COPPER(II) BROMIDE

1

Copper(II) Bromide

CuBr

2

[7789-45-9]

Br

2

Cu

(MW 223.36)

InChI = 1/2BrH.Cu/h2*1H;/q;;+2/p-2/f2Br.Cu/h2*1h;/q2*-1;m/

rBr2Cu/c1-3-2

InChIKey = QTMDXZNDVAMKGV-NZVHWWHRCV

(brominating agent; oxidizing agent; Lewis acid)

Alternate Name:

cupric bromide.

Physical Data:

mp 498

◦

C; d 4.770 g cm

−3

.

Solubility:

very sol water; sol acetone, ammonia, alcohol;

practically insol benzene, Et

2

O, conc H

2

SO

4

.

Form Supplied in:

almost black solid crystals or crystalline

powder; also supplied as reagent adsorbed on alumina (approx.
30 wt % CuBr

2

on alumina).

Purification:

recryst from H

2

O and dried in vacuo.

35

Handling, Storage, and Precautions:

anhydrous reagent is

hygroscopic and should therefore be stored in the absence of
moisture.

Original Commentary

Nicholas D. P. Cosford
SIBIA, La Jolla, CA, USA

α

α

α

-Bromination of Carbonyls.

Copper(II) bromide is an effi-

cient reagent for the selective bromination of methylenes adjacent
to carbonyl functional groups.

1

Thus 2

′

-hydroxyacetophenone

treated with a heterogeneous mixture of CuBr

2

in CHCl

3

–EtOAc

gives complete conversion to 2-bromo-2

′

-hydroxyacetophenone

with no aromatic ring bromination (eq 1).

2

OH

O

CuBr

2

,

∆

EtOAc-CHCl

3

100%

OH

O

(1)

Br

Similar selectivity is obtained with a homogeneous solu-

tion of the reagent in dioxane.

3

A limitation of the reaction is

observed with 2

′

-hydroxy-4

′

,6

′

-dimethoxyacetophenone, which

undergoes aromatic nuclear bromination with CuBr

2

.

4

Steroidal

ketones have been selectively α-brominated with CuBr

2

in the

presence of a double bond without bromination of the alkene
(eq 2),

5

while γ-bromination occurs in other steroidal enones.

1

AcO

O

AcO

O

CuBr

2

THF

(2)

Copper(II) bromide has been used to α-brominate diketotetra-

quinanes

6

and to introduce a double bond into a prostanoid

nucleus in a one-pot bromination–elimination procedure (eq 3).

7

3,7-Dibromo-2H,6H-benzodithiophene-2,6-diones (eq 4)

8

and 5-

bromo-4-oxo-4,5,6,7-tetrahydroindoles (eq 5)

9

are prepared by

the selective α-bromination of their respective ketone starting
materials without bromination of the aromatic or heterocyclic
rings. 4-Carboxyoxazolines are converted to the corresponding
oxazoles using a mixture of CuBr

2

and 1,8-Diazabicyclo[5.4.0]

undec-7-ene

(eq 6).

10

O

CO

2

Me

O

CO

2

Me

CuBr

2

,

∆

EtOAc-CHCl

3

66%

6

6

(3)

CuBr

2

MeOH

83%

S

O

S

O

S

O

S

O

Br

(4)

Br

(5)

CuBr

2

EtOAc,

∆

R = Ts, 98%
R = Bz, 74%

N

R

O

N

R

O

Br

(6)

CuBr

2

, DBU

X = OR, NR

2

X

N

O

O

R

X

N

O

O

R

EtOAc-CHCl

3

Bromination of Alkenes and Alkynes.

Heating copper(II)

bromide in methanol with compounds containing nonaromatic
carbon–carbon multiple bonds leads to di- or tribromination.

11

For example, under these conditions allyl alcohol is converted
to 1,2-dibromo-3-hydroxypropane in 99% yield (eq 7), while
propargyl alcohol produces a mixture of trans di- and tribromo-
allyl alcohols (eq 8). 2

′

-Hydroxy-5

′

-methyl-4-methoxychalcone

undergoes a bromination–ring-closure reaction, affording 3-
bromo-6-methyl-5

′

-methoxyflavanone when heated with CuBr

2

in refluxing dioxane (eq 9).

12

The mechanism of the bromination

of cyclohexene to 1,2-dibromocyclohexane with CuBr

2

has been

studied.

13

CuBr

2

MeOH

99%

OH

Br

OH

Br

(7)

CuBr

2

MeOH

99%

OH

Br

Br

OH

Br

OH

Br

Br

(8)

+

30%

18%

CuBr

2

dioxane

∆

Ar

O

OH

O

Br

Ar

O

(9)

Avoid Skin Contact with All Reagents

2

COPPER(II) BROMIDE

Bromination of Aromatics.

Aromatic systems are bromi-

nated by copper(II) bromide. For example, 9-bromoanthracene
is prepared in high yield by heating anthracene and the reagent
in carbon tetrachloride (eq 10).

14

When the 9-position is blocked

by a halogen, alkyl, or aryl group, the corresponding 10-
bromoanthracene is formed.

15

Under similar conditions, 9-

acylanthracenes

give

9-acyl-10-bromoanthracenes

as

the

predominant products.

16

The aromatic nuclear bromination of

monoalkylbenzenes has been shown to proceed cleanly under
strictly anhydrous conditions (eq 11).

17a

Polymethylbenzenes are

efficiently and selectively converted to the nuclear brominated
derivatives by CuBr

2

/Alumina.

17b

In the absence of alumina,

a mixture of products resulting from benzylic halogenation is
isolated. 3-Acetylpyrroles are nuclear monobrominated at the
4-position in high yield by CuBr

2

in acetonitrile at ambient

temperature (eq 12).

18

The reaction also proceeds with ethyl

3-pyrrolecarboxylates to give 4-bromopyrrole derivatives,

19

while an excess of brominating agent at 60

◦

C affords 4,5-

dibromopyrroles.

20

CuBr

2

∆

H

R

Br

R

(10)

R = H, Me, Ph, Ac

CuBr

2

D

Br

Br

(11)

+

1:2

CuBr

2

MeCN

25 °C

N

Ph

O

X

R

2

R

1

N

Ph

O

X

R

2

R

1

Br

(12)

Bromination of Allylic Alcohols.

Silica gel-supported

copper(II) bromide has been used for the regioselective bromi-
nation of methyl 3-hydroxy-2-methylenepropanoates and 3-
hydroxy-2-methylenepropanenitriles (eq 13).

21a

In the absence

of silica gel, no reaction occurs between CuBr

2

and these sub-

strates, while adsorption onto Al

2

O

3

, MgO, or TiO

2

leads to

side reactions rather than the clean allylic bromination observed
with CuBr

2

/SiO

2

. The reaction is stereoselective with respect to

formation of the (Z) isomer.

CuBr

2

SiO

2

Ar

HO

X

Ar

X

Br

(13)

X = CO

2

Me, CN

Benzylic Bromination.

Toluene and substituted methyl-

benzenes undergo benzylic bromination using CuBr

2

and tert-

Butyl Hydroperoxide

in acetic acid or anhydride (eq 14).

21b

While

the yields (43–95%) are not quite as high as those obtained using
N-Bromosuccinimide

, the copper(II) bromide procedure allows

the benzylic bromination of compounds which are insoluble in
nonpolar solvents.

CuBr

2

t

-BuOOH

Br

X

AcOH, D

43–95%

X

(14)

X = H, hal, CO

2

H

Esterification Catalyst.

Highly sterically hindered esters are

prepared by the reaction of S-2-pyridyl thioates and alcohols in
acetonitrile with copper(II) bromide as the catalyst.

22

The reac-

tion proceeds at ambient temperature under mild conditions and
affords high yields of a range of sterically crowded esters such as
t

-butyl 1-adamantanecarboxylate (eq 15).

t

-BuOOH

CuBr

2

MeCN

25 °C

89%

N

S

O

O-t-Bu

O

(15)

Conjugate Addition Catalyst.

The 1,4-addition of Grig-

nard reagents to α,β-unsaturated esters is promoted by catalytic
CuBr

2

(1–5 mol %) with Chlorotrimethylsilane/HMPA (eq 16).

23

Under these conditions the copper(II) species is not reduced by
the Grignard reagent, resulting in high yields of the conjugate
addition products.

CuBr

2

TMSCl

HMPA

n

-BuMgBr

99%

CO

2

Me

CO

2

Me

n

-Bu

(16)

Oxidation of Stannanes and Alcohols.

Allylstannanes have

been oxidized with copper(II) bromide in the presence of vari-
ous nucleophilic reagents (H

2

O, ROH, AcONa, RNH

2

) to afford

the corresponding allylic alcohols, ethers, acetates, and amines.

24

This chemistry has been extended to trimethylsilyl enol ethers,
which undergo a CuBr

2

-induced carbon–carbon bond forming

process with allylstannanes (eq 17).

25

Alkoxytributylstannanes

may be converted to the corresponding aldehyde or ketone with
two equivalents of CuBr

2

/Lithium Bromide in THF at ambi-

ent temperature (path a, eq 18).

26

A combination of copper(II)

bromide/Lithium tert-Butoxide oxidizes alcohols to carbonyl
compounds quite rapidly and in high yield (path b, eq 18).

27

A list of General Abbreviations appears on the front Endpapers

COPPER(II) BROMIDE

3

CuBr

2

CHCl

3

25 °C

R

SnBu

3

OTMS

O

R

(17)

+

R = Ph(Ch

2

)

2

, 57%

(a) or (b)

OX

R

1

H

R

2

R

1

R

2

O

(18)

(a) X = SnBu

3

(a) = CuBr

2

, LiBr, Bu

3

SnO-t-Bu

(b) X = h

(b) = CuBr

2

, LiO-t-Bu

Desilylbromination.

β

-Silyl ketones are desilylbrominated

to α,β-unsaturated ketones with CuBr

2

in DMF.

28

This occurs

spontaneously in cyclic ketones, while with open-chain ketones
sodium bicarbonate is required to eliminate HBr from the
β

-bromo ketone thus formed. The carbon–silicon bond in organo-

pentafluorosilicates prepared from alkenes and alkynes is cleaved
with copper(II) bromide to give the corresponding alkyl and
alkenyl bromides (eq 19).

29

The reaction is stereoselective; thus

(E)-alkenyl bromides are obtained from (E)-alkenylsilicates.

K

2

1. HSiCl

3

H

2

PtCl

6

2. KF

R

1

R

SiF

5

R

R

1

R

1

R

Br

(19)

CuBr

2

Reagent in the Sandmeyer and Meerwein Reactions.

Diazonium salts of arylamines are converted to aryl halides
(Sandmeyer reaction)

30

in the presence of copper(II) halides.

Recent procedures have utilized t-butyl nitrite/CuBr

2

31

or t-butyl

thionitrite/CuBr

2

32

combinations to afford aryl bromides from

the corresponding arylamines in high yields (eq 20). The copper
salt-catalyzed haloarylation of alkenes with arenediazonium salts
(Meerwein reaction) also proceeds with copper(II) halides. For
example, treatment of p-aminoacetophenone with t-butyl nitrite/
CuBr

2

in the presence of excess acrylic acid gives p-acetyl-

α

-bromohydrocinnamic acid (59% yield, eq 21).

33

The intra-

molecular version of this reaction, which affords halogenated
dihydrobenzofurans, has been accomplished by reacting arene-
diazonium tetrafluoroborates with CuBr

2

in DMSO (eq 22).

34

Br

NH

2

X

X

CuBr

2

t

-BuONO

MeCN, D

(20)

X = H, hal, CO

2

R, NO

2

, OMe, etc.

CuBr

2

t

-BuONO

MeCN, 25 °C

59%

NH

2

O

CO

2

H

O

Br

CO

2

H

(21)

+

CuBr

2

DMSO

25 °C

82%

N

2

BF

4

–

O

O

Br

(22)

First Update

Liming Zhang & Guotao Li
University of Nevada, Reno, NV, USA

α

α

α

-Bromination

of

Carbonyl

Groups

and

One-pot

Elimination.

CuBr

2

α

-brominates a variety of carbonyl com-

pounds. Recent examples include regioselective α-bromination
of enone esters with carefully controlled reaction temperature
(eq 23),

36

α

,α

′

-dibromination of ketones (eq 24),

37

and α-

bromination of 2-acetyl-5-methylthiothiophene.

38

Subsequent

one-pot elimination of HBr to yield alkenes is viable when an
aromatic ring is formed

39

and/or the β-hydrogen is acidic.

40

Interestingly, for β-dimethylphenylsilylketones, bromination
is followed by debromosilation during the reaction, affording
enones directly (eq 25).

41,42

EtO

Ph

O

O

EtO

Ph

O

O

Br

CuBr

2

, CHCl

3

EtOAc, 55 °C, 2 h

72%

(23)

O

H

H

O

H

H

Br

Br

OH

H

CuBr

2

, MeCN

50 °C, 72 h

(+)-totarol

(24)

76%

Me

Me

O

Si

Ph

Me

O

Me

CuBr

2

, CHCl

3

AcOEt, 1 h, reflux

(25)

55%

Bromination and Bromocyclization of C–C π

π

π

Bonds.

Dibromination of alkenyl glycosides is realized in excellent yields
with the combination of CuBr

2

/LiBr (1:2). This reagent combi-

nation performs much better than Br

2

/Et

4

NBr and NBS/Et

4

NBr

with phthaloyl-protected glucosamines and tolerates a range of
carbohydrate protecting groups (eq 26).

43

In the presence of

an appropriate internal nucleophile, bromocyclization of C–C
π

bonds takes place. For example, β-bromobutenolides are ob-

tained in excellent yields from 2,3-allenoic acids in the presence
of 4 equiv of CuBr

2

(eq 27),

44

Moreover, CuBr

2

-mediated bro-

mocyclization of 2-alkynylthioanisoles and 2-alkynylbenzoates
(assisted by 0.1 equiv of Cy

2

NH · HBr) affords 2-substituted

3-bromobenzo[b]thiophenes

45

and

5-bromoisocoumarins,

46

respectively, in generally good yields. Bromolactonization with

Avoid Skin Contact with All Reagents

4

COPPER(II) BROMIDE

CuBr

2

/Al

2

O

3

47

has been used as key step in the synthesis of

(−)-stemoamide (eq 28).

48,49

O

BnO

OBn

NPhth

OBn

O

O

BnO

OBn

NPhth

OBn

O

Br

Br

CuBr

2

(5 equiv)/LiBr

2

(10 equiv)

MeCN:THF(3:1), rt, 16 h

99%

(26)

•

Me

CO

2

H

O

O

Br

Me

CuBr

2

(4 equiv)

Acetone:H

2

O (2:1)

65–70 °C, 2 h

98%

(27)

N

O

H

Me

MeO

2

C

O

H

O

O

Me

Br

N

N

O

H

O

O

Me

Et

3

N

+

25%

31%

1. NaOH
2. CuBr

2

/Al

2

O

3

CHCl

3

(28)

Bromination of Alkylidenecyclopropanes.

Depending on

the amount of CuBr

2

, di- or tetrabromination of benzylidene-

cyclopropane can be realized (eq 29). Using 2 equiv of CuBr

2

,

synthetically useful Z-2,4-dibromobutenes are formed in excel-
lent yields.

50

Cyclopropylideneacetic acids and/or esters, upon

reacting with CuBr

2

at 85

◦

C, undergo rearrangement, yielding

either furanones or dihydropyranones depending on the α-
substitution (eq 30).

51

Ph

Ph

Br

Br

Ph

Br

Br

Br

Br

CuBr

2

(2 equiv)

65 °C, 14 h, MeCN

82%

CuBr

2

(4 equiv)

85 °C, 4 h, MeCN

82%

(29)

COOEt

R

O

O

Br

O

O

Br

Me

79%

CuBr

2

, 85 °C, 30 h

MeCN/H

2

O (4:1)

R = H

R = Me

CuBr

2

, 85 °C, 10 h

MeCN/H

2

O (4:1)

81%

(30)

Bromination of Aromatics.

Various azaindoles and diaza-

indoles have been selectively brominated at the 3-position in good
efficiency with CuBr

2

, even in the presence of electron-rich aryl

substituents (eq 31).

52,53

Similarly, CuBr

2

selectively brominates

the pyrrole ring of 2-(2

′

-hydroxybenzoyl)pyrrole, yielding the 4,5-

dibrominated product in 95% yield.

54

N

N
H

O

Br

O

N

N
H

CuBr

2

(3 equiv)

MeCN, rt

90%

(31)

Conversion of Hydrazones into gem-Dibromides.

Treat-

ment of hydrazones derived from either aliphatic aldehydes or
ketones with CuBr

2

/LiO

t

Bu gives gem-dibromides in fair to good

yields (eq 32 ).

55

Moreover, LiO

t

Bu can be conveniently replaced

with Et

3

N without affecting yield.

56

The hydrazone prepared from

α

-tetralone leads to the vinyl bromide instead,

57

but an aromatic

aldehyde has been converted into an α,α-dibromotoluene deriva-
tive via the hydrazone intermediate.

58

O

Br

Br

1. NH

2

NH

2

, MeOH, 4 Å MS, rt

2. LiO

t

Bu-CuBr

2

, rt

81%

E

:Z = 3:2

E

:Z = 3:2

82%

1. NH

2

NH

2

, MeOH, 4 Å MS, rt

2. CuBr

2

, Et

3

N, 0 °C

(32)

Oxidation of Amines.

Secondary amines are oxidized to

imines by premixed CuBr

2

/LiO

t

Bu in good yields in less than

30 mins.

59

For unsymmetrical cases such as benzyl alkyl amines,

benzylic oxidation is preferred (eq 33). Primary amines can be
oxidized to nitriles with slightly more than 4 equiv of the reagent.
Nitriles are also prepared in good yields from α-monosubstituted
glycines using the same reagent (eq 34), while ketones are
obtained from α,α-disubstituted glycines after hydrolysis, and
from α,α-disubstituted α-hydroxy acids.

60

A list of General Abbreviations appears on the front Endpapers

COPPER(II) BROMIDE

5

Ph

N
H

MeO

N

MeO

Ph

N

MeO

Ph

3 : 2

95%

LiO

t

Bu-CuBr

2

(2.2 equiv)

THF, rt, 22 min

(33)

LiO

t

Bu-CuBr

2

(4.4 equiv)

THF, rt, 2.5 h

72%

COO

–

NH

3

N

(34)

Oxidation of 1,2-Diols.

CuBr

2

/LiO

t

Bu oxidatively cleaves

tert

-1,2-diols at ambient temperature, yielding ketones. This

method is particularly useful for oxidizing trans-cyclic diols,
where NaIO

4

is ineffective and toxic Pb(OAc)

4

performs the

reaction only slowly.

61

Oxidation of N

′′′

-Phenylhydrazides.

CuBr

2

/LiO

t

Bu also

oxidizes N

′

-phenylhydrazides efficiently, converting them into

t

-butyl esters in fair to good yields (eq 35).

62

The parent

hydrazides do react but less efficiently.

Cbz

H
N

N
H

NHPh

O

Me

Me

Cbz

H
N

O

t

Bu

O

Me

Me

LiO

t

Bu-CuBr

2

(4 equiv)

THF, rt, 2 h

78%

(35)

Oxidation of Primary Carboxamides and N-Substituted

Ureas.

CuBr

2

/LiO

t

Bu oxidizes primary carboxamides to

N

-(t-butoxycarbonyl)amines in good yields (eq 36).

63

Sim-

ilar to Hoffmann reaction, a nitrene intermediate is pro-
posed. Hindered amides are also substrates, but oxidation of
3-phenylpropionamide gives poor results. Similarly, the car-
bamoyl group in N-substituted ureas can be oxidized to a
nitrene-type intermediate, which upon dimerization and fur-
ther oxidation, yields Boc-protected amines.

64

CuBr

2

works

well with N-arylureas (eq 37), but CuCl

2

is preferred with

N

-alkylureas. N,N-Disubstituted ureas do not afford the car-

bamates. The proposed intermediates, N,N

′

-dialkyldiazenedi-

carboxamides, can be easily prepared and indeed are oxidized
readily by CuBr

2

/LiO

t

Bu to render Boc-protected amines (eq 38).

To avoid the strong basicity of lithium tert-butoxide, lithium
4-nitrophenoxide is a viable alternative. Moreover, this improved
oxidizing system allows one-pot synthesis of trisubstituted ureas
via in situ trapping of the isocyanate intermediate.

65

NH

2

O

Me

H
N

CO

2

t

Bu

Me

LiO

t

Bu-CuBr

2

(4.2 equiv)

THF, rt, 3 h

93%

(36)

Me

N
H

O

t

Bu

O

Me

N
H

NH

2

O

85%

LiO

t

Bu-CuBr

2

(4.2 equiv)

THF, 50 °C, 5 min

(37)

N
H

O

t

Bu

O

N
H

NBn

2

O

N
H

N

O

N

N
H

O

97%

p

-O

2

NPhOLi-CuBr

2

(4 equiv)
Bn

2

NH, THF, 50 °C,

20 min

86%

LiO

t

Bu-CuBr

2

(6 equiv)

THF, rt, 20 min

(38)

Oxidant in Pd-catalyzed Reactions.

In Pd(II)-catalyzed

functionalization of alkenes, excess CuBr

2

is used to oxidize

Pd–C bonds to Br–C bonds or to regenerate Pd(II) from Pd(0).
For example, highly enantioselective dibromination of terminal
alkenes is realized using PdBr

2

[(S)-BINAP] and CuBr

2

/LiBr

(eq 39),

66

and Pd(O

2

CCF

3

)

2

catalyzes intramolecular bromo-

amination of alkenes in the presence of CuBr

2

(eq 40).

67

In

the PdBr

2

-catalyzed cyclization of 2-alkynylphenols, 0.2 equiv

Et

3

NHI is found to be essential for selective alkoxybromination

to form 3-bromobenzofurans in the presence of CuBr

2

(3 equiv).

68

A combination of Pd(OAc)

2

(cat), Cu(OAc)

2

, and CuBr

2

has been

used to realize a selective ortho-bromination of acetanilide.

69

O

i

Pr

i

Pr

O

Br

Br

i

Pr

i

Pr

PdBr

2

[(S)-BINAP] (2.5 mol %)

LiBr (0.2 M), CuBr

2

(2.2 M)

H

2

O/THF (1:6), rt, O

2

, 4d

*

95%

94% ee

(39)

NHTs

N
Ts

Br

N
Ts

Br

+

: 1

99%

(40)

Pd(O

2

CCF

3

)

2

(0.1 equiv)

CuBr

2

(3 equiv), K

2

CO

3

THF, rt, 24 h

3

Avoid Skin Contact with All Reagents

6

COPPER(II) BROMIDE

Synthesis of Bromosilanes from Hydrosilanes.

In the pres-

ence of a catalytic amount of CuI, CuBr

2

(2 equiv) converts hy-

drosilanes into monobromosilanes at room temperature in good
yield.

70

Substrates include monohydrosilanes, dihydrosilanes, tri-

hydrosilanes, and 1,2-dihydrodisilane. However, with di- and
trihydrosilanes the second bromination employing 4 equiv of
CuBr

2

is much slower.

Lewis Acids.

A substoichiometric amount of CuBr

2

promotes

the one-pot imino Diels–Alder reaction between in situ gener-
ated N-benzylideneanilines and electron-rich alkenes, affording
tetrahydroquinolines in good yield (eq 41).

71

Water formed dur-

ing the reaction and aniline substrates seemingly do not deac-
tivate CuBr

2

. Bis(indol-3-yl)methanes are prepared efficiently

from various aldehydes and indole in the presence of 5 mol % of
CuBr

2

(eq 42). The reaction is slow and incomplete with ketone

substrates.

72

CuBr

2

also catalyzes the desilylation of TBS ethers,

tolerating functional groups such as ketals, alkenes, and allyl and
benzyl groups. However, TBDPS and THP groups are cleaved,
albeit in a lesser extent.

73

A combination of CuBr

2

/Bu

4

NBr

has been used to activate thioglycoside donors although the
selectivity for α-glycosidic linkages varies.

74

–

76

Using the same

reagent combination, the alkylthio group in alkoxy-/siloxymethyl
alkyl sulfide can be similarly replaced with alkoxy, phenoxy, and
carboxy groups, offering a mild and neutral method for hydroxyl
group protection.

77

CuBr

2

and especially CuCl

2

can activate sugar

oxazolines, leading to efficient formation of β-glycosides.

78

O

O

Ph

H
N

PhCHO

PhNH

2

76%

cis

/trans = 21/79

(41)

+

+

CuBr

2

(50%)

MeCN, rt, 2 h

N
H

CHO

O

O

N
H

O

O

+

90%

2

(42)

CuBr

2

(5 mol %)

MeCN, rt, 35 min

)

Related Reagents.

Bromine; N-Bromosuccinimide; Copper(I)

Bromide.

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Avoid Skin Contact with All Reagents