Other copper catalyzed alcohol oxidations

In 2007 Repo and co-workers reported a slightly modified mechanism (Scheme 96).¹⁵⁸ Their proposal mainly followed the Sheldon mechanism. A major difference is the reoxidation of copper(I), which is achieved by oxygen and not by TEMPO as in Sheldon’s mechanism. Repo and co-workers analyzed the reaction intermediates with high resolution ESI-MS and were able to identify many interesting complexes. Among these were (phen)Cu(HSO4)⁺, (phen)2Cu⁺, (phen)Cu(TEMPO)⁺, (phen)Cu(BnOH)⁺. Similar complexes were also indentified with a bipyridyl ligand.

Scheme 96. A modified mechanism reported by Repo and co-workers in 2007.¹⁵⁸

Below I present some mechanistic alternatives, which differ from each other quite substantially. Some evidence on the catalyst intermediates is given, but do not provide proof for any of the postulated mechanistic alternatives. Although Brackman and Gaasbeek (1966)¹⁴⁹ are usually not recognized for their early findings, the later developments by Semmelhack (1984),¹⁵⁰ Knochel (2000),^159a Gree (2002)^159b and Sheldon (2003)¹⁵⁴ have led to ever increasing interest on such catalytic systems.¹⁵⁹

In the early 1980 Munakata et al. reported a copper(I) catalyzed oxidation of ethanol and few other alcohols under aerobic conditions (Scheme 97).¹⁶⁰ The catalytic cycle of the oxidation of ethanol was described to generate water instead of hydrogen peroxide.

This was proven by measuring the quantity of water by Karl Fischer titration. The ratio between acetaldehyde and water was found to be 1:1, which was an indication of a 4e^- reduction of oxygen. Hydrogen peroxide was also transformed to water but the yield for acetone was only 75% (with respect to consumed H2O2). Some of the hydrogen peroxide might have disproportionated to O2 and H2O via copper(I) catalysis, which might explain the reduced ratio. Although this system was not very efficient, it has an important role in understanding the catalytic cycle, since Munakata et al. provided actual proof for the generation of water in the copper catalyzed alcohol oxidation.

Scheme 97. Copper catalyzed oxidation of ethanol by Munakata et al. in 1980.¹⁶⁰

Sawyer and co-workers described a similar system where (bpy)2Cu²⁺ is the initial catalyst.¹⁶¹ Their catalyst system required the use of catalytic amounts of base. This system was able to oxidize benzyl alcohol to benzaldehyde in 37% yield (over 8h). The Sawyer mechanism is extremely complex and has a very strange Cu(III)hydroperoxide radical intermediate. This complex would have 23 valence shell electrons, which makes is even more unbelievable. Also it is not probable that copper(II) is oxidized to copper(III) by oxygen. This hydroperoxide radical is believed to oxidize benzyl alcohol, generating water as the side product. The subsequent copper(III)O^• can oxidize another molecule of benzyl alcohol. Although the mechanism is totally unrealistic, this work by Sawyer and co-workers has been the starting point of research by other groups.

Scheme 98. Copper catalyzed oxidation of benzyl alcohol by Sawyer and co-workers in 1993.¹⁶¹

In 1993 Maumy and co-workers reported a more realistic mechanism in a concurrent study (Scheme 99).¹⁶² Their method was able to oxidize diphenylmethanol to benzophenone in 99% yield in only two hours. This method was also functional for the oxidation of primary and secondary benzylic alcohols. The catalyst was generated from 10 mol % CuCl and 1 equivalent of bipyridine in acetonitrile. Smaller amounts of bipyridine led to poorer conversion. The reaction was performed in 60 °C, but was also shown to work at room temperature in a kinetic isotope effect (kH/kD = 2.0) experiment of PhCDH(OH). Maumy and co-workers described a mechanism were the oxidation of (bpy)Cu^IOCH2Ph results in a binuclear copper(II) 1,2-μ-peroxo species. This intermediate undergoes peroxide bond homolysis into a radical form, which is able to abstract the α-proton from the alcohol. Alternatively, the radical form can be considered to be a copper(III) oxo species which can oxidize the substrate via oxidative rearrangement. Oxidation of the subtrate alcohol reduces copper to (bpy)Cu^IOH. Ligand exchange with the substrate alcohol produces water as a side product and completes the catalytic cycle.

Scheme 99. A mechanism proposed by Maumy and co-workers in 1993.¹⁶²

In 1996 Markó et al. reported a totally different type of copper catalysis on aerobic oxidation of various alcohols.¹⁶³ Their quest for an improved alcohol oxidation with oxygen led them to further investigate some earlier findings from other groups. A catalytic CuCl-phenanthroline (5 mol %) system with stoichiometric amounts of K2CO3

showed some promise in alcohol oxidation, but usually led to early catalyst deactivation. The mechanism for this catalytic system was described to be the same as reported earlier by Maumy (Scheme 100). Markó et al. postulated that the catalyst deactivation is derived from copper(II) salt formation, which was not able to reenter the reaction cycle. They tested some hydrazine additives which are known to reduce copper(II) to copper(I). Remarkably, these additives were able to enhance the catalyst lifetime and at the same time increase the rate of the reaction.

(phen)Cu^II

O O Cu^II(phen) O

O (phen)Cu^I

OH

R H

R H (phen)Cu^IIO

O R

H

(phen)Cu^IOCH₂R RCH₂OH

H₂O

O₂

(phen)Cu^IIO O Cu^II(phen) N NH

CO₂t-Bu t-BuO₂C

N HN

t-BuO₂C CO₂t-Bu (phen)Cu^I

N N H CO₂t-Bu t-BuO₂C

(phen)Cu^I OH N N

CO₂t-Bu t-BuO₂C

(phen)Cu^I O N N

CO₂t-Bu t-BuO₂C

H R

RCH₂OH H₂O

O₂ RCHO

RCHO

Scheme 100. Azodicarboxylate promoted aerobic oxidations of alcohols reported by Markó et al.¹⁶³

A new mechanism was postulated where azodicarboxylate acts as a mediator in an Oppernauer type oxidation (Scheme 100). This oxidation is also known as Mukaiyama oxidation when t-BuOMgBr is used as the metal source and 1,1‘-(azodicarbonyl)- dipiperidine as the oxidant.¹³⁷ The mechanism involves reoxidation of a copper(I)- hydrazine complex, generating a binuclear copper(II) 1,2-μ-peroxo species. Homolysis of the peroxide bond reoxidizes hydrazine to the azodicarboxylate in combination with the reduction of copper(II) to copper(I). Markó’s catalytic system is one of the most mature aerobic oxidations, and is capable of oxidizing a variety of primary and secondary alcohols. The latest version uses only a catalytic amount of base but still suffers from relatively high reaction temperature (70-80 °C), which detracts from its utility.^163c-d

Above were described some examples of copper catalyzed alcohol oxidations, which are not promoted by a radical meditor. Similarly, these oxidations are gaining popularity and new variants appear every year.¹⁶⁴