the P-nitro alkoxides are protonated to give the expected p-nitro alcohols. 

Concerning the reaction mechanism, the transformation of an aldehyde into a nitroalkene can occur via two different pathways the first involves nitroalcohol formation through a traditional Henry reaction, which is then followed by water elimination to form the double bond the second proceeds through an imine intermediate rather than the nitroalcohol. The authors predicted that nitroalkene formation goes through an imine intermediate (Scheme 3.9) rather than the nitroalcohol as they did not observe nitroalcohol formation at any point in the reaction. In addition, when the nitroalcohol is placed in the presence of swollen capsules, no nitroalkene formation is observed this inability to... 

The base-catalyzed solid-phase condensation through a Henry reaction of jS-formyl enamides 143 with nitromethane in the presence of pyrrolidine produced pyridine derivatives 148 in 80 90% yields under MWI for 8-10 min. The conventional heating in toluene for 8-10 h gave lower yields (62-74%). The mechanism... 

Palladium-catalyzed aromatic C-H acetoxylation was first reported in 1966 [100, 101]. In 1971, Henry proposed Pd(IV) intermediates in the Pd-catalyzed acetoxylation of benzene with K2Cr207 in AcOH [102], Subsequent reports by Stock [103] and Crabtree [104] also discussed the possible intermediacy of Pd(IV) complexes in the acetoxylation of benzene (Fig. 27a). In 2004, Sanford reported the regioselec-tive ort/to-acetoxylation of 2-arylpyridines and proposed a reaction mechanism involving aromatic C-H metallation at Pd(II), oxidation of the resulting aryl Pd(II) intermediate to a Pd(IV) complex, and product-forming C-O reductive elimination (Fig. 27b) [105-108]. 

The Pd(ll)-catalyzed exchange of allylic groups as illustrated in Eq. (107) (Atkins et al., 1970) could be regarded as a nucleophilic attack on an incipient allyl carbonium ion, but the reaction mechanism probably involves a simple aminopalladation, followed by dehydroxypalladation (Henry, 1973). 

The effect of substrate concentration on enzymatic reaction was first put forward in 1903 (Henri, 1903), where the conversion into the product involved a reaction between the enzyme and the substrate to form a substrate-enzyme complex that is then converted to the product. However, the reversibility of the substrate-enzyme complex and its final breakdown into the substrate and free enzyme regeneration was generally ignored. In 1913, Michaelis and Menten took this into consideration and proposed the scheme shown in Equation 4.1 for a one-substrate enzymatic reaction. Experimental data, that is, the initial reaction rates, were collected to support their analysis. The reaction mechanism, which is one of the most common mechanisms in enzymatic reactions, was based on the assumption that only a single substrate and product are involved in the reaction. 

The scope, limitations and mechanisms of asymmetric Henry reactions catalysed by transition metal complexes have been reviewed. ... 

In 2010, Stepehenson and coworkers developed aza-Henry reactions of tetrahydroisoquinolines 14 on the assumption that electron-rich tertiary alkylamines serve as electron donors to be converted into iminium ion through SET photoredox processes [50]. They showed that the Ir photocatalyst is more efficient than the Ru photocatalyst, [Ru(bpy)3]Cl2. Proposed reaction mechanism based on the reductive quenching cycle is illustrated in Scheme 10. The photoex-cited Ir species undergoes SET from tetrahydroisoquinoline 14 to give the... 

Scheme 29.5 Proposed mechanism for the phosphonium salt mediated asymmetric Henry reaction.

A similar reaction mechanism could be assumed for the aza-Henry reaction catalyzed by urea 38 [46], In this particular case, the sulfinyl group acts both as an acidifying agent and a chiral controlling element, and allows the stereoselective addition of nitroethane to aromatic and, in two instances, aliphatic N-Boc imines (Scheme 29.21). 

A purely ionic hydrogen bond activation mechanism might be involved in the aza-Henry reaction between a-iminoesters, a very reactive subclass of imines, and various nitroalkanes catalyzed by the BINOL phosphoric acid 44 [54]. The corresponding P-nitro-a-amino acid esters were produced in good yields, diastereo- and enantioselectivities (Scheme 29.23). The authors postulated a dual role of catalyst 44 through activation of the a-iminoester by protonation and control over the nitroaUcane/nitronate equilibrium (Scheme 29.24). 

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