BENZYL CHLORIDE

1

Benzyl Chloride

Ph

Cl

[100-44-7]

C

7

H

7

Cl

(MW 126.59)

InChI = 1/C7H7Cl/c8-6-7-4-2-1-3-5-7/h1-5H,6H2
InChIKey = KCXMKQUNVWSEMD-UHFFFAOYAV

(benzylating agent for a variety of heteroatom functional groups

and carbon nucleophiles; precursor to benzyl organometallics)

Physical Data:

bp 177–181

◦

C; d 1.100 g cm

−3

.

Solubility:

freely miscible in ethereal, chlorinated, and dipolar

aprotic solvents.

Form Supplied in:

99% pure liquid.

Handling, Storage, and Precautions:

the reagent is a mutagen

and possibly a carcinogen. It should be used in a fume hood.

Benzylation of Heteroatom Functional Groups.

Benzyl

chloride is a versatile benzylating agent for heteroatom func-
tional groups and is commonly used to introduce this protecting
group.

1

Benzylation of alcohols with this reagent is achieved

under strongly basic conditions such as KOH, either in an alco-
holic solvent

2

or under phase transfer conditions with n-Bu

4

-

NHSO

4

.

3

Silver oxide in DMF is also effective.

4

A procedure

involving Ni(acac)

2

has also been reported.

5

Phenols may also be

benzylated under basic conditions.

6

Amino groups are readily benzylated when treated with benzyl

chloride in the presence of carbonate or hydroxide base,

5

although

dibenzylation of primary amines is a competing reaction.

7

Thiols

are benzylated with sodium hydroxide or cesium carbonate in po-
lar solvents such as ethanol or DMF.

8

Dibenzyl sulfide is produced

by reaction of benzyl chloride with elemental sulfur and sodium
triethylborohydride.

9

Amides can be N-benzylated with this reagent under the

influence of strong bases such as metal hydrides.

10

A benzyl car-

boxylate ester may be formed from benzyl chloride and the cor-
responding sodium salt of the acid in DMSO.

11

Benzyl cyanide can be prepared from benzyl chloride and KCN

with an ion exchange resin.

12

Benzyl azide is formed by reaction

with trimethylsilyl azide in HMPA.

13

Benzylation of Active Methylene Compounds.

The an-

ions or dianions of β-ketoesters,

14

substituted malonate esters,

15

β

-ketoaldehydes,

16

β

-diketones,

17

β

-ketoamides,

18

and β-

ketonitriles

19

all react effectively with benzyl chloride to afford

C

-benzylated products. When the dianion of a β-ketoamide,

β

-ketoester, or β-diketone is generated and treated with benzyl

chloride, benzylation is observed at the least acidic position.
Nitrile-stabilized carbanions are readily benzylated in ethereal
solvents, ammonia, or DMSO.

15,20

Benzyl chloride also reacts

well with carbanions derived from ketones,

21

esters,

22

imines

(metalloenamines),

23

oximes,

24

and hydrazones.

23

When benza-

lacetophenone is treated sequentially with 2 equiv of potassium in
ammonia and then with benzyl chloride in ether, a formal conju-
gate addition of the benzyl group is observed (eq 1).

25

If a second

equivalent of benzyl chloride is added, benzylation occurs at both
the α- and β-positions.

Ph

Ph

O

Ph

Ph

O

Ph

1. K (2 equiv), NH

3

(1)

2. BnCl (1 equiv)
Et

2

O

73%

Reactions with Metals and Organometallics. Benzylmag-

nesium chloride can be prepared satisfactorily by rapid addi-
tion of benzyl chloride to magnesium in ether.

26

Benzyl chlo-

ride is readily dimerized by lithium naphthalenide,

27

sodium and

tetraphenylethane,

28

zinc in the presence of catalytic nickel(II)

bromide,

29

with titanocene dichloride and diiodomethane,

30

(PPh

3

)

3

CoCl,

31

and by electrolysis.

32

The cross-coupling reac-

tions of benzyl chloride with other organometallics is demon-
strated by the benzylation of organolithiums,

33

as in the case

of a directed lithiation product (eq 2),

32a

Grignard reagents,

34

and organocuprates.

35

Vinyl boranes, derived from the addition

of boron tribromide to alkynes and subsequent alkylation with
organozincs (eq 3),

35a

couple with benzyl chloride under palla-

dium catalysis.

36

Benzyl chloride will add to an α-diketone in the

presence of powdered nickel to give the α-ketol (eq 4).

37

(2)

Li

N(i-Pr)

2

O

SPh

Bn

N(i-Pr)

2

O

SPh

BnCl, THF

83%

Ph

Bn

1. BBr

3

, CH

2

Cl

2

2. PhZnCl, PdCl

2

(PPh

3

)

2

(3)

3. BnCl

77%

(4)

O

O

O

HO Bn

BnCl

Ni

0

powder

DME

78%

1.

(a) Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic
Synthesis

, 2nd ed.; Wiley: New York, 1991. (b) Protective Groups in

Organic Chemistry

, McOmie, J. F. W., Ed.; Plenum: New York, 1973.

2.

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3.

Freedman, H. H.; Dubois, R. A., Tetrahedron Lett. 1975, 3251.

4.

Kuhn, R.; Löw, I.; Trischmann, H., Chem. Ber. 1957, 90, 203.

5.

Yamashita, M.; Takegami, Y., Synthesis 1977, 803.

6.

Heer, J.; Billeter, J. R.; Miescher, K., Helv. Chim. Acta 1945, 28, 991.

7.

Velluz, L.; Amiard, G.; Heymès, R., Bull. Soc. Chem. Fr., Part 2 1954,
1012.

8.

(a) Frankel, M.; Gertner, D.; Jacobson, H.; Zilkha, A., J. Chem. Soc.
1960, 1390. (b) Vogtle, F.; Klieser, B., Synthesis 1982, 294.

9.

Gladysz, J. A.; Wong, V. K.; Jick, B. S., J. Chem. Soc., Chem. Commun.
1978, 838.

10.

(a) Xia, Y.; Kozikowski, A. P., J. Am. Chem. Soc. 1989, 111, 4116.
(b) Bryant, D. R.; Work, S. D.; Hauser, C. R., J. Org. Chem. 1964, 29,
235.

Avoid Skin Contact with All Reagents

2

BENZYL CHLORIDE

11.

Shaw, J. E.; Kunerth, D. C.; Sherry, J. J., Tetrahedron Lett. 1973, 689.

12.

Sukata, K., J. Org. Chem. 1985, 50, 4388.

13.

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14.

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J. Am. Chem. Soc. 1946

, 68, 1053.

15.

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16.

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, 24, 959.

17.

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18.

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19.

Baraldi, P. G.; Pollini, G. P.; Zanirato, V., Synthesis 1985, 969.

20.

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21.

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22.

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23.

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24.

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91

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25.

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26.

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27.

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28.

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29.

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30.

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31.

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32.

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33.

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34.

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35.

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36.

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37.

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William E. Bauta

Sandoz Research Institute, East Hanover, NJ, USA

A list of General Abbreviations appears on the front Endpapers