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Reduction of Acid Chlorides to Aldehydes
using Sodium Borohydride and Pyridine

James H. Babler
Synthetic Communications 12(11), 839-846 (1982)

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Abstract

By use of sodium borohydride in N,N-dimethylformamide solution containing a molar excess of pyridine as a borane scavenger, direct conversion of both aliphatic and aromatic acid chlorides to the corresponding aldehydes can be achieved in >70% yield with minimal (5-10%) alcohol formation.

One of the most useful synthetic transformations in organic synthesis is the conversion of an acid chloride to the corresponding aldehyde without overreduction to the alcohol. Until recently, this type of selective reduction was difficult to accomplish and was most frequently effected by catalytic hydrogenation (the Rosenmund reduction1). However, in the past few years, several novel reducing agents have been developed2 to accomplish the desired transformation.

In view of its selectivity as a reducing agent, ease of handling, and low cost, sodium borohydride would seem to be an attractive reagent for effecting the selective reduction of an acid chloride to an aldehyde. However, the latter transformation was consistently reported to occur with overreduction to the alcohol until Johnstone and coworkers3 discovered that the intermediate aldehyde could indeed be isolated in fair to good yield if such reductions are conducted at 0C in acetonitrile in the presence of certain metal ions complexed with N,N-dimethylformamide (DMF). In the absence of metal salts aldehydes were isolated, albeit in low yield, only if the reduction was effected at -70C.

Since this metal-assisted borohydride reduction of acyl halides suffers from low to moderate yields (24-58%) obtained with aliphatic compounds and results in a significant amount (always >10%) of alcohol from overreduction, we decided to investigate the reaction further. Our initial studies4 revealed that sodium borohydride in a mixture of DMF-tetrahydrofuran (THF) is capable of converting both aliphatic and aromatic acyl chlorides to the corresponding aldehydes in high yield without the presence of any additional metal salts if the reaction is quenched by use of a mixture of propionic acid - dilute hydrochloric acid - ethyl vinyl ether. Unfortunately, aldehydes could be isolated in good yield using this methodology only if the reaction was conducted at low temperature. For example, treatment5 of o-chlorobenzoyl chloride with sodium borohydride in DMF - THF at -70C afforded a product mixture containing the corresponding aldehyde and alcohol in a 5:1 ratio. However, a similar experiment6 conducted at 0C resulted in a substantial amount of overreduction since o-chlorobenzyl alcohol comprised 75% of the product mixture. Somewhat unexpectedly, doubling the reaction time prior to the quench had little effect on the overreduction in the latter reaction an indication that overreduction might be occurring during the quench. Since the procedures used in quenching the reactions at -70C and 0C were virtually identical7, this disparity of results offers further evidence8 of the stability of the initial reaction intermediate (1) at -70C (and lack thereof, with generation of borane, at 0C).

In addition to the disadvantage of requiring a low reaction temperature, our previous methodology4 presented two other difficulties. The aldehydes in all cases were contaminated with varying amounts of material derived from ethyl vinyl ether; and the unusual quench presented a serious hazard due to the vigorous evolution of hydrogen. This communication reports that such problems can be circumvented if the reduction is effected in the presence of pyridine, which serves as an efficient scavenger of the borane presumably liberated9 if the reaction is conducted at 0C.

In contrast to the results obtained at 0C in the absence of pyridine, it was found that treatment of o-chlorobenzoyl chloride with sodium borohydride in DMF-THF containing a molar excess of pyridine using a procedure only slightly different10 from that described below afforded the corresponding aldehyde contaminated with less than 20% of the corresponding alcohol. Accompanying these two products was a substantial amount of pyridine borane (2)11. The apparent stability of the latter compound (2) in the presence of the aldehyde is consistent with the known12 properties of this reducing agent i.e., it reduces aldehydes and ketones only at elevated temperature. Since pyridine borane is virtually insoluble in water and very soluble in ether, a chromatographic separation seemed called for. Unexpectedly, when the aldehyde-pyridine borane mixture was applied neat to a column of Florisil13, rapid elution with 84:16 hexane/ether did succeed in leaving pyridine borane on the column but afforded a 95:5 mixture of alcohol:aldehyde! Equally frustrating were attempts to destroy pyridine borane with strongly acidic quenches (20mL of 2M aqueous hydrochloric acid; 20mL of propionic acid- 9mL of 4M aqueous hydrochloric acid) prior to reaction workup. Such efforts consistently led to a reaction product in which only alcohol could be detected by both NMR and IR analysis! In retrospect, such observations are consistent with the enhanced reducing properties amine borane complexes are known14 to exhibit in the presence of Lewis acids.

Table I

Starting Acid Chloridea
Yieldb
Aldehyde:Alcohol Ratioc
o-Chlorobenzoyl chloride
77%
8:1
Lauroyl chloride
76%
12:1
10-Undecenoyl chloride
74%
10:1

a) Aldrich Chemical Co., Milwaukee, Wisconsin, U.S.A.
b) This yield is based on the molar amount of NaBH4
utilized for the reaction and refers to distilled product.
c) Determined by NMR (CHO vs. CH2OH signals).
For the aliphatic substrates, product ratios were
determined by GC. Retention times: alcohol>aldehyde.

Eventually a facile method (see the following procedure) was developed to remove pyridine borane in a non-destructive manner from the reaction mixture prior to isolation of the aldehyde. As the results in Table I indicate, this methodology seems to be applicable to both aromatic and aliphatic acid chlorides. A more detailed study of this reduction, including its scope and use of other types of borane scavengers15, is presently being initiated and results will be reported in a future article.

Experimental

Standard Reduction Procedure16

To a solution of 129 mg (3.4 mmoles) of sodium borohydride and 2.0 mL of pyridine in 5.0 mL of DMF and 3.0 mL of anhydrous THF cooled to approximately 0C (external bath temperature) was added rapidly (<5 seconds) a solution of 4.0 mmoles of an acyl chloride in 2.0 mL of anhydrous THF. This mixture was subsequently stirred at 0C for 1 minute before 0.50 mL of water was added to the flask to hydrolyze the excess acid chloride. Stirring of this mixture was continued at 0C for an additional 60 seconds, after which 50 mL of 4:1 (v/v) hexane: solvent ether was quickly introduced into the flask. The globules of pyridine borane which appeared at this point can be separated from the reaction product by rapid filtration of the reaction mixture through a small column of Florisil (25 mL). An additional 25 mL portion of 4:1 (v/v) hexane: solvent ether was used to rinse out the reaction flask and ensure quantitative elution of the desired aldehyde (and any of the corresponding alcohol17) from the Florisil column18. 25 mL of ether was added to the combined filtrate, and this organic phase was washed successively with 15% aqueous NaCl (2x100mL), 1:1 (v/v) 2M aqueous hydrochloric acid:brine (1x100mL), 4:1 (v/v) 1M aqueous NaOH:brine (2x100mL), and saturated brine (100 ml). The organic layer was then dried (MgSO4) and the solvent removed in vacuo.

References and Notes

  1. For a review see: Mossettig, E. and Mozingo, R., Org. Reactions, 4, 362 (1948)
  2. Among the reagents that are available for the partial reduction of acyl chlorides to aldehydes are:
    1. bis(Triphenylphosphine)cuprous borohydride [See: Fleet, G.W.J., Fuller, C.J., and Harding, P.J.C., Tetrahedron Lett., 1437 (1978); Sorrell, T.N. and Spillane, R.J., Tetrahedron Lett., 2473 (1978); Sorrell, T.N. and Pearlman, P.S., J. Org. Chem., 45, 3449 (1980)]
    2. Lithium tri-tert-butoxyaluminum hydride [See: Brown, H.C. and Subba Rao, B.C., J. Am. Chem. Soc., 80, 5377 (1958)]
    3. Complex copper cyanotrihydridoborate salts [See: Hutchins, R.O. and Markowitz, M., Tetrahedron Lett., 21, 813 (1980)]
    4. Anionic iron carbonyl complexes [See: Watanabe, Y., Mitsudo, T., Tanaka, M., Yamamoto, K., Okajima, T., and Takegami, Y., Bull. Chem. Soc. Jpn., 44, 2569 (1971); Cole, T.E. and Pettit, R., Tetrahedron Lett., 781 (1977)]
    5. Tri-n-butyltin hydride in the presence of tetrakis(triphenylphosphine)palladium(0) [See: Four, P. and Guibe, F., J. Org. Chem., 46, 4439 (1981)]
  3. Johnstone, R.A.W. and Telford, R.P., J. Chem. Soc., Chem Commun., 354 (1978)
  4. Babler, J.H. and Invergo, B.J., Tetrahedron Lett., 22, 11 (1981)
  5. Procedure A described in our previous communication (ref 4) was utilized for this reaction.
  6. The procedure utilized involved rapid addition (5-10 seconds) of a solution of 3.4 mmoles of NaBH4 in 5mL of DMF to 4.0 mmoles of o-chlorobenzoyl chloride dissolved in 6.0mL of anhydrous THF at 0C, followed by stirring of the mixture for an additional 60 seconds at 0C and rapid quenching with propionic acid - dilute hydrochloric acid - ethyl vinyl ether (at either 0C or ambient temperature).
  7. To ascertain if the temperature of the quenching mixture had any effect on the extent of overreduction, the reduction conducted at 0C was quenched in a mixture of propionic acid - dilute aqueous hydrochloric acid - ethyl vinyl ether at both 0C and ambient temperature. In both experiments, identical aldehyde:alcohol ratios were obtained.
  8. Previous experiments4 had demonstrated that surprisingly no precipitate of sodium chloride was observed if slightly less than one molar equivalent of NaBH4 was utilized for the reduction of acyl chlorides at -70C an indication that the initial reaction intermediate (1) might be stable under these conditions. In sharp contrast, similar reductions at 0C led to instantaneous formation of a white precipitate (presumably NaCl).
  9. Results of studies conducted at 0C using o-chlorobenzoyl chloride appear to indicate that pyridine borane (2) may actually be formed by direct reaction between pyridine and intermediate 1 (prior to its collapse). For example, if the addition of pyridine was delayed until 1 minute after the addition of the acid chloride, the product mixture contained approximately 90% alcohol. No significant decrease in overreduction was observed if 1-2 minutes was allotted after addition of pyridine before the quench with 0.5 mL of water. Apparently the reaction between pyridine and borane (once liberated) is not that facile under these conditions.
  10. The procedure was identical to that described in this communication with the following exceptions: (a) the reaction mixture was diluted with 50 mL of solvent ether one minute after the addition of 0.50 mL of water; (b) no filtration through Florisil was performed; and (c) the 2M aqueous hydrochloric acid:brine wash was omitted.
  11. This compound is readily characterized by a strong infrared absorption band at 2360 cm-1.
  12. Barnes, R.P., Graham, J.H., and Taylor, M.D., J. Org. Chem., 23, 1561 (1958)
  13. Further studies of the enhanced reducing properties of pyridine-borane on Florisil and other solid supports are now in progress.
  14. Andrews, G.C. and Crawford, T.C., Tetrahedron Lett., 21, 693 (1980) and references therein.
  15. Ethyl vinyl ether has now been shown to be much less effective than pyridine in preventing overreduction of the aldehyde during the reaction quench. Rapid addition of 4 mmoles of o-chlorobenzoyl chloride in 2 mL of anhydrous THF to a solution of 3.4 mmoles of NaBH4 in 5 mL of DMF - 2mL of THF - 3 mL of ethyl vinyl ether at 0C, followed by stirring of this mixture for 60 seconds at 0C and subsequently quenching with 5 mL of 1:1 (v/v) acetic acid:water, led to isolation of a product mixture containing >85% of the undesired alcohol. Such results seem to indicate that the borane liberated during the reduction of the acid chloride does not rapidly react with ethyl vinyl ether in THF-DMF at 0C. As expected, during the acidic quench further reduction of the aldehyde can occur.
  16. All reactions were run under a nitrogen atmosphere. DMF and pyridine, spectrophotometric grade, were purchased from Aldrich Chemical Co. and were not further purified.
  17. Authentic samples of the alcohols obtained as minor by-products in these reductions were readily recoverable from a Florisil column by elution with 9:1 hexane/ether.
  18. The pyridine borane adsorbed on the Florisil column could be destroyed by addition of the packing in small portions to a beaker containing 50 mL of 2M aqueous hydrochloric acid (Caution: H2 evolution!).