Unravelling the underlying mechanism of the reduction of aldehydes/ketones with metal borohydride in an aprotic solvent

Abstract

The reduction mechanism of aldehyde/ketones with M(BH₄)_n is not fully understood, even though the hydroboration mechanism of weak Lewis base borane complexes is known to involve a four-membered ring transition state. Herein, the reduction mechanism of M(BH₄)_n in aprotic solvents has been elucidated for a six-membered ring, in which hydride transfer to the C atom from the B atom, formation of an L·BH₃ adduct, and disproportionation of (BH₃(OR)⁻) borane are involved. The metal cations and solvents participate in and significantly influence the reaction procedure. We believe that this mechanistic study would provide a further reference for the application of M(BH₄)_n in organic reactions.

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Since metal borohydrides (M(BH₄)_n, M = Li, Be, Ca, Al, and Na) were discovered in the 1940s,¹ thousands of reports concerning the applications of NaBH₄ as a reducing agent in organic synthesis and other fields have appeared due to the relatively mild reducibility, inexpensive cost, and easy handling of NaBH₄.^2–4 Despite a large number of studies being reported on NaBH₄ as a reducing agent, the studies of the kinetics and mechanisms of reducing aldehydes and ketones in aprotic solvents are relatively rare.^3,4c,5 In 1957, Brown reported that the reaction of NaBH₄ with ketone in isopropyl alcohol was a simple second-order kinetics involving four successive processes (Scheme 1a).^3d,4c Wigfield, based on his work and others, claimed that results in the first two steps could be confirmed, but the latter stages could not demonstrate whether disproportionation occurred during the reaction (Scheme 1b).⁶

Scheme 1 Mechanisms of carbonyl reductions by NaBH₄ in alcohols. ^a Sequential mechanism. ^b Disproportionation mechanism.

The term hydroboration, first proposed by Brown, describes reactions in which a B–H bond is added to a double or triple bond, such as C=C, C=O, and C≡N, a type of reduction.⁸ For these reactions, a four-membered ring mechanism is well-accepted for the hydroboration with these types of boranes.⁹ In contrast, the BH₄⁻ anion is essentially a Lewis base when it is used as a reducing reagent from which the free BH₃ moiety cannot be released. Brown indicated that NaBH₄ acts as a nucleophile to attack the electron-deficient centre to initiate the reaction but did not provide detailed information on the mechanism.^8c Therefore, it is believed that the reaction mechanism of the metal salts of the BH₄⁻ anion with the aldehyde/ketone must be different from the reaction with L·BH₃ (L = THF or (CH₃)₂S). However, there is a lack of consolidated evidence to support this hypothesis.

In recent years, our group has been devoted to research into boron chemistry and has systematically elaborated the nucleophilic properties of B–H bonding pair electrons.^10,11 Through experimental and theoretical studies, a simple scheme for chemically selective reduction of carboxylic acids to primary alcohols using NaNH₂(BH₃)₂ as a reduction reagent has been developed, and their mechanism has been elucidated, revealing the transfer of hydrogen from the B atom to the C atom.¹² Based on these studies, we further explore the reduction reactions of aldehydes/ketones by metal borohydrides, including the general reaction mechanism in an aprotic solvent.

Metal borohydrides can be used as a reducing reagent in many reactions, as reported in the literature. The following facts were presented in the literature even though the reaction mechanism is not well understood. (1) The solvents influence reducing power, resulting in different mechanisms in aprotic and protic solvents.^3,4a Isopropyl alcohol possesses the advantage because in which NaBH₄ is quite stable, and the kinetic studies of the reduction of aldehydes and ketones with it have been carried out thoroughly.^2,4a,13 (2) Mixture with LiCl, AlCl₃, or alkaline earth metal halides, the reduction performance of NaBH₄ improves, which may be due to the formation of borane complexes or the corresponding borohydrides of lithium, aluminum, and alkaline earth metal,^14,15 implying that the metal cations influence reactions. (3) The addition of iodine into NaBH₄ results in the formation of diborane¹⁶ in a similar way to Lewis acids.¹⁷ (4) NaBH₄ reacts with benzoic acid,^18a NaHCO₃,^18b CO₂ or aldehydes,^18c and even H₂O,^18d to form borane complexes with 1°-, 2°-, 3°- and heteroaromatic amines.

After taking into account all these results from the literature and our recent work, we proposed a possible reaction mechanism for aldehydes/ketones and M(BH₄)_n in aprotic solvents (THF or DME). In the reaction, the metal cation and borohydrides are associated as an ionic pair in THF.⁷ The metal cation interacts with the carbonyl oxygen. Meanwhile, one of the nucleophilic hydrides in BH₄⁻ attacks the carbonyl carbon to transfer a hydride from the B atom to the C atom through a six-membered ring, resulting in the formation of the Lewis base (solvent) borane complex (THF·BH₃) (Scheme 2a). The formed alkoxyl anion replaced THF to afford an alkoxyl anion coordinated borane complex anion (BH₃OCHR₁R₂⁻) because the nucleophilicity of the alkoxyl anion (−OCHR₁R₂) is higher than that of a neutral solvent molecule (THF). These observations are consistent with calculated results (see ESI,† Fig. S1). On the one hand, formed alkoxy-borohydridoborates have higher reactivity than parent borohydrides, and thus, they could similarly reduce aldehydes or ketones (Scheme 2d).^19b,c On the other hand, formed alkoxyborohydridoborate anions are unstable and may redistribute to form BH₄⁻ and B(OCHR₁R₂)₄⁻, as shown in Scheme 2b.¹⁹ The formed BH₄⁻ restarted a new cycle reduction reaction.

Scheme 2 (a) Reduction reaction of aldehyde/ketones by M(BH₄)_n, (b) disproportionation of the formed BH₃OCHR₁R₂⁻, (c) Hydroboration reaction of aldehydes/ketones by THF·BH₃, and (d) Li⁺ cation participating in the reduction reaction of aldehydes/ketones by THF·BH₃.

The proposed mechanism of the reduction reaction is different from the hydroboration reaction of THF·BH₃ with aldehydes/ketones in which the B–H bond was added to C=O through a four-membered ring mechanism to form a monoalkoxyborane. A similar process is repeated to transfer all hydride groups from the B atom to the C atom to form a borate ester, as shown in Scheme 2c.

To verify the proposed mechanism, a series of experiments were carried out. Cinnamaldehyde and 4-fluorophenylacetone were selected as standard substrates, and lithium, calcium, and sodium salts of the BH₄⁻ anion were used as reducing reagents. The reaction process was monitored by ¹¹B NMR spectroscopy.

As the aprotic solvent molecule (Lewis base, THF) coordinated borane (THF·BH₃) is a vital intermediate in the proposed mechanism, capturing this species is crucial in understanding the proposed mechanism in an aprotic solvent. Therefore, we set up experiments to prove the formation of THF·BH₃ in the reaction. Considering its better solubility in THF, LiBH₄ was selected to react with aldehydes/ketones. Based on the proposed mechanism, the formed BH₃ rapidly coordinates with THF to afford THF·BH₃ and is then converted to alkoxyl anion-coordinated borane. To capture the released BH₃ group, we added Et₃N into the reaction with an anticipation that it would preferentially react with the BH₃ to form Et₃N·BH₃ because Et₃N has strong Lewis basicity relative to THF (Fig. S1, ESI†). As the reducing power of Et₃N·BH₃ is particularly weak (Fig. S16, ESI†), it cannot further reduce the aldehydes/ketones in the reaction; thus, only one equiv. of hydride of the BH₄⁻ anion was consumed after the reaction was completed. When the reactant ratio of cinnamaldehyde, LiBH₄, and Et₃N was set to 2 : 1 : 4, and the reaction procedure was monitored in THF by ¹¹B NMR spectroscopy, the signal of Et₃N·BH₃ appeared, proving that the BH₃ group had formed successfully (Fig. S17, ESI†).

Based on the stoichiometric coefficient of reaction, one mole of BH₄⁻ can reduce four moles of aldehydes/ketones. Therefore, a series of reactions were carried out with cinnamaldehyde, LiBH₄, and Et₃N in different ratios of 10 : 2 : x (x = 0, 2, 4, 6, 8, 10, 15, and 20, see ESI† for details). In the absence of Et₃N, the reaction of LiBH₄ with cinnamaldehyde in THF led to the formation of almost 8 mmol of alcohol based on the integrated values of signals in ¹H NMR spectra (Fig. 1), indicating that all eight equiv. of hydrides of the two BH₄⁻ anions took part in the reaction. As the amount of Et₃N increased, the amount of the alcohol product decreased; at the same time, the amount of Et₃N·BH₃ increased. When Et₃N was over four equivalents, the quantity of cinnamyl alcohol and the formed Et₃N·BH₃ approached 2 mmol (Fig. 1). These results indicate that one BH₄⁻ only used one equiv. of hydride to reduce 1 mmol cinnamaldehyde to form one equiv. of Et₃N·BH₃ at the same time, supporting the proposed mechanism.

Fig. 1 Reactions of LiBH₄ with cinnamaldehyde and different equivalents of Et₃N in THF at room temperature. (LiBH₄: cinnamaldehyde:Et₃N = 2 : 10 : x, where x = 0, 2, 4, 6, 8, 10, 15, and 20).

Similar results were obtained for the reactions of LiBH₄ with 4-fluorophenyl-acetone in THF (Fig. S3, ESI†). When the reaction with aldehydes or ketones is in the same solvent, the amount of aldehyde reduction products is more than that of ketone products, which is consistent with the high activity of aldehydes (Fig. S4, ESI†).

We also carried out a low-temperature experiment to directly capture the THF·BH₃ intermediate of the reaction. When the reaction was carried out at −40 °C, THF·BH₃ was observed in ¹¹B NMR spectra, as shown in Fig. S5d (ESI†), proving the formation of THF·BH₃ by comparing the J value of the formed THF·BH₃ and authentic THF·BH₃ (Fig. S5e and f, ESI†). Additionally, a signal of the B₂H₇⁻ anion is observed in ¹¹B NMR (Fig. S5, ESI†). The formation of B₂H₇⁻ is based on the reaction of BH₄⁻ and BH₃,^11a supporting the formation of BH₃. Another experimental evidence to support the formation of BH₃ is that a small amount of the reduction product of the C=C bond can be observed in the ¹H NMR spectra (Fig. S6, ESI†) because it is well-known that the BH₄⁻ anion cannot reduce the C=C bond,^2,8a but BH₃ or B₂H₆ can.^8c,20 Therefore, this observation implied that THF·BH₃ was formed in the reaction.

When the first hydride of the BH₄⁻ anion is transferred to the C atom of the carbonyl group, an alkoxyl anion and a BH₃ group form at the same time. BH₃ coordinates with a THF solvent molecule to form THF·BH₃. We speculate that the alkoxyl anion formed here could replace THF to form alkoxyl anion-coordinated borane (alkoxyborohydridoborates, BH₃OCHR₁R₂⁻) because of the high nucleophilicity of the alkoxyl anion (Fig. S1, detailed information see ESI†).

Metal cations play significant roles in the reduction reactions of aldehyde/ketones, as reported in the literature.^4a,21a This characteristic is also demonstrated in the proposed mechanism because the metal cations participate in reaction procedures. Therefore, we examined reactions with different metal borohydrides. A similar trend was observed by replacing LiBH₄ with Ca(BH₄)₂, but differences were apparent (Fig. S9 and S10, ESI†). The electrophilic Mⁿ⁺ attacks the oxygen atom on the carbonyl group to facilitate reduction, while polarizing the BH₄⁻ anion to activate the B–H bond.^6,21 The ability of these cations to activate carbonyl groups is consistent with their polarization power, which is measured by the field strength of the anion, following the trend of Li⁺ > Ca²⁺ > Na⁺.^3b,21 Therefore, the reaction time of Ca(BH₄)₂ to reduce the carbonyl group is slightly longer than that of LiBH₄. At the same time, the amount of aldehydes or ketones reduced by Ca(BH₄)₂ is less than that of LiBH₄ under the same conditions, based on ¹H NMR analysis.

The reaction of NaBH₄ is different and not as convincing as the reactions of LiBH₄ and Ca(BH₄)₂, even though the ¹¹B NMR spectra look clear (Fig. S11, ESI†). The reaction is very slow, and some by-products are detected, probably due to the weak ability of Na⁺ to activate the carbonyl group, indicating the influence of the metal cation on this reduction reaction.^21,22

The reaction of THF·BH₃ with aldehydes or ketones is a hydroboration reaction undergoing a four-membered ring mechanism (Scheme 2c). However, when LiCl is added to the reaction, it goes faster than the control reaction (Table S1 and Fig. S12 and S14, ESI†). It is believed that when LiCl is added to the reaction, the Li⁺ cation participates in the reaction by interacting with the O atom of carbonyl to facilitate the reaction because of the stronger activating ability of the Li⁺ cation than the B atom.⁶ In this case, the reaction proceeds through a six-membered ring mechanism (Scheme 2d). Interestingly, when LiO^tBu was added to the reaction, it proceeded much faster than reactions with the addition of LiCl (Table S1 and Fig. S12, S13, ESI†). It is reasonable to infer that, except for the activating role of the Li⁺ cation, the ^tBuO⁻ anion replaced THF of THF·BH₃ to form BH₃(O^tBu)⁻, which then took part in the reaction as analyzed above. These observations support that the metal cations participate in and influence the reactions.^4a

It is worth noting that in these reactions, the breaking of the B–H bond in BH₄⁻ to transfer a hydride to the C atom from the B atom and release a BH₃ group generally has a high energy barrier, and thus, it is difficult to realize.¹² However, the BH₃ group can rapidly react with THF to form THF·BH₃, which facilitates the hydride transfer process. This is similar to the case of the reduction of carboxylic acid by NaNH₂(BH₃)₂, where ADB forms. The theoretical work supports this conclusion.¹²

The impact of solvents on the reaction was explored. As a result, the coordinating ability of solvents influences the reaction (Fig. S15, detailed information see ESI†).

The proposed mechanism provides a general description of the reduction of aldehydes/ketones by alkali or alkaline metals in borohydrides based on the comprehensive consideration of influencing factors, such as the interaction between the metal cation and the BH₄⁻ anion, solvents, and cations. An essential basis of the proposed mechanism is the contact ion pair relationship in the metal borohydrides. However, when a chelating solvent, such as crown ether, coordinates with a metal cation or in a dilute solution, the metal borohydrides may predominantly occur as solvent-separated ion pairs. In these cases, the reduction may undergo other mechanisms. Conversely, an exchange of the proton of alcohol and hydride of borohydride is observed in THF, indicating that the B-coordinated η²-H₂ fragment may form as an intermediate in the process.²³ Thus, the six-membered ring mechanism proposed here may not be unique for the reduction of aldehydes/ketones by borohydrides in an aprotic solvent, and further studies are underway in our lab.

In conclusion, we have proposed a mechanism for the reaction of aldehydes/ketones with metal borohydrides in aprotic solvents; this reaction is proved to be a reduction rather than a hydroboration. The B–H bond of the BH₄⁻ anion attacks the carbon atom of the carbonyl group with the assistance of Mⁿ⁺, interacting with the oxygen atom to activate the carbonyl group. During the breakage of the B–H bond, the BH₃-forming moiety coordinates with a solvent molecule to generate L·BH₃, which rapidly converts to an alkoxyl anion-coordinated complex, BH₃(OR)⁻, after the anion (OR⁻) replaces the solvent molecule. The BH₃(OR)⁻ complex was redistributed to afford B(OR)₄⁻ and BH₄⁻, and the latter restarted a new cycled reaction. We selected template reactions of MBH₄ (M = Li, Na, and Ca) and aldehydes/ketones in THF or DME to gather evidence to support the proposed mechanism. The formed BH₃ was captured by the strong Lewis base, Et₃N, and the disproportionation of the formed BH₃(OR)⁻ complex was experimentally confirmed. We examined the influence of the metal cations and solvents on the reactions. The activation of the carbonyl group by the metal cations and the assistance of the solvent molecules in breaking the B–H bond play significant roles in the whole process that cannot be ignored. This paper fills the gap in the understanding of the reduction mechanism of NaBH₄ in aprotic solvents and provides a foundation for the application of MBH₄ in organic reactions.

This work is supported by the National Natural Science Foundation of China (No. 22171246 and 22271256).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, supplementary figures and NMR spectra. See DOI: https://doi.org/10.1039/d3cc06108f

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