Sodium borohydride mechanism

Sodium borohydride and lithium aluminum hydride react with carbonyl compounds in much the same way that Grignard reagents do except that they function as hydride donors rather than as carbanion sources Figure 15 2 outlines the general mechanism for the sodium borohydride reduction of an aldehyde or ketone (R2C=0) Two points are especially important about this process... 

The mechanism of lithium aluminum hydride reduction of aldehydes and ketones IS analogous to that of sodium borohydride except that the reduction and hydrolysis... 

FIGURE 15.2 Mechanism of sodium borohydride reduction of an aldehyde or ketone. 

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

When a pyridinium salt such as (27) is treated with sodium borohydride, the final product is the tetrahydropyridine (30). The mechanism for this reaction was proposed by Katritzky (65) and experimentally verified by Anderson and Lyle (66-68). The sequence is visualized as reduction of the... 

Stage 4 Preparation of 1-l2-Phenyi-2-Methoxyl -Ethyi-4-[3-Phenyl-3-Hydroxypropyl] -Piperazine Dihydrochioride - In a double-neck flask equipped with a thermometer and a mechanical stirrer, there is placed in suspension in 800 ml of methanol, 233 grams of 1-[2-phenyl-2-methoxy]-ethyl-4-[2-benzoyl-ethyl]-piperazine dihydrochioride (0.55 mol). It is cooled to approximately 5°C, and 46 grams of NaOH pellets dissolved in 80 ml of HjO are added. When the temperature is about 5°C, one addition of 29,2 grams of sodium borohydride in 40 ml HjO is made. The ice-bath is then removed and stirring continued at ambient temperature for 6 hours. 

The most plausible mechanism for the interconversion of la and Ih is shown in Scheme 2. Similar mechanism has been put forward for epimerization of a-substituted ketones under basic conditions and for the equilibration via an enolate prior to nucleophilic substitution was observed by Numazawa et al. (ref. 13). The same mechanism seems to operate in the reduction of some steroid a-haloketones (ref. 14) or tra/ty-3-chloroflavanone (ref. 15) with sodium borohydride where an inversion of configuration takes place at the a carbon parallel to the reduction of the... 

The nitro group of aromatic nitro compounds has been removed with sodium borohydride. This reaction involves an addition-elimination mechanism. 

Amides can also be deacylated by partial reduction. If the reduction proceeds only to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroac-etamides are readily cleaved by sodium borohydride in alcohols by this mechanism.237 Benzamides, and probably other simple amides, can be removed by careful partial reduction with diisobutylaluminum hydride (see Section 5.3.1.1).238... 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Wee, T. G., Frey, P. A. Studies on the mechanism of action of uridine diphosphate galactose 4-epimerase. Substate dependent reduction by sodium borohydride. J. Biol. Chem. 248, 33—40 (1973). 

B. (3-Bromo-3,3-difluoropropyl)trimethylsilane. A 1-L, four-necked flask is equipped with a mechanical stirrer, thermometer, Claisen adapter, septum inlet, reflux condenser (the top of which is connected to a calcium chloride drying tube), and a solid addition funnel. The flask is charged with (1,3-dibromo-3,3-difluoropropyl)trimethylsilane (78.3 g, 0.25 mol), and anhydrous dimethyl sulfoxide (200 mL), and the solid addition funnel is charged with sodium borohydride (11.5 g, 0.30 mol) (Notes 7 and 8). The stirred solution is warmed to 80°C, and sodium borohydride is added at a rate sufficient to maintain a reaction temperature of 80-90°C (Note 9). Toward the end of the addition, an additional portion of dimethyl sulfoxide (200 mL) is added via syringe to lower the viscosity of the reaction mixture. After the addition is complete, the mixture is cooled in an ice-water bath, diluted with 100 mL of pentane, and cautiously quenched with 12 M hydrochloric acid until no further gas evolution occurs. The mixture is transferred to a separatory funnel and washed with three, 100-mL portions of 5% brine. The pentane extract is dried over calcium chloride and the solvent removed through a 15-cm Vigreux column. Further fractionation yields 41.5 g (72%) of 3-bromo-3,3-difluoropropyltrimethylsilane, bp 139-141 °C (Note 10). 

R.A. Varin, Ch. Chiu, Structural stability of sodium borohydride (NaBH ) during controlled mechanical milling , J. Alloys Compd. 397 (2005) 276-281. 

A similar mechanism and stoichiometry underlie reactions of organic compounds with lithium and sodium borohydrides. With modified complex hydrides the stoichiometry depends on the number of hydrogen atoms present in the molecule. 

Alkyl bromides and especially alkyl iodides are reduced faster than chlorides. Catalytic hydrogenation was accomplished in good yields using Raney nickel in the presence of potassium hydroxide [63] Procedure 5, p. 205). More frequently, bromides and iodides are reduced by hydrides [505] and complex hydrides in good to excellent yields [501, 504]. Most powerful are lithium triethylborohydride and lithium aluminum hydride [506]. Sodium borohydride reacts much more slowly. Since the complex hydrides are believed to react by an S 2 mechanism [505, 511], it is not surprising that secondary bromides and iodides react more slowly than the primary ones [506]. The reagent prepared from trimethoxylithium aluminum deuteride and cuprous iodide... 

The reaction has broad applications and a large number of secondary and especially tertiary amines was prepared in isolated yields ranging from 60% to 84% [1136]. Although the mechanism of this reaction is not clear it is likely that the key step is reduction of the acid by borane, generated in situ from sodium borohydride and the acid, to an aldehyde which reacts with the amine as described in the section on reductive amination (p. 134-136). 

Strong reducing agents like sodium borohydride and lithium aluminum hydride are capable of reducing aldehydes to primary alcohols and ketones to secondary alcohols. The general reaction is the reverse of the reactions used to form aldehydes and ketones by the oxidation of primary and secondary alcohols, respectively (to review, see the earlier section Oxidation reactions ). However, the mechanisms for reduction are different. 

Sodium borohydride is the reagent of choice for the reduction of the pyridine ring in isoquinolinium salts. It reacts so rapidly that even the carbonyl group of a 1-aroyl substituent can survive (equation 154) (63JCS2487). A 1,2-dihydro intermediate has been isolated during the cyclization of (253) to 2,3-dimethoxyberbine by sodium borohydride, which suggests that a similar mechanism to that described above is operative here (equation 155) (60JOC90). 

Treatment of the reaction mixture with sodium borohydride-f followed by acidic hydrolysis led to major fractions of 6-deoxy-D-glucose-f and D-fucose-t, together with a minor fraction of D-galac-tose-4-f.422 This fact indicates that 109 is formed as an enzyme-bound intermediate, and allows the exclusion of a possible, alternative mechanism, shown in Fig. 3 as B, for the conversion of 107a into 108a through an intermediate glycos-5-ene derivative 111. 

In 1962 too, Fridovich showed that the addition of sodium borohydride to a mixture of acetoacetate decarboxylase and acetoacetate inactivates the enzyme, whereas the addition of borohydride to a buffered solution of the enzyme alone has no effect on the rate at which it can promote the decarboxylation of acetoacetate (Fridovich and Westheimer, 1962) this work confirmed the ketimine mechanism that had previously been advanced for the decarboxylation. Subsequent work (beyond the scope of this review) showed that the reaction product, on hydrolysis, yielded e-isopropyllysine [8], formed by the reduction of the ketimine of acetone (11), and control experiments showed that this ketimine was actually an intermediate in the enzymic pathway, as had been postulated (Warren et al., 1966). 

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