Hydrogen auto-transfer, also known as borrowing hydrogen, is the activation of a chemical reaction by temporary transfer of two hydrogen atoms from the reactant to a catalyst and return of those hydrogen atoms back to a reaction intermediate to form the final product. [1] [2] [3] [4] Two major classes of borrowing hydrogen reactions exist: (a) those that result in hydroxyl substitution, [1] [2] and (b) those that result in carbonyl addition. [3] [4] In the former case, alcohol dehydrogenation generates a transient carbonyl compound that is subject to condensation followed by the return of hydrogen. In the latter case, alcohol dehydrogenation is followed by reductive generation of a nucleophile, which triggers carbonyl addition. As borrowing hydrogen processes avoid manipulations otherwise required for discrete alcohol oxidation and the use of stoichiometric organometallic reagents, they typically display high levels of atom-economy and, hence, are viewed as examples of Green chemistry.
The Guerbet reaction, reported in 1899, [5] is an early example of a hydrogen auto-transfer process. The Guerbet reaction converts primary alcohols to β-alkylated dimers via alcohol dehydrogenation followed by aldol condensation and reduction of the resulting enones. Application of the Guerbet reaction to the development of ethanol-to-butanol processes has garnered interest as a method for the production of renewable fuels. [6] In 1932 using heterogeneous nickel-catalysts Adkins reported the first alcohol aminations that occur through alcohol dehydrogenation-reductive amination. [7] Homogenous catalysts for alcohol amination based on rhodium and ruthenium were developed by Grigg [8] and Watanabe [9] in 1981. The first hydrogen auto-transfer processes that convert primary alcohols to products of carbonyl addition were reported by Michael J. Krische in 2007-2008 using homogenous iridium and ruthenium catalysts. [10] [11] [12]
Alcohol aminations are among the most commonly utilized borrowing hydrogen processes. [13] [14] [15] In reactions of this type, alcohol dehydrogenation is followed by reductive amination of the resulting carbonyl compound. This represents an alternative to two-step processes involving conversion of the alcohol to a halide or sulfonate ester followed by nucleophilic substitution
As shown below, alcohol amination has been used on kilogram scale by Pfizer for the synthesis of advanced pharmaceutical intermediates. [16] Additionally, AstraZeneca has used methanol as an alternative to conventional genotoxic methylating agents such as methyl iodide or dimethyl sulfate. [17] Nitroaromatics can also participate as amine precursors in borrowing hydrogen-type alcohol aminations. [18]
The formation of carbon–carbon bonds have been achieved through borrowing hydrogen-type indirect Wittig, [19] aldol, [20] Knoevenagel condensations [21] and also through various carbon nucleophiles. [22] [23] Related to the Guerbet reaction, Donohoe and coworkers have developed enantioselective borrowing hydrogen-type enolate alkylations. [24]
As exemplified by the Krische allylation, dehydrogenation of alcohol reactants can be balanced by reduction of allenes, dienes or allyl acetate to generate allylmetal-carbonyl pairs that combine to give products of carbonyl addition. [3] [4] In this way, lower alcohols are directly transformed to higher alcohols in a manner that significantly decreases waste. [25]
In 2008, borrowing hydrogen reactions of 1,3-enynes with alcohols to form products of carbonyl propargylation was discovered. [26] An enantioselective variant of this method was recently used in the total synthesis of leiodermatolide A. [27]
Hydrogen auto-transfer, also known as borrowing hydrogen, is the activation of a chemical reaction by temporary transfer of two hydrogen atoms from the reactant to a catalyst and return of those hydrogen atoms back to a reaction intermediate to form the final product. [1] [2] [3] [4] Two major classes of borrowing hydrogen reactions exist: (a) those that result in hydroxyl substitution, [1] [2] and (b) those that result in carbonyl addition. [3] [4] In the former case, alcohol dehydrogenation generates a transient carbonyl compound that is subject to condensation followed by the return of hydrogen. In the latter case, alcohol dehydrogenation is followed by reductive generation of a nucleophile, which triggers carbonyl addition. As borrowing hydrogen processes avoid manipulations otherwise required for discrete alcohol oxidation and the use of stoichiometric organometallic reagents, they typically display high levels of atom-economy and, hence, are viewed as examples of Green chemistry.
The Guerbet reaction, reported in 1899, [5] is an early example of a hydrogen auto-transfer process. The Guerbet reaction converts primary alcohols to β-alkylated dimers via alcohol dehydrogenation followed by aldol condensation and reduction of the resulting enones. Application of the Guerbet reaction to the development of ethanol-to-butanol processes has garnered interest as a method for the production of renewable fuels. [6] In 1932 using heterogeneous nickel-catalysts Adkins reported the first alcohol aminations that occur through alcohol dehydrogenation-reductive amination. [7] Homogenous catalysts for alcohol amination based on rhodium and ruthenium were developed by Grigg [8] and Watanabe [9] in 1981. The first hydrogen auto-transfer processes that convert primary alcohols to products of carbonyl addition were reported by Michael J. Krische in 2007-2008 using homogenous iridium and ruthenium catalysts. [10] [11] [12]
Alcohol aminations are among the most commonly utilized borrowing hydrogen processes. [13] [14] [15] In reactions of this type, alcohol dehydrogenation is followed by reductive amination of the resulting carbonyl compound. This represents an alternative to two-step processes involving conversion of the alcohol to a halide or sulfonate ester followed by nucleophilic substitution
As shown below, alcohol amination has been used on kilogram scale by Pfizer for the synthesis of advanced pharmaceutical intermediates. [16] Additionally, AstraZeneca has used methanol as an alternative to conventional genotoxic methylating agents such as methyl iodide or dimethyl sulfate. [17] Nitroaromatics can also participate as amine precursors in borrowing hydrogen-type alcohol aminations. [18]
The formation of carbon–carbon bonds have been achieved through borrowing hydrogen-type indirect Wittig, [19] aldol, [20] Knoevenagel condensations [21] and also through various carbon nucleophiles. [22] [23] Related to the Guerbet reaction, Donohoe and coworkers have developed enantioselective borrowing hydrogen-type enolate alkylations. [24]
As exemplified by the Krische allylation, dehydrogenation of alcohol reactants can be balanced by reduction of allenes, dienes or allyl acetate to generate allylmetal-carbonyl pairs that combine to give products of carbonyl addition. [3] [4] In this way, lower alcohols are directly transformed to higher alcohols in a manner that significantly decreases waste. [25]
In 2008, borrowing hydrogen reactions of 1,3-enynes with alcohols to form products of carbonyl propargylation was discovered. [26] An enantioselective variant of this method was recently used in the total synthesis of leiodermatolide A. [27]