Cannizzaro reaction solvents

The solvent-free Cannizzaro reaction has some advantages. In addition to simplicity and cleanness of the procedure, the solvent-free reaction proceeds much faster than a solution reaction. For example, reaction of 51 in 60% aqueous NaOH takes 24 h to complete [10], although the solvent-free reaction is completed within 5 min [9]. 

Scheme 6.40 Solvent-free crossed Cannizzaro reaction using paraformaldehyde.

If HB is a weak acid, this reaction is rather slow, but it nevertheless takes place. Substances that are unable to react with O2 can also be involved when the solvent-reactant mixtures contain water or other proton donor compounds, even in traces. Thus, benzaldehyde is absolutely resistant to the action of the superoxide ion. However, benzaldehyde transforms into benzylic alcohol and benzoic acid on the action of O2 in the presence of moisture. Sawyer and Gibian (1979) described the following superoxide variant of the Cannizzaro reaction 202 + H2O —>62 + HOO + OH and 2PhCHO + OH + H2O PhCOOH + PhCH20H. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

Aromatic aldehydes can also be converted selectively into the corresponding benzylic alcohols in a crossed Cannizzaro reaction, if NaOH is used as a base. Similarly, the reaction is performed under solvent-free conditions by mixing the aldehyde with the base and an excess of paraformaldehyde and irradiating with microwave for 20—25 s. An alternative protocol uses 40% formalin solution and basic alumina to obtain comparable yields. The thermal reaction in refluxing methanol was found to require 12 h, providing considerably lower yields of the benzylic alcohols (Scheme 4.22)42. 

To avoid strongly basic conditions that might lead to the formation of by-products with sensitive substrates, a more recent report quotes the use of KF-A12C>3 in combination with paraformaldehyde for the crossed Cannizzaro reaction of aromatic aldehydes. Similarly, microwave irradiation completed the solvent-free reaction within a few minutes, whereas the thermal reaction in dioxane required reaction times of up to 3 h (Scheme 4.23)43. 

Varma, R.S., Naicker, K.P. and Liesen, P.J., Microwave-accelerated crossed Cannizzaro reaction using barium hydroxide under solvent-free conditions, Tetrahedron Lett., 1998, 39, 8437-8440. 

Except as noted above, aqueous alkali alone is usually a sufficient solvent (or diluent) vigorous shaking to form an emulsion of the aldehyde in the caustic solution is recommended. The use of alcohol or other solvent inert to the alkali may aid rather involution or dispersion of the aldehyde and is sometimes advantageous. The crossed Cannizzaro reaction is carried out in methyl alcoholic solution. 

Typically, reactions are carried out open to air, at room temperature (rt), using a mixture of tBuOH/water (9 1) or MeCN/water (9 1) as solvent and sodium or potassium hydroxide as base. The presence of water suppresses undesired side reactions (e.g., Cannizzaro reaction, Williamson alkylation, solvent reactivity) [37]. Benzyl bromides are most commonly reported as the halide component. 

Radical intermediates were proposed at an early stage in the history of the Cannizzaro reaction, and this possibility has been resurrected to account for the detection of some 20% of a-D-benzyl alcohol in the products of the Cannizzaro reaction of a-D-benzaldehyde in aqueous alkaline dioxan. This has been rationalized in terms of formation of the benzaldehyde radical anion, which abstracts a H-atom from the solvent (Chung, 1982). Epr spectroscopy of reacting solutions of p-Cl-,/ -NO 2 and / -CF3-benzaldehyde as well as benzaldehyde itself in THF HMPA (9 1) yielded spectra of the aldehyde radical anions identical to those produced by the action of metallic... 

Which step would be rate-determining for this mechanism It could not be step 1 since, if this were the case, then the rate law would be first-order with respect to the aldehyde rather than the observed second-order relationship. Also, if the reaction is carried out in water labelled with oxygen-18, the oxygen in the benzaldehyde exchanges with the 180 from the solvent much faster than the Cannizzaro reaction takes place. This can only be because of a rapid equilibrium in step 1 and so step 1 cannot be rate-determining. 

The overall reaction is currently regarded as an apparent hydride transfer (for review, see ) because a) hydrogen is transferred directly between the reactants in most cases, without exchange with the solvent, 2) the base-catalyzed disproportionation of benzaldehyde to benzyl alcohol and benzoic acid (Cannizzaro reaction) i ems to be a hydride transfer (3) stereospecificity can be observed in model reactions. In addition, Verhoeven and coworkers have analyzed the thermodynamics of the photoinduced reaction between l-benzyl-3-carbamido-l,4-dihydropyridine and l,l-dimethyl-4,4 -bipyridylium dication, and have concluded that a thermal 1 e reaction between a 1-alkyl-1,4-dihydronicotinamide and a carbonyl compound is unlikely. 

Yoshizawa, K., Toyota, S., Toda, F. Solvent-free Claisen and Cannizzaro reactions. Tetrahedron Lett. 2001,42, 7983-7985. 

Cross Cannizzaro reactions. Under solvent-free conditions the microwave irradiation of a mixture of aldehydes with formaldehyde and barium hydroxide gives alcohols. 

The factors leading to isoracemisation can lead to misinterpretation of isotope-ex-change experiments. The lack of exchange of the proton with solvent protons is classical evidence for hydride transfer in the Cannizzaro reaction and Meerwein-Pondorff-Verley reduction and in the rearrangements involved in steroid biosynthesis. For some time the lack of deuterium exchange in the glyoxalase reaction was attributed to a hydride-transfer mechanism (Eqn. 64). 

A more realistic separation is given in a modern practical book after a Cannizzaro reaction. You will meet this reaction in Chapters 26 and 39 but all you need to know now is that there are two products, formed in roughly equal quantities. Separation of these from starting mate-riai and solvent, as well as from each other, makes this a useful reaction. 

Step 6 is the final step in the cellulose-to-lactic acid cascade, involving the isomerization of the 2-keto-hemi-acetal (here pyruvic aldehyde hydrate) into a 2-hydroxy-carboxyhc acid. This reaction is known to proceed in basic media following a Cannizzaro reaction with 1,2-hydride shift [111], Under mild conditions, Lewis acids are able to catalyze this vital step, which can also be seen as an Meerwein-Ponndorf-Verley reduction reaction mechanism. The 1,2-hydride shift has been demonstrated with deuterium labeled solvents [110, 112], Attack of the solvent molecule (water or alcohol) on pymvic aldehyde (step 5) and the hydride shift (step 6) might occur in a concerted mechanism, but the presence of the hemiacetal in ethanol has been demonstrated for pyruvic aldehyde with chromatography by Li et al. [113] andfor4-methoxyethylglyoxal with in situ CNMRby Dusselier et al. (see Sect. 7) [114]. 

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