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In addition, the Sodium Borohydride Digest is a guide to sodium borohydrides relative position among reducing reagents.
We include table showing common functional groups and their general reducibility by sodium borohydride, sodium borohydride
derivatives and by some analogous aluminohydride reducing agents. Within the market of chemical reducing agents in organic
synthesis, NaBH4 is the primary reductant used on industrial scale, with a estimated (equivalent) market share greater than 50%.
Some of the benefits of using borohydride chemistry include :
- the least expensive metal hydride commercially available (on a hydride equivalent basis)
- safe with regards to storage and use & handling
- industrial implementation requires no or limited equipment investment
- ease of work-up (water soluble boron salts)
- ubiquitous solvents such as water and methanol are typically employed
- unique and versatile as a hydride reducing agent for both chemo- and diastereo-selectivity
Rohm and Haas welcomes request for additional information and will gladly provide technical assistance to those interested
in developing or optimizing sodium borohydride applications. Our research and technical service groups can provide assistance by
telephone or, if appropriate, by visiting your facility. We can furnish technical literature on a wide variety of applications. Finally,
Rohm and Haas, as a subscriber to the Responsible Care Codes, is committed to the safe use of our products. We have wide variety
of information and presentations on safety and handling.
Please feel free to send us your questions via venpure@rohmhaas.com, or contact one of our offices
in America:
Rohm and Haas Company
Borohydride Applications
60 Willow Street
Phone: 1-978-557-1832
Fax: 1-978-557-1879
in Asia:
Rohm and Haas China, Inc.
23rd Floor, Hitech Plaza
No. 488 S. Wu Ning Road
Shanghai, China
Phone: +86 21 6230 6366
Fax: +86 21 6230 6377
in Europe:
Rohm and Haas France S.A.
la tour de Lyon
185, rue de Bercy
F-75579 Paris
Phone: +33-1 4002 5210
Fax : +33-1 4002 5441
TABLE OF CONTENTS
I. Properties
A. Physical and Thermodynamic
B. Solubility
C. Stability
II. Organic Reductions
A. Theory
B. Practice
C. Carbonyl groups
Aldehydes
Ketones
Acids
Amides
Anhydrides
Acid Halides
Esters
Enol Esters
Imides
Lactone
D. Carbon-Nitrogen Compounds
Reductive Amination
Azides
Deamination
Diazonium Salts
Page #
6
7
9
14
16
28
28
35
51
55
57
59
63
71
72
74
77
82
85
86
87
92
97
98
101
105
107
110
114
116
119
122
125
128
133
135
140
141
143
143
145
155
160
Sodium Cyanoborohydride
160
Polymer Bound borohydrides
161
Other Solid Supports
162
NaBH2S3 Lanacetts Reagent
162
NaBH(OR)3 Sodium Hydridotrialkoxyborates
163
NaBH4 Polyamine Polymer
163
Lithium Borohydride
164
Potassium Borohydride
164
Calcium Borohydride
164
Zinc Borohydride
164
Mixed Hydrides
165
Esters and Acids
165
Acetals and Ketals
165
166
Hydroboration with NaBH4
Other Derivatives
167
IV/ Analytical Procedures
A. Assay Methods
179
Trace Methods for Borohydrides 180
NaBH4 AssayHydrogen Evolution Method 182
Iodate Method
185
Trace NaBH4 AssayHydrogen evolution 188
Iodate Method
191
NBC Method
193
195
V. Availability
VI. Personal Protective Equipment
VII. First Aid
VIII. Reactivity
IX. Fire Fighting/ Flammability
X. Spill And Waste Disposal
XI. Toxicity
XII. Storage And Handling
XIII. Shipping
198
199
200
202
204
205
207
208
210
I. PROPERTIES
A. Physical and Thermodynamic Properties
These properties are listed in the following two
tables. Infrared and Raman spectra of both sodium and
potassium borohydrides have been reported (1).
Table I Selected Physical Properties of Sodium
Borohydride
Properties
Formula
NaBH4
Molecular Weight
37.84
Purity
>98.5%
Color
White
Crystalline
Form Face Centered cubic
(anhydrous)
a= 6.15
(dihydrate)Exists
below 36.5 oC
Melting Point
505 oC (10 atms H2)
Decomposes
above
400 oC In Vacuum
Thermal Stability
Will not ignite above
400 oC on a hot plate
Ignites from free flame
in air, Burning quietly
Density
1.074g/cm3
Apparent Bulk Density 5lb/gal
*For Online Consulting Only
Fo298
Ho298
So
Co p
Fo298
-30.1
kcal/mol
-45.53
kcal/mol
+24.26
cal/omol
+20.67
cal/omol
-5660 cal/mol
3
2
5
3
4
Fo298
Ho298
So298
+28.6
kcal/mol
+12.4
kcal/mol
+25.5
cal/omol
4
4
4
Fo298
Fo298
Eo298
-88.8
kcal/mol
-228.9
kcal/mol
+1.24 V
4
4
4
B. Solubility
1. Water
The solubility of sodium borohydride in water,
the most commonly used solvent, has been accurately
measured at the different temperatures by Jensen (6).
The data presented in the following graph shows the
equilibrium temperature of the two crystal forms NaBH4
and NaBH42 H2O. The curve below 36.4oC represents
the solubility of the dihydrate, and above 36.4oC, the
solubility of anhydrous NaBH4.
55
50
45
40
35
30
25
0
20
40
60
Temperature o C
2. Nonaqueous Solvents
The solubility of sodium borohydride in different
solvents has been determined accurately at different
temperatures for many alcohols, amines, and glycol ethers. In
general, sodium borohydride is soluble in polar compounds
containing a hydroxyl or amine group. A point to note is the
glycol ethers differ from most solvent in that their ability to
solubilize sodium borohydride decreases as solvent
temperature increases. See table III.
Solvent
Water
Liquid Ammonia
Methylamine
Ethylamine
N-Propylamine
Iso-Propylamine
N-Butylamine
Cyclohexylamine
Morpholine
Aniline
Pyridine
Monoethanolamine
Ethylenediamine
Methanol
Ethanol
Temp(oC)
0
25
60
25
-22.0
17
28
28
28
28
25
75
75
25
75
25
75
20
20
Solubility
25.0
55.0
88.5
104.0
27.6
20.9
9.6
6
4.9
1.8
1.4
2.5
0.6
3.1
3.4
7.7
22.0
16.4 (reacts)
4.0 (reacts
slowly)
Iso- Propanol
Tert-Butanol
25
60
25
0.37
0.88
0.11
2-Ethylhexanol
Tetrahydrofurfuryl
Alcohol
Ethylene glycol
dimethyl ether
Diethylene glycol
dimethyl ether
Triethylene glycol
dimethyl ether
Tetraethylene glycol
dimethyl ether
Dimethylformamide
Dimethylacetamide
Dimethylsulfoxide
Acetonitrile
Tetrahydrofuran
60
25
20
0
20
0
25
45
75
0
25
50
100
0
25
50
75
100
20
20
25
28
20
01.8
0.01
14.0 (reacts
slowly
2.6
0.8
1.7
5.5
8.0
0.0
8.4
8.7
8.5
6.7
8.7
9.1
8.4
8.5
4.2
18.0
14.0
5.8
2.0
0.1
3. Non-Solvents
In cases where sodium borohydride is not
soluble, traces amounts of water or low molecular
weight alcohols can be added to the organic solvent to
effect reduction. In general, two moles of water are
needed for every mole of sodium borohydride. This
procedure has proven effective with very high
molecular weight alcohols. In some cases, however, an
organic borohydride such as tetraethylammonium
borohydride will be more effective because of its greater
solubility. The use of NaBH4 on solid supports such as
silica gel, alumina, and zeolites in nonpolar solvents has
been published (See section IIIC).
C. Stability
Sodium borohydride is very stable thermally.
It decomposes slowly at temperatures above 400oC in
vacuum or under a hydrogen atmosphere. Sodium
borohydride absorbs water rapidly from moist air to
form the dihydrate complex, which decomposes slowly
forming
hydrogen
and
sodium
metaborate.
Decomposition in air is therefore a function of both
temperature and humidity. Generally higher reaction
temperatures favor borohydride reductive chemistries.
1. Aqueous Solutions
The stability of sodium borohydride in water is dependent
upon the temperature and the pH. Increasing the temperature
and lowering the pH accelerates the hydrolysis reaction.
NaBH4 + 4 H2O NaB(OH)4 + 4 H2
As the borohydrides are alkaline, the higher the concentration,
the more stable the resulting solutions. See Table IV.
Table IV pH of Solutions of NaBH4 at 24oC
Concentration of
pH
NaBH4
1.000M
10.48 0.02
0.100M
10.05 0.02
0.010M
9.56 0.02
The kinetics of the hydrolysis reaction has been studied by
Gardiner and Collat (7,8), Wang and Jolly (9), and by Kreevoy
(10,12). The reaction is pseudo-first order and is subject to
general acid catalysis. First order kinetics also applies in
strongly alkaline solution (13).
The decomposition rate of aqueous NaBH4 solutions can be
estimated conveniently (14) using equation
Log10t1/2(mins)= pH-(0.034T-1.92)
10
(a) Effect of pH
It is obvious, therefore, that the addition of sodium
hydroxide will stabilize aqueous sodium borohydride
solutions. This was demonstrated by Jensen (6) over a pH
range of 12.9 to 13.8 (calc.)
At higher pH values there is essentially no decomposition
during storage.
100
98
% NaBH4
96
0.10 N NaOH
0.25 N NaOH
1.00N NaOH
94
92
90
88
86
0
50
100
150
Time (hours)
11
a rate of only 5x10-6% per day at 21oC and at 4x10-5% per day
at 54oC.
100
% NaBH4
90
80
24.0 oC
47.0o C
70
60
50
40
0
50
100
Time (hour)
4. Alcohol Solutions.
NaBH4 is unstable in acidic alcohols (e.g. phenol) and low
molecular weight primary alcohols such as methanol, ethanol
and ethylene glycol due to solvolysis but is stable in secondary
and tertiary alcohols such as isopropanol, t-butanol and 2ethylhexanol, even at elevated temperatures (24,25). It reacts
with higher molecular weight primary alcohols.
The instability in lower alcohols can be overcome by the
addition of base, as in aqueous solutions. For example, Jensen
(6) has reported that ethanol only 5.7% of the sodium
borohydride is lost in 144 hours at 24oC in the presence of 2 N
sodium hydroxide. Studies undertake at Rohm and Haas have
demonstrated that the addition of as little as 0.01 N MeONa to
a methanol solution or 0.01N NaOEt to an Ethanol solution of
80
No NaOMe
added
0.010 N
NaOMe
60
40
20
30
% NaBH4 Consumed
% NaBH4 consumed
100
25
20
0.001 NaOEt
15
0.1 NaOEt
10
No NaOEt
5
0
0
0
0
10
20
30
2
Time, Hours
40
Time (minutes)
12
60
40
0.1N at 50 oC
20
0
0
200
Ti m e ( M i nu t e s)
3
2,5
2
1,5
1
0,5
0
0.01NaOEt at 50C
0.01NaOEt at 30C
0,5
Ti m e ( ho ur s)
13
O
D
O
R
W
+
Least reactive
Most reactive
Because of this, any substituent that increases the
fractional positive charge on the carbonyl carbon atom
will increase the rate of reduction. If the fractional
positive charge is decreased by substituents, then the
rate is slowed. Jensen (6), for example, has shown that
the rate of reduction for substituted benzaldehyde
derivatives is as shown in Figure 8.
In this case, the inductive effect leading to a greater
positive charge is overcome by the resonance effect.
100
90
80
70
% Reduction
14
Benzaldehyde
60
Salicyladehyde
50
m-hydroxybenzaldehyde
40
p-hydroxybenzaldehyde
b-Resorcylaldehyde
30
20
10
0
0
50
100
Time (minutes)
NaBH4
+
OH
O
15
K1
O
H
H
R'
H
H
R'OH
Figure 9
H
R
K2
+
NaBH3OR'
H103o
H
O
R
M
HO
P,L
H
H-
R
M
P,L
cation adds steric bulk to the molecule, which will increase the
specificity of the attack of the hydride.
HR
P,L
R
16
S
M
S
Metal
H
OH
L
OH
S
P,L
Figure 10
In 1968 Felkin improved on Cram's model by
proposing that the bulkiest substituent could also be the
most electron-withdrawing group regardless of steric
size. (37) These new conclusions were later
substantiated by the theoretical calculations of Ahn. (3840) The theoretical calculations also showed that the
hydride attacking the carbonyl group approaches at a
103o angle instead of 90o.
Another model set forth by Cram in 1952
proposed that substrates containing a chelating group in
the or position will chelate with a metal cation to
form a five or six membered ring. (41) The chelating
17
18
Cl
O
R
+
OH
Cl
NMM, DME
N
N
Cl
3h, RT
O
R
NaBH4, H2O
N
N
Cl
0 oC
OH
19
5) Co-catalyst:
The use of catalysts to increase the chemo and stereo
selectivity of sodium borohydride has been demonstrated
recently. Adiminato Co(II) complexes have reduced ketones
as well as carboxyamides and imines functional groups
stereoselectively (102-106). Other inorganic and organic
catalysts have been reported (107).
6) Supported borohydrides
The impregnation of organic and inorganic polymers
such as ion exchange resins, zeolites, silica gel, alumina or
aluminophosphates with sodium borohydride or derivative has
been used to stereoselectively and chemoselectively reduce
organic functional groups. Depending on the nature of the
support, the type of borohydride reagent used and the type of
co-reagent are used, different chemo and stereoselectivities can
be achieved. These reductive systems have advantages such as
with the exchange resins, the spent borohydride are easily
separated from the product by filtration and with silica gel and
alumina reactions can be done in aprotic solvents such as
hexane.
7) In situ or ex situ production of diborane.
Diborane, B2H6 can be synthesized directly from
borohydride in high yields using many different reagents.
Reagents that can accomplish this transform are H2SO4 (108-
20
21
References:
1) Davis, W.D.; Mason, L.S.; Stegeman, G J. Am.
Chem. Soc. 1949, 71, 2774; Chem. Abstr. 43,
7805d
2) Douglas, T.; Harman, A.W. J. Res. Nat. Bur. Std.
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9361d
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1971, 49, 3272
6) Jensen, E.H. "A Study on Sodium Borohydride",
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1954- (Out of Print)
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1965, 87, 1692; Chem. Abstr, 62, 13899b.
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22
38)
39)
40)
41)
42)
43)
44)
45)
46)
47)
48)
49)
23
24
75) Kim, S.; Oh, C.H.; Ko, J.S.; Ahn, K.H.; Kim, Y.J.
J. Org. Chem. 1985, 50, 1927
76) Ranu, B.C.; Jana, U.; Sarkaar, A. Synth. Commun.
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2321
25
26
27
C. Carbonyl Coumpounds
ALDEHYDES
Alembic 18, 32, 48, 50, 52, 55, 58
Aldol
benzaldehyde
phenylacetaldehyde
4-tolualdehyde
naphthaldehyde
2-ethoxybenaldehyde
2-chlorobenzaldehyde
hexanal
methacrylaldehyde
glyceraldehyde
28
NH(CH2)2NEt2
NH(CH2)2NEt2
NaBH4
C
OH
29
References
14,15
16-21
22-24
25
26-27
22,28
17,24,29
30. 31
32
17,18,27,32-36,
28,34
38
18,39-41
40
42
43-48
30
31
32
55)
56)
57)
58)
59)
60)
61)
62)
63)
64)
65)
66)
67)
68)
69)
70)
33
34
KETONES
Alembic: 7, 18, 21, 26, 31, 48, 50, 52, 55, 58, 62
Under normal conditions, NaBH4 reduces
ketones at a slower rate than aldehydes. While in most
cases aldehydes undergo reactions within a few minutes,
the reduction of ketones usually takes 30-90 minutes. A
few examples of ketones that are reduced at least 90 %
at room temperature are:
Time required for 90 % Reduction
Ketone
(min)
Acetone
40
3-hydroxy-2-butanone
2
acetophenone
100
benzophenone
130
benzoin
6
cyclopentanone
90
cyclohexanone
4
2-methylcyclohexanone
7
menthone
90
isatin
2
furoin
12
As indicated in the table, -substituents which
increase the fractional positive charge on the carbonyl
35
36
k2x104
(L mol-1 sec-1)
93
97
15.1
37
Temperature oC
0
15
25
35
k2 x104
(L mol-1 sec-1)
15.1
36.1
63
105.0
38
O
OH
NaBH4
O
Ph
O
Ph
39
Class of compounds
Steroid ketones
Amino ketones
Prostaglandines
Menthanones
CNS suppressants
Synthetic juvenile hormones
Gibberellic acids
Antibiotics
Artificial flavors and coloring
Triterpenoids
Flavanoids
Adamantanone
Methadones
Epoxy ketones
Polymeric ketones
Antiinflammatories
Beta-Blockers
Antiulcer compounds
Antihypertensives
Fungicides/herbicides
Anti HIV
Antipsychotic
Anti viral
Taxol
ref
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85-91
58-60,
188-192
193
194- 197
198- 201
201, 202
203-210
211- 214
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216- 218
219- 221
222- 224
225
226 -228
229- 231
232- 234
235, 236
237- 239
240- 143
244- 247
248
249
250
40
41
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Chiaroni, A.; Riche, C.; Grierson, D.S. J Org. Chem.
1995, 60, 2753; Chem. Abstr. 124 30187
208) U.S. 5,869,449 1999
209) U.S. 5,648,456 1997
210) U.S. 5,869,449 1999
211) Ger. Offen. 2,035,901 1971; Chem. Abstr. 75, 35259s
212) U.S. 3,558,712 1971; Chem. Abstr. 74, 100242b
213) U.S. 4,269,862 1981; Chem.Abstr. 95, 95775e
214) Jpn. Kokai Tokkyo Koho 82 28,079 1982; Chem. Abstr.
96, 218067f
215) Nasipuri, D.; Mukherjee, P.R.; Pakrashi, C.S.; Datta, S.;
Ghosh-Dastidar, P.P. J. Chem. Soc. Perkin 1 1976, 321;
Chem. Abstr. 84, 105838s
216) Grouiller, A.; Pacheco, H.C. R. Acad. Sci., Ser. C 1971,
272, 2085; Chem. Abstr 75, 75584a
49
50
CARBOXYLIC ACIDS
Alembic: 48, 49, 55, 61, 62
Carboxylic acids are not normally reduced with
sodium borohydride in protic solvents. However, there
are a few techniques that permit the direct borohydride
reduction of carboxylic acids or their easily prepared
derivatives.
A number of aromatic and aliphatic carboxylic
acids (and esters) have been reduced to their
corresponding alcohol using sodium borohydride at high
temperatures (300o C) in the presence or absence of any
solvent (1,2).
C5H11COOH + NaBH4 C6H13OH
Using a 0.25 mole equivalent of borohydride to acid, the
hexyl caproate was obtained.
Enol esters derived from the reaction of
carboxylic acids with N-ethyl-5-phenylisoxazolium-3sulfoxate can be reduced with sodium borohydride in
water to the alcohols (3).
A series of perfluorinated acids were reduced
to the alcohols with NaBH4 (4):
51
OH
NaBH4
H
H
OH
CF3
CF3
+
OH Cl
O NaBH4
OEt
O
O
OH
R
EtO
52
53
54
AMIDES
Alembic: 9, 47, 50, 61, 62
Amides were once considered to be not reducible
by NaBH4. Attempts to reduce primary amides in
boiling diglyme led to the formation of nitriles with
the elimination of water (1). In refluxing pyridine,
primary amides form the nitrile, secondary amides
do not react and tertiary amides are slowly reduced
to amine (2,3). When catalyzed by salts of
transition metals, such as cobalt, nickel and
zirconium, NaBH4 has been shown to reduce
primary and secondary amides to the amine. (4, 5)
Zn(BH4)2 can reduce both aromatic and aliphatic
amides to amines in high yields in refluxing THF.
(6) A cobalt complex recently developed will
reduce amides using NaBH4 as the hydride source
(7)
A number of useful techniques to accomplish
amides reductions are now known. These include
reduction with TiCl4/NaBH4 (8,9) reduction with
Bu4NBH4 in dichloromethane (10), reduction with
NaBH4 via imino derivatives using POCl3 (11), and
reduction via thioamides and (alkylthio)
methyleniminium salts (12).
The asymmetric
reduction of pyruvamides has also been reported
55
References:
1) Elzey, S.E. Jr.; Mack, C.H.; Connick, W.J. Jr. J.
Org. Chem. 1967, 32, 846; Chem. Abstr. 67, 2860n
2) Kikugawa, Y.; Ikegami, S.; Yamada, S. Chem.
Pharm. Bull 1969, 17, 98; Chem. Abstr. 70, 97491
3) Saito, I.; Kiugawa, Y.; Yamada, S. Chem. Pharm.
Bull. 1970, 18, 1731; Chem. Abstr. 73, 110093x
4) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai,
Z. Tetrahedron Lett. 1969, 4555; Chem. Abstr.94,
1499e
5) Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis 1988, 995
6) Narasimhan, S.; Madhavan, S.; Balakumar, R.;
Swarnalakshmi, S. Synth. Commun. 1997, 27, 391
7) Yamada, T.; Ohtsauka, Y.; Ikeno, T. Chem. Lett.
1998, 1129
8) Kano, S.; Tanaka, Y.; Sugino, E.; Hibino, S.
Synthesis 1980, 695; Chem. Abstr. 94, 14599e
9) Jp. Okai Tokkyo Koho 80, 162, 756 1980; Chem.
Abstr. 95, 62023e
10) Wakamatu, T.; Inaki, H.; Ogawa, A.; Watanabe, M.
Ban, Y. Heterocycles 1980, 14, 1437; Chem. Abstr.
94, 3027a
11) Kuehne, M.E. Shannon, P.J. J. Org. Chem. 1977,
42, 2082; Chem. Abstr. 87, 22928g
12) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21,
4061; Chem. Abstr. 94, 156223b
56
13) Munegumi, T.; Harada, K. Bull Chem. Soc. Jpn. 1983, 56,
298; Chem. Abstr. 99, 53287z
14) Prasa, A.S.B.; Kanth, J.V.b.; Periasamy, M. Tetrahedron,
1992, 48, 4623
15) Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl.
1989, 28, 218
16) Sengupta, S.; Sahu, D.P.; Chatterjee, S.K. Indian J. Chem.
1994, 33b, 285
17) Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem.
1981, 46, 2579
18) Akabori, S.; Takanohashi, Y. J. Chem. Soc.; Perkin Trans
1, 1991, 479
19) Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean
Chem. Soc. 1983, 27, 434
20) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976,
763; Chem. Abstr. 85, 20719z
21) Malawska, B.; Gorczyca, M. Pol. J. Chem. 1985, 59, 811;
Chem. Abstr. 105, 226250e
22) Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46,
2579; Chem. Abstr. 95, 5881j
23) Maki, Y.; Kikuchi, K.; Sugiyama, H.; Seto, S. Chem. Ind.
1976, 322; Chem. Abstr. 85, 62767u
24) Lee, B.H.; Clothier M.F. Tetrahedron Lett. 1999, 40, 643
ACID ANHYDRIDES
Alembic: 50
Because of their chemical nature, acid
anhydrides cannot be reduced by borohydride in
aqueous solvents. Early literature reports only a
few instances of carboxylic anhydrides reductions
with NaBH4 in ether solvents, The products being
either lactones (1-4), diols (5), or alcohols (6).
Cyclic anhydrides are readily reduced by
NaBH4 to and -lactones in very good yields (713) to form antibiotics, (14) growth factors (15) and
-amino acids (16,17) . Additional reports of the
use of NaBH4 for reducing anhydrides have
appeared in the literature (18- 21)
Mixed carboxylic-diphenylphosphoric acid and
diphenylphosphorochloridate in the presence of
triethylamine, were reduced with excess NaBH4 to
the corresponding primary alcohols in fair yield.
Nitro, ester, amides groups and conjugated double
bonds were not affected (22).
The NaBH4/TiCl4 (4:1) system in diglyme has
been reported to reduce acid anhydrides to diols
(23).
57
58
59
ACID HALIDES
Cl
Alembic: 50, 58
O
NaBH4
NaBH4
O
H
Cl
HO
N
H
OEt
Cl
O
N
Ar
Cl
NaBH4
N
Ar
OH
Cl NaBH4
(OC)3Fe
OH
(10)
OEt
H
H
NaBH4
OH
H
(9)
Cl
OH
N
(OC)3Fe
OH
H
H
H
(11)
O
NaBH4
(12)
HO
HO
Cl
O
HO
H
H
The
reduction
of
acid
chlorides
with
tetrabutylammonium borohydride in dichloromethane
provides instantaneous reactions and nearly quantitative
yields (13). Similar reactions of quaternary
borohydrides in binary solvents or the use of NaBH4
with a phase transfer catalyst, have been reported (14).
Phosphonium borohydride can reduce acid chlorides to
alcohols in high yields in aprotic solvents at RT. (15)
The Luche method, using CeCl3 with NaBH4,
has been applied to the reduction of conjugated
unsaturated acid chlorides to the corresponding
unsaturated alcohol (16).
NaBH4 reduces acid chlorides to aldehydes in
good yield in the presence of cadmium chloride and
DMF (17,18). The reagent bis-(triphenylphosphine)
copper (1) borohydride, easily prepared from NaBH4,
also gives high yields of aldehydes from acid chlorides
(19-22). Reduction to aldehydes by NaBH4 without
added metal salts has been studied (23). Careful control
of the ratio of NaBH4 to acid chloride, operation at
*For Online Consulting Only
60
61
62
ESTERS
Alembic: 10, 36, 48, 50, 55, 57, 60, 61
Traditionally the reduction of simple aliphatic
esters with sodium borohydride in protolytic solvents is
extremely slow and therefore not practical for industrial
processes. In aprotic solvents such as dichloromethane,
the reduction of ethyl laurate with the soluble
tetrabutylammonium borohydride is only 25% complete
after 4 days at 25oC (1).
In comparison
tetrabutylammonium borohydride in CCl3H at reflux
temperatures will reduce aliphatic esters to alcohols in
70 % yields after 5h (2).
A large number of activated esters can be
reduced directly with sodium borohydride in protolytic
solvents. Electron withdrawing groups alpha to the
ester carbonyl group increase the positive charge on the
carbonyl carbon making it much more susceptible to
attack by the borohydride ion (3).
Examples of electron withdrawing groups and
their borohydride reduction products are:
Hydroxyl-Sugar Esters Primary alcohols (4-7).
and Lactones
63
O
O
NaBH4
OEt
O
H
pH 2-3
NH3+ClH
H
OH
OCH3 NaBH4
O
OH
O
Cl
HO
NaBH4
H
Cl
CH3
OCH3
O2N
O
OR NaBH4
H2O
OH
CH3
64
H
H
OH
H
(24)
Ph
Ph
Ph
CN
O2N
NaBH4
Ph
O
NaBH4
Ph
diglyme
OEt 15-20 oC Ph
CN
(25)
H
H
HO
CN
NaBH4
OEt EtOH
CN NaBH4 R
H
OEt
CN
H (26)
H
H
HO
OH
O
OCH3 NaBH4 H
H3CO
OH
(28)
EtOH
OCH3
NH2
N
H2N
HO
NaBH4
NH2
H
H
NH2
N
H2N
(29)
N
NH2
65
66
Ph
+
NaBH4
H3C
BH3-Na+
+ H2
N
Ph
67
References:
1) Raber, D.J.; Guida, W.C. J. Org. Chem. 1976, 41 690;
Chem. Abstr. 84 880n
2) Narasimhan, S.; Swarnlakshmi, S.; Balakumar, R.;
Velmathi, S. Synlett. 1998. 1321
3) Schenker, E. "Newer Methods of Preparative Organic
Chemisty", Vol IV, 1968, 196, Verlang, Chemie,
Weinheim
4) Wolfrom, M.L.; Anno, K. J. Am. Chem. Soc. 1952, 74,
5583; Chem. Abstr. 8, 134e
5) Wolfrom, M.L.; Wood, H.B. J. Am. Chem. Soc. 1951, 73,
2933; Chem. Abstr. 46, 3961a
6) Barton, D.H.R. et. al. J. Chem. Soc. Perkin Trans. 1 1975,
2069; Chem. Abstr. 84, 31342b
7) Ger. Offern. 2,911,377, 1980; Chem. Abstr. 94, 121935h
8) Heymann, H.; Fiesser, L.F. J. Am. Chem. Soc. 1951, 73,
5252; Chem. Abstr. 47, 592d
9) Leonard, N.J.; Conrow, K.; Fulmer, R.W. J. Org. Chem.
1957, 22, 1445; Chem. Abstr. 52, 8134c
10) Soai, K.; Oyamada, H. Synthesis 1984, 605; Chem. Abstr.
101, 229944n
11) Brown, G.R.; Foubister, A.J. J. Chem. Soc., Chem.
Commun. 1985, 455; Chem. Abstr. 103, 122724e
12) Seki, H. et. al. Chem. Pharm. Bull. 1965, 13, 995; Chem.
Abstr. 63, 14971d
68
26) Marshall, J.A.; Caroll, R.D. J. Org. Chem. 1965, 30, 2748;
Chem. Abstr. 63, 11387d
27) Giumanini, A.G.; Tubaro, F. J. Prakt. Chemie. Band
1990, 332, 755
28) Span. 41324 1976; Chem. Abstr. 86, 106401x
29) Wong, J.; Brown, M.S.; Matsumoto, K.; Oesterlin, R.;
Rapoport, H. J. Am. Chem. Soc. 1971, 93, 4633; Chem.
Avstr. 86, 106401x
30) Yonemitsu, O.; Hamada, .; Kanaoka, Y. Tetrahedron Lett.
1968, 3575; Chem. Abstr. 69, 87454x
31) Nichols, B.W.; Safford, R. Chem. Phys. Lipids 1973, 11,
222 Chem. Abstr. 80, 47412
32) Takahashi, S.; Cohen, L.A. J. Org. Chem. 1970, 35, 1505;
Chem. Abstr. 73, 3270f
33) Nystrom, R.F.; Chaikin, S.W.; Brown, W.G. J. Am. Chem.
Soc. 1949, 71, 3245; Chem. Abstr. 44, 1017e
34) Paul, R.; Joseph, N. Bull. Soc. Chim. France 1952, 550;
Chem. Abstr. 47, 32651
35) Kollonitsch, J. Fuchs, O.; Gabor, V Nature 1955, 175,
346; Chem. Abstr. 50, 1774d
36) Brown, H.C.; Mead, E.J.; Subba Rao, B.C.; J. Am. Chem.
Soc. 1955, 77, 6209; Chem. Abstr. 50, 8529h
37) Jpn. Kokai Tokkyo Koho 80, 133,369, 1980; Chem.
Abstr. 94, 174915h
38) U.S.; 4512,991 1985; Chem. Abstr. 103, 71338x
69
70
71
ENOL ESTERS
In mixed solvent systems containing water, NaBH4
reduces enol esters to the alcohol. The enol ester is first
hydrolyzed to the ketone, which is reduced by the
borohydride:
NaBH4
H2O
Aco
HO
HO
References:
1) Belleau, B.; Gallagher, T.F. J. Am. Chem. Soc. 1951, 73,
4458; Chem. Abstr. 47, 138I
2) Kurath, P.; Capezzuto, M. J. Am. Chem. Soc. 1956, 78,
3527; Chem. Abstr. 51, 1229h
3) Djerassi, C. et. al. J. Am. Chem. Soc. 1958, 80, 2596;
Chem. Abstr. 52, 20262a
4) Smith, S.H.; Turner, A.B. J. Chem. Soc. Perkin 1 1975,
1751; Chem. Abstr. 84 5241y
5) Gruenke, L.D.; Craig, J.C. J. Labeled Compd.
Radiopharm. 1979, 16, 495; Chem. Abstr. 92, 59077h
6) Fendrich, G.; Abeles, R.H. Biochemistry 1982, 21, 6685;
Chem. Abstr. 98, 2166f
72
IMIDES
While broadly definitive papers on the imide
reductions by NaBH4 have not appeared in the literature,
many specific reductions have been described and the
products obtained vary with starting imide. In some
cases, carbonyl reductions accompanied by ring opening
are obtained. For example, several cyclic imides have
been reduced by sodium borohydride in methanol as
shown below(1).
R
HO
Me
N
Ph
NaBH4
Me
R
H
N
Ph
H
N
Ph
O
Me
HO
O
N CH
3
Me
N CH (84%)
3
Me
OH
NaBH4
OH
(16%)
N CH
3
Me
O
OEt
NH
NaBH4
H
NH2
SnCl4
73
74
LACTONES
Alembic: 50
O NaBH4
X
O
O
OH
OH
H3C
NaBH4
H3C
H3C
(11)
HN
Ph
Ph
Lithocarpic lactone
H
H
O
O
X
H3C
O
R
O
NaBH4
PGF2
H
NaBH4
HO
HO
O
O
NaBH4
O
(13)
HO
HO
Aflatoxins B1 and B2
O
OH
OH
O
NaBH4
O
(14)
OCH3
OCH3
N
O
N
N
NaBH4
HO
(15,16)
HO
75
76
77
REDUCTIVE AMINATION
Alembic: 6, 7, 28, 52, 55
The little known reaction of N-ethylation of
amines by a combination of formaldehyde and sodium
borohydride involves the sequential treatment of a
primary or secondary amine with the reagents.
It is analogous to the Eschweiler-Clarke
reaction, except that reduction of the imine or
immonium intermediate with sodium borohydride
occurs at room temperature, instead of requiring reflux
conditions on the steam bath.
This reaction has found most frequent us in
alkaloid synthesis, to convert cyclic amines to their Nmethyl derivatives, the tetrahydroisoquinoline nucleus
being the most common substrate (1-5)
NaBH4
N
H CH2=O
CH3
H
NaBH4
CH3
CH2=O
H
N
N
H
NaBH4
N CH2=O
N
N
N
N
CH3
78
79
80
81
AZIDES
Alembic: 50, 52, 55, 58
N3
Ac
H
H
N
Ac
H
H
H
H
NH2
OH
O2N
OH
N3
NH
NaBH4
O2N
OH
NH
Cl2HC
Cl2HC
O
S
N
NaBH4
H
N3
OH
HO
OH
CH3
CH3
NaBH4
HO
NH2
HN
HN
82
N3
"RR'N
NaBH4
CH3
CH3
O
HO
And to the acyl azides of N-substituted, 6aminopenicilanic acids, to give the corresponding
penicillanyl alcohols (8).
It has been used in the synthesis of
antidepressant aryloxyphenylpropylamines (9) and
antigenic glycopeptides (10).
Azide reductions with bis(triphenylphosphine)
copper (1) borohydride (11) and with NaBH4 under
phase transfer conditions (12,13) have also been
reported.
Alky and aromatic azides can be reduced to
amines with transition metals and sodium borohydride
under mild reaction conditions. (14,15, 16) Some of
these reactions are also catalytic.
Zinc borohydride
formed in situ or complexed with DABCO can reduce
alkyl and aromatic azides to amines in high yield.
(17,18)
Reaction of sodium borohydride with 1,3
dithiolethane forms a reactive species which will reduce
azides easily.(19) Methanol is another reagent when
added to a solution of sodium borohydride will reduce
both aromatic and aliphatic azides. (20,21) Trifluoro
actic acid with sodium borohydride will n-alkylate azide
groups. (22)
Borohydride exchange resin with and with out
nickel acetate in methanol at RT will reduce aromatic
83
84
REDUCTIVE DEAMINATION
The alkaline cleavage of compounds of the
type RN(NO)ONH2 with NaBH4 has been reported (1)
to give the hydrocarbon RH. The reaction proceeds via
an
intermediate
cabonium
ion,
similar
to
dehalogenantion with NaBH4.
In hexameylphosphoraide, N,N-disulfonimides
of primary amines, e.g. RN(SO2C6H4Me-p)2 where R=
decyl, or 2,5-Me2C4H3CH2 are reduced to the
hydrocarbon RH by NaBH4 in good yield.
Other deamination, e.g. of amidines (3), have
been reported.
References:
1) Kimse, W.; Shuette, H. Liegig, Ann. Chem. 1968,
718, 86; Chem. Abstr. 70, 36855s
2) Hutchns, R.O.; Cistone, F.; Goldsmith, B.;
Heuman, P. J. Org. Chem. 1975, 40, 2018; Chem.
Abstr. 83, 58333r
3) Okamoto, Y.; Kinoshita, T. Chem. Pharm. Bull
1981, 29, 1165; Chem. Abstr. 95, 97752u
85
DIAZONIUM SALTS
NaBH4 has been reported to reduce diazonium
fluoroborates in high yields (1,2) using either methanol
or dimethylformamide as solvent. This is a reliable
means of replacing diazonium groups by hydrogen, and
thus of removing from aromatic rings groups easily
converted to the diazonium salts, such as nitro, amino,
and carbonyl groups.
N2+ BF4NaBH4
H
R
86
References:
1) Hendrickson, J.B. J. Am. Chem. Soc. 1961, 83, 1251;
Chem. Abstr. 55, 13345c
2) Xu, G; Shi, X; Liu, M. Lanzhou Daxue Xueao, Ziran
Kexueban 1983, 19, 112; Chem. Abstr. 99, 21739g
3) Traylor, T.G.; McKenna, C.E. J. Am. Chem. Soc. 1971,
93, 2323; Chem. Abstr. 75, 5372f
4) Koenig, E.; Musso, H; Zahorszky, U.I. Angew Chem, Int.
Ed. Engl. 1972, 11, 45; Chem. Abstr. 76, 85126h
5) Bandgar, B. P.; Thite, C. S. Synth. Commun. 1997, 27,
635-639; Chem. Abstr. 126211857
6) HU 50108, 1989; Chem. Abstr. 113 5904
87
CO2R
CO2R
NaBH4
N
H
CO2R
RO2C
N
H
Quinoxalines (3),
O
N
NH
N
Ph
H
N
NaBH4
AcOH, 5oC
R
N
H
O
N
Pyracrimycin A (4),
N
H
NaBH4
CONH2
N
H
H
H
CONH2
in which neither the C=C bond nor the amide group is reduced.
88
RO
RO
N* HCl
RO
Me
NaBH4
OH
HO
RO
OH
HO
CO2Me
CO2Me
Me
Me
Me
Me
HO
NaBH4
N
N
Me
N
H
NaBH4
HO
H2N
O
N
HN
Cl
HN
NaBH4
H2N
N
H
Cl
CO2H
89
References:
1) Maki, Y. Chem. Pharm. Bull. 1976, 24, 234; Chem. Abstr.
84, 180161u
2) Booker, E.; Eisner, U. J. Chem. Soc., Perkin Trans 1
1975, 929; Chem. Abstr. 83, 79041j
3) Rao, K.V.; Jackman, D. J. Heterocycl. Chem. 1973, 10,
213; Chem. Abstr. 79, 18669r
4) Coronelli, C.; Vigevani, A.; Cavalleri, B.; Gallo, G.G. J.
Antibiot. 1971, 24, 495; Chem. Abstr. 76, 140387a
5) Vassova, A Voticky, Z.; Tomko, J.; Ahond, A. Collect.
Czech. Chem. Commun. 1976, 41, 2964; Chem. Abstr. 86,
90128a
6) Dornyei, G.; Szantay, C. Acta Chim. Acad. Sci. Hung.
1976, 89, 161; Chem. Abstr. 86, 29595j
7) Woodward, R.B. et. al. J. Am. Chem. Soc. 1956, 78, 2023;
Chem. Abstr. 50, 13967b
8) Woodward, R.B. et. al. Tetrahedron, 1958, 2, 1; Chem.
Abstr. 52, 11870f
9) Velluz, L. et. al. Bull. Soc. Chim. France 1958, 673;
Chem. Abstr. 52, 18478d
10) Protiva, M.; Novak, L. Naturwiss. 1959, 46, 579; Chem.
Abstr. 54, 6775I
11) Protiva, M.; Ernest, I. Naturwiss. 1960, 47, 156; Chem.
Abstr. 54, 19746e
12) Zharekeev,
B.K.;
Telezhenetskaya,
M.V.;
Khashimov, K.; Tunusov, S.Y. Khim, Prir. Soedin.
1974, 679; Chem. Abstr. 82, 73290x
13) Taylor, E.C.; Kobylecki, R. J. Org. Chem. 1978,
43, 680; Chem. Abstr. 88, 89628y
14) Pendergast, W.; Hall, W.R. J. Org. Chem. 1985, 50,
388; Chem. Abstr. 102, 78834u
15) Boyle, P.H.; Keating, M.T.; J. Chem. Soc. Chem.
Commun. 1974, 375; Chem. Abstr. 81, 105452z
16) Ramaswamy, S.G.; Adams, E. J. Org. Chem. 1977,
42, 3440; Chem. Abstr. 87, 184925f
17) Maki, Y.; Suzuki, M.; Ozeki, K. Tetrahedron Lett.
1976, 1199; Chem. Abstr. 85, 94314j
18) Beisler,J.A.; Abbai, M.M.; Driscoll, J.S. U.S. Pat.
Appl. 712, 854 (Aug. 8, 1976); Chem. Abstr. 87,
62862n
19) Smith, R.J. Enzyme 1984, 31, 115; Chem. Abstr.
101, 2755c
20) Levkovskaya, L.G.; Sazanov, N.V. et. al. Khim.
Geterotsiki. Soedin. 1985, 122; Chem. Abstr. 103,
37460w
21) Cho, H.; Shima, K. et. al. J. Org. Chem. 1985, 50,
4227; Chem. Abstr. 103, 178228p
22) Hung. Teljes 30,591 1984; Chem. Abstr. 101,
152163x
90
35) Evans, B.E., et. al. J. Med. Chem. 1987, 30, 1229
36) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda,
M.; Suginome, H. J. Org. Chem. 1999, 64, 6583
37) Roberts, D.; Jopule, J.A.; Bos, M.A.; Alvarez, M. J.
Org. Chem. 1997, 62, 568
91
92
HYDRAZONES
Alembic 12
The reduction of hydrazones (R-CH=NNHR')
to either hydrocarbon or hydrazides has been reported.
(1-3) Tris 2,4-methanoprotoadamantane is synthesized
by reducing the tosylhydrazone derivative in EtOH(4).
NNHTs
NaBH4
OMe
NaBH4
MeOH
NH
Ts
This has also been applied to the synthesis of 1-methyl1-dihalomethyl cyclohexane derivatives (5).
A number of hydrazides have been prepared by
The
NaBH4 reduction of the hydrazones (6,9).
hydrazones C=N bond is selectively reduced e.g. in the
synthesis of 3,4,5-trimethxybenzol hydrazides (10) .
MeO
MeO
O
N
H
NaBH4
MeO
MeO
R'
MeO
H
N
H
MeO
R
R'
93
94
95
IMINES
Alembic 23, 33, 43, 62
NH2
H
NO2 NaBH
4
N
AcOH
Me
HO
NO2
Me
Me
R
CO2H
N
R'
H
C
CO2H
H
NaBH4
R"
N
H
R'
R"
OH
OH
OH
Me
H
HO
Cl
Cl
96
7) Shin, W.S.; Lee, K.; Oh, D.Y. Tetrahedron Lett. 1995, 36,
281
8) De Kimpe, N.; Stanoeva, E.; Verhe, R.; Schamp, N.
Synthesis 1988, 587
9) Lakhani, B.B.; Merchant, J.R. J. Inst. Chem. 1977, 49,
172; Chem. Abstr. 87, 167668g
10) Ger. Offen. 3,034,664 1982; Chem. Abstr. 97, 55815c
11) U.S. 4,454,226 1984; Chem. Abstr. 101, 70879w
12) Merrettt, M.; Stammers, D.K.; White, R.D.; Wootton, R.;
Kneen, G. Biochem. J. 1986, 239, 387; Chem. Abstr. 105,
218622n
13) Lustenberger, N.; Lange, H.; Hempel, K. Angew. Chem.
Int. Ed. Engl. 1972, 11, 227; Chem. Abstr. 76, 148553x
14) Ger. Offen 2,606,662 1977; Chem. Abstr. 88, 23335u
15) Eur. Pat. Appl. 129,433 1984; Chem. Abstr. 103,6367s
16) Hung, P.D.; Adam, G.J. Prakt. Chem. 1984, 326, 253;
Chem. Abstr. 101, 38694w
17) Coatwes, R.M.; Cummins, C.H. J. Org. Chem. 1986, 51,
1383; Chem. Abstr. 104, 186037m
18) U.S. 4,578,290 1986; Chem. Abstr. 105, 97344n
19) Oveman, L.E.; Mendelson, L.T.; Jacobsen, E.J. J. Am.
Chem. Soc. 1983, 105, 6629; Chem. Abstr. 99, 176116a
20) Borne, R.F.; Fifer, E.K.; Waters, I.W. J. Med. Chem.
1984, 27, 1271; Chem. Abstr. 101, 1306113s
21) W.S. 4,537,885 1985; Chem. Abstr. 104, 155969n
22) S. Aferican 83 08,227 1985; Chem. Abstr. 105, 114934z
97
NITRILES
Alembic 50, 55, 60
Examples of nitrile reduction by NaBH4 are
limited to few heterocyclic compounds in which the
CN groups are activated by the heteroatom ring, e.g.,
the indole derivative (1) and some pyridine, quinoline
(2) and napthalene (3) derivatives.
Ph
Ph
C
N
NH2
NaBH4
N
H
N
H
98
99
19)
20)
21)
22)
23)
24)
25)
26)
27)
28)
29)
100
NITRO COMPOUNDS
Alembic: 4, 6, 9, 48, 51, 52, 61
Under normal conditions, NaBH4 does not
reduce the nitro group, except in a few aromatic nitro
compounds. For example, nitroanthraquinones are
reduced to the corresponding amines in 65 to 100 %
yield (1) in H2O, alcohols, aqueous DMF and THF.
Reduction to the amine has also been reported for the 2carbenthoxyindole derivatives (2).
Ordinarily, aliphatic nitro compounds are not reactive
with NaBH4, and the reduction of nitrobenzene
generally results in a number of products, e.g. azo,
azoxy, hydrazo derivatives and aniline (3,4).
In the presence of thiols, NaBH4 reduces nitro groups to
amine, hydroxylamines, azo and azoxy compounds, and
the activity is attributed to the thiolate derivatives (5).
A number of transition metal complexes have
been reported to catalyze the borohydride reduction of
nitro compounds, e.g., PdCl2(N-methylpyrrolidinone)2
(6), K2Ni(CN)4 (7), NiX2P2(8), and Co(NH3)6 3+ (9),
MoO3 (10).
NaBH4 can also convert a number of aromatic
nitro compounds to the amines in the presence of
palladium on charcoal (11-16). Cobalt and nickel
borides, generated from Co(II) and Ni(II) salts and
101
102
103
23) He, Y.; Zhao, H.; Pan, X.; Wang, S. Synth. Commun.
1989, 19, 3047
24) Lalancette, J.M.; Brindle, J.R. Can. J. Chem. 1971, 49,
Chem. Abstr. 151488q
25) Jpn. Kokai Tokkyo Koho 85, 152, 497 1985; Chem.
Abstr. 104, 69119d
26) Satoh, T.; Mitsuo, N.; Nishiki, M; Inoue, Y.; Ooi, Y.
Chem. Pharm. Bull. 1981, 29, 1443; Chem. Abstr. 95,
97224y
27) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Chin. Chem.
Lett. 1995, 6, 553; Chem. Abstr 123 313453
28) Ren, P.; Pan, S.F.; Dong, T.W.; Wu, S.H. Synth. Commun.
1995, 25, 3799
29) Borah, H.N.; Prajapati, D.; Sandhu, J.S. J. Chem. Res. (s)
1994, 228
30) Pan, S.F.; Ren, P.D.; Dong, T.W. Chinese Chem. Lett.
1996, 7, 981
31) Ren, P.; Pan, S.; Dong, T.; Wu, S. Synth. Commun. 1996,
26, 3903
32) Shao, J.G.; Wang, L.C.; Zheng, M.; Zhong, Q. Chinese
Chem Lett. 1997, 8, 683
33) Suwinski, J.; Wagner, P.; Holt, E.M. Tetrahedron 1996,
52, 9541
34) Ballini, R.; Bosica, G. Synthesis 1994, 723
35) Gohain, S.; Prajapati, D.; Sandhu, J.S. Chem. Lett. 1995,
72
104
NaBH4
N
OH
47 %
NaBH4
NO
Co(DMGH)2
NH2
Pd/C
NO
NaBH4
NMe2
NMe2
NITROSO COMPOUNDS
ON
105
41 %
12 %
NH2
106
OXIMES
Alembic 8, 50
The reduction of oximes may give amines,
hydroxylamines or alcohols. Thus, ketoximes are
reduced to the primary amines (1).
O
N
OH
OH
NaBH4
Me
H
N H
NOH
NHBz HO
S
NaBH4
OH
NHBz
OH
NaBH4
R' R"CO2H
OH
O
OH
OH
Me
NHBz
107
HO
R
HO
NaBH4
R"
R'
R"
R"CO2H
108
109
QUATERNARY COMPOUNDS
Alembic: 15, 28
A wide variety of cyclic quaternary ammonium
salts containing >C=N+< unsaturations have been
reduced with NaBH4, including pyridinum (1-7)
pyrazinium (8,9), pyrazolium (10,11), isoquinolinium
(12,13,14), quinolium (15,16), pyroliumum (17),
Pyoladine (18), oxazolium(19,20,21), thiazolium
(22,23), and indoloquinolizium (24,25) in these the
>C=N+< is effectively hydrogenated to the amine. One
of the most interesting reactions of this type is the
complete reduction of quaternized 4-aminopyridines to
the 4-aminopiperidines (26), and the reduction of
oxidopyrazinium iodides to 1-hydroxypiperazines (8),
OH
O
N
Me
Me
N+
Me
Me
R
R
NaBH4
N+
O
O
+
NaBH4
NaBH4
NH2
NH2
110
R'
R'
R
R'
NO2
S
+
NaBH4
NO2
Even nitrilium salts (-C+N-R), by way of imino ester [C(OR)=N-R], are reduced in good yield to the
secondary amine (31).
Iminium
salts
have
been
reduced
stereoselectively with sodium borohydride. (32,33,34)
Trimethyl propogyl ammonium iodide can be reduced
with sodium borohydride to an alkene and isopropyl
alcohol in high yield (35)
Nickel (II) chloride with sodium borohydride
can reduce quartarnary ammonium salts in high yields
(36).
111
112
113
Alembic: 6
C+
H
NaBH4
C
H
H+
C
R'
R'
"R
ClO4-
NaBH4
R
R'
"R
H
C
H
H
C
114
R'
ClO4R
H
NaBT4
C
R'
T
R
115
REDUCTIVE CLEAVAGES
R"
Y
NaBH4
EtOH
R'
R"
H
N
OH
N
H2N
OH
N
N
H2N
HO
CH3 N
H
(2)
N
N
N
H
HO
NaBH4
(3)
O
NH
O
NaBH4
X or Y = NR2, OR, SR
H
N
116
NH2
NaBH4
(5)
R
Ph
NaBH4
Ph
CN
(7)
117
References:
1) Shimizu, K.; Ito, K.; Sekiya, M. Chem. Pharm. Bull. 1974,
22, 1256; Chem. Abstr. 81, 120403c
2) U.S. 3,983,118 1976
3) U.S. 3,714,186 1973; Chem. Asbstr. 82, 170620m
4) Rautio, M. Farm. Aikak. 1974, 83, 131; Chem. Abstr. 82,
170620m
5) Parker, W.L.; Johnson, F. J. Org. Chem. 1973, 38, 2489;
Chem. Abstr. 79, 53201d
6) Jpn. Kokai Tokkyo Koho 84, 161,3445 1984; Chem.
Abstr. 102, 149102s
7) Jpn. 74 19,243 1974; Chem. Abstr. 82, 97816z
8) Takahashi, K.; Kurita, H.; Ogura, K.; Ida, H. J. Org.
Chem. 1985, 50, 4368; Chem.Abstr. 103, 178145j
9) Liao, M.J.; Huang, K.S.; Khorana, H.G. J. Biol. Chem.
1984, 259, 4200; Chem. Abstr. 100, 187575h
10) Sahimamura, M.; Inoue, Y., S. Arch. Biochem.. Biophys.
1984, 232, 699; Chem. Abstr. 101, 106875h
11) Ud-Din, N.; Jeanloz, R.W. et. al. J. Biol. Chem. 1986,
261, 1992; Chem. Abstr. 104, 166504h
12) Mawhinney, T.P. J. Chromatog. 1986, 351, 91; Chem.
Abstr. 104, 65133f
13) Rautio, M. Acta Chem. Scand. Ser. B. 1979, B33, 770;
Chem. Abstr. 93, 71685h
14) Rautio, M.; Heeso, A.; Rahkamaa, E. Arch. Pharm.
(weinheim) 1981, 314, 622; Chem. Abstr. 95, 114299w
118
119
REDUCTIVE CYCLIZATION
Several interesting reductive cyclization
involving sodium borohydride have been reported. For
instance, NaBH4 reduction of beta and gamma keto
(aldehydro) esters (or acids) yields lactone derivatives
in good yields (1-8):
R"
R"
NR'
N
CCl3
O
NaBH4
R
N
N
H
OH
R'
NaBH4
CN
R'
R'
OH NaBH4
R
"R
O
O
R
CN
"R
NO2
NaBH4
CO2Et Pd/C
N
H
N
OH
O
CN
R'
"R CO R
2
NO2
R'
NaBH4
Pd/C
R"
OH
Recent
publications
include
reductive
cyclization of gamma imino compounds (22,23)
photocatalyzed NaBH4 cyclizations (24-27) and even
cyclization to form epoxides (28,29)
Organic compounds containing alkenes and
halides, tin trichlorides or hydrazones are reductively
cyclized with sodium borohydride or cyanoborohydride
to from cyclic hydrocarbons. (30,31,32 )
Cyclic amines can be formed by the reductive
amination/cyclization of ketones with amines or azides
with borohydrides.(33,34) The five membered rings
contained in Protocin C and D can be synthesized the
same methodology. (35). It has been demonstrated that
imines and O-mesty groups can be reductively cycilized
to form cyclic amines in high yields with NaBH in
MeOH (36). Other functional groups that have been
120
121
DEHALOGENANTIONS
Alembic: 9, 52, 55, 61
Under normal reaction conditions, alkyl and
aryl halides are inert to NaBH4. Under solvolytic
conditions, however, secondary and tertiary alkyl
halides which are capable of forming stable carbonium
ions are reducible to the corresponding hydrocarbon (13).
Good to excellent yields are reported in
dehalogenantion of bezhydril chloride to diphenyl
methane, t-cumyl chloride to cumene and triphenyl
methyl chloride to triphenylmethane. (See also section
on carbonium ion reductions.)
In addition, several authors have reported
dehalogenantion of gem-dihalo compounds with sodium
borohydride (4,5).
New developments in the catalyzed NaBH4
reduction of halo compounds have broaden the
applicability of this reaction.(6-8) Photo-catalyzed
reduction of halogenated aromatic hydrocarbons has
been reported (9-11). Inorganic catalysts such as
palladium chloride or nickel chloride (in situ nickel
boride) have proven effective for site specific
deuteration of aryl halides (12,13), for dechlorination of
various pesticides and PCBs (14-17) and for analytical
determination of organic solids bound halides (18,19).
122
123
34) Zhang, H.R.; Wang, K.K. J. Org. Chem. 1999, 64, 7996
124
DEMERCURATIONS
The oxymercuration of olefinic bonds,
followed by reductive demercuartion with sodium
borohydride, is an extremely efficient method for the
stereoselective, high yield Markownikov hydration of
olefins: (1)
OH
Hg(OAc)2
R
CH2
R
THF/H2O
OH
HgOAc NaBH4
NaOH
H
H
R
H
125
References:
1) Russell, G.A.; Jiang, W.; Hu, S.S.; Khanna. R.K. J. Org.
Chem. 1986, 51, 5499
2) Brown, H.C.; Geoghegan, P. J. Am. Chem. Soc. 1967, 89,
1522; Chem. Abstr. 67, 99540u
3) Lorock, C. Angew. Chem. Int. Ed. Engl. 1978, 17, 27
4) Seyferth, D. Organomet. Chem. Rev., Sec. B, Ann. Rev.
1971, 8, 425; Chem. Abstr. 76, 59682w
5) Quirk, R.P.; Lea, R.E. J. Am. Chem. Soc. 1976, 98, 5973;
Chem. Abstr. 85, 191940u
6) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1971, 93,
6902; Chem. Abstr. 76, 33692z
7) Pasto, D.J.; Gontarz, J. A. J. Am. Chem. Soc. 1969, 91,
719; Chem. Abstr. 70, 67337d
8) Giese, B.; Kretzschmar, G. Chem. Ber. 1984, 117, 3175;
Chem. Abstr. 102, 61581m
9) Jasseerand, D. et. al. Tetrahedron 1976, 32, 1535; Chem.
Abstr. 86, 43091y
10) Kitching, W.; Atkins, A.R.; Wickham, G.; Albert, V. J.
Org. Chem. 1981, 46, 563; Chem. Abstr. 94, 83505h
11) Harding, K.E.; Marman, T.H. J. Org. Chem. 1984, 49,
2838; Chem. Abstr. 101, 72865n
126
127
128
DOUBLE BONDS
Olefinic bonds are reducible by sodium
borohydride only when activated. Any functional group
which sufficiently polarizes the double bond can
activate this group for borohydride reduction. Several
classes of activated double bonds have been reported
including: unsaturated nitriles (1-4), aldehydes,
ketones (5), nitro (6,8), esters (9-11) and lactones
(12,13): carbon-carbon double bonds alpha to an aryl
ring (14,15); unsaturated amines (e.g. enamines 16-21).
Several examples where activated double bonds have
been reduced are shown below:
R"
R"
N
NaBH4
(17)
R
N
R'
R'
O
O
O
O
O
NaBH4
O
O
(20)
NMe
NaBH4
HN
NMe
(16)
AcO
AcO
O2N
H
H
O2N C
H
C
NaBH4
HN
O
CO2R
(22)
CO2R
O
NaBH4
NaBH4
OH
OH
h
(23)
129
OH
HO
OH
OH
130
131
132
EPOXIDES
Alembic 48, 50, 55
Sodium borohydride is generally unreactive
toward any epoxide groups and ahs been effectively to
remove impurities in materials such as ethylene oxides
(1), propylene oxide (2), and glycidylmethacrylate (3).
However, some authors have reported the use
of sodium borohydride for selective opening of strained
or activated epoxides (4-8). In some instances it is not
clear whether the borohydride ion BH4- or an in situ
generated derivative e.g. B(OR)3H- was actually
responsible for the ring opening reaction.
In sodium borohydride reduction of vicinal
epoxy alcohols, only the trans epoxy alcohol and not the
corresponding cis compound was reduced (9). This
selective reactivity should be extremely useful in the
synthesis of pharmaceutical compounds.
The use of supported borohydride reagents has
gained popularity in reducing many functional groups
including epoxides. The use of zinc borohydride on
zeolites, aluminophosphates and silica gel has been
demonstrated to ring open epoxides. (10-12)
Sodium borohydride in low molecular weight
alcohols have been shown to reduce epoxy esters to
133
134
N
S
O
(1)
S
NR
135
NaBH4
R'
HS
R'
H
S
+
X
NaBH4
X= O
X=S
R1
R
R3
NO2
NO2
NaBH4
Se
Se
Ph
NaBH4
2 Ph
SeNa
R4
V R1=R2= OCH3; R3,R4=H R1=OCH3;R2=OH;R3=R4=H
VI R1=R2= H; R3,R4= OCH3 R1;R2=H;R3=OH, R4=OCH3
Ph
NMe
R2
S
+
136
NO2
NaBH4
SeCN
NO2
Se-
2
R
2 NaHSe
Amine
Se
Se
OTs
N
CH2OMs NaBH4
H
CH3
137
138
139
OZONIDES
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
References:
1) Warnell, J.L.; Shriner, R.L. J. Am. Chem. Soc.
1957, 79, 3165; Chem. Abstr. 51, 15509f
14)
140
OOH
O
I
Bu
OH
O
NaBH4
Ph
Ph
141
142
143
144
145
146
References:
1) James, D.B. Wallbridge, M.G.H. Prog. Inorg.
Chem. 1970, 11, 99; Chem. Abstr. 73, 41276v
2) Marks, T.J.; Kolb, J.R. Chem. Rev. 1977, 77, 263;
Chem. Abstr. 86, 140116t
3) Kadlec, V.; Kadlecova, H; Masek, J. Chem. Listy
1976, 70, 673; Chem. Abstr. 85, 136308u
4) Jula, T.F. Inorganic Reductions with sodium
borohydride Ventron Corp. 1974
147
148
149
150
151
107)
108)
109)
110)
111)
112)
113)
114)
115)
152
153
154
B. Organometallic
155
References:
1) Sugiura, Y.; Kikuchi, T.; Tanaka, H. J. Chem. Soc., Chem.
Commun. 1977, 795
2) Gerlach, D.H.; Peet, W.G.; Muetterties, E.L. J. Am. Chem.
Soc. 1972, 94, 4545; Chem. Abstr. 77, 62114p
3) Dapporto, P.; Fallani, G.; Midollini, S.; Sacconi, L. J. Am.
Chem. Soc. 1973, 95, 2021; Chem. Abstr. 78, 13154k
4) Giannoccaro, P.; Sacco, A. Inorg. Synth. 1977, 17, 69;
Chem. Abstr. 88, 12113d
5) Carriedo, C.; Gomez-Sal, P. et. al. J. Organomet. Chem.
1986, 301, 79; Chem. Abstr. 104, 179029g
6) Ogoshi, H.; Sntsune, J.; Tyoshida, Z. J. Am. Chem. Soc.
1977, 99, 3869; Chem. Abstr. 887, 135837v
7) Dolphin, D.; Sams, J.R.; Tsin, T.B.; Wong, K.L. J. Am.
Chem. Soc. 1976, 98, 6970
8) Jpn. Kokai Tokkyo Koho 78, 112, 900 1978; Chem.
Abstr. 90, 121679v
156
19) Teo, S.B.; Tech, S.G. Inorg. Chem. Acta 1985, 107, 35;
Chem. Abstr. 103, 63855y
20) Koola, J.D.; Brintzinger, H.H. J. Chem. Soc., Chem.
Commun. 1976, 388; Chem. Abstr. 85, 124088j
21) Nesmeyanov, A.N.; Chapovskii, Y.A.; Ustynyuk, Y.A.
Izv. Akad. Nauk SSSR, Ser. Khim. 1966, 1871; Chem.
Abstr. 66, 64860a
22) Chao, T.; Epsenson. J.H. J. Am. Chem. Soc. 1987, 100,
129; Chem. Abstr. 88, 111148r
23) Saito, T.; Munakata, H.; Imoto, H. Inorg. Synth. 1977, 17,
83; Chem. Abstr. 88, 121313e
24) Takagi, K. Chem. Lett. 1986, 265; Chem. Abstr. 105,
208796h
25) Meakin, P.; Guggenberg, L.J.; Peet. W.G.; Muetterties,
E.L.; Jesson, J.P. J. Am. Chem.Soc. 1973, 95, 1467; Chem.
Abstr. 78, 101033c
26) Corey, E.J.; Suggs, J.W. J. Org. Chem. 1975, 40, 2554;
Chem. Abstr. 83, 130658v
27) Birnbaum, E.R.; Javora, P.H. J. Organomet. Chem. 1967,
9, 379; Chem. Abstr. 68, 22026u
28) Young, R.; Wilkinson, G. Inorg. Synth. 1977, 17, 75;
Chem. Abstr. 88, 105484f
157
158
51)
52)
53)
54)
159
160
C. NaBH4 Derivatives
NaBH3CN
Alembic 1, 3, 7, 8, 15, 18, 23, 44, 46
Sodium cyanoborohydride, which is soluble
in a wide variety of solvents and is hydrolytically
stable to a pH of approximately 3, has extremely
interesting properties (1-4). Under neutral conditions
in water and methanol, the reduction of aldehydes and
ketones is insignificant; however, at pH 3-4, rapid
reduction to the alcohol occurs (5,6). The imine
group, >C=N-, is reduced by cyanoborohydride much
more rapidly than carbonyls, providing a convenient
and efficient route to the reductive amination of
aldehydes and ketones (5,7-10).
RRC=O + RNH2 + NaBH3CN RRCHNHR
The reaction is general for ammonia, primary and
secondary amines, all aldehydes and unhindered
ketones. Smooth reductions of acid chlorides and
enamines are also possible with NaBH3CN, the latter
N
H
H+
BH3CN-
N+
N
H
100
BER in MeOH
80
60
161
NaBH4 in MeoH
40
BER in 95%Et OH
20
0
0
50
100
NaBH4 in
95%Et OH
Ti m e M i nu t e s
Alembic: 4
162
163
164
Mixed Hydrides
Several systems have been devised, adding to
the number of functional groups that can be reduced
effectively with NaBH4. In these, the reducing power
of NaBH4 is enhanced to differing degrees.
165
Hydroboration
Alembic 60
Diborane, prepared from NaBH4 and I2, BF3,
Me3SlCl, TiCl4 or H2SO4 reacts rapidly and
quantitatively in ether solvents with organic
unsaturation to form organoboranes (155,156),
>B-H + CH2=CHR B-CH2CH2R
which can serve as reactive intermediates in organic
synthesis. This methodology is also capable of
reducing the following functional groups: nitrile
(157,158), epoxides (159,160), carboxylic acids (161171), amides (172-176), esters (177), oximes (178),
nitro (179,180), olefinic bonds (181, 182) as well as
reductive amination of ketones and aldehydes (183186). Stereoconfiguration is retained and, in contrast
with Grignard reagents, the reagent is compatible with
most functional groups.
The intermediates organoboranes undergo a
wide variety of reactions, as shown in Table VI,
including isomerization (187,188), displacement (189,
166
Reactants
C-B
2 (C-B)
C-C H-B
Means
H2NOSO3H
Alk. AgNO3
heat
Prodcdut
C-NH2
C-C
C-B
Displacment
Homologation
1C
2C
R-C-C-B
RCH=CH2
RCH=CH2
C-B
3C
CO
-haloester
(+ KOtBu)
CH2=CHCHO
4C
CH2=CHC(O)CH3
C-C-B
CCH2CO2R
CCH2CH2CHO
CCH2CH2C(O)CH3
C-C-C-B
Isomerization
Metalation
Oxidation
To alcohols
To Ketones
To Acids
Protonation
C-C-C
B
C-B
heat
Alk. M salt
Alk. H2O2
H2CrO4
1. H2CrO4
2. RCOOOH
RCOOH + heat
C-M
C-OH
C=O
C-CO2H
C-H
Other Derivatives
The reducing power of sodium borohydride can
further be enhanced in the presence of a reagent such as
carboxylic acid, thiol compounds or anilide. Such systems are
becoming more important and have greatly extended the scope
of this reagent. The active species in these systems have not
been isolated and the reducing agent are prepared and used insitu. Table VII summarizes the results.
167
Proposed
intermediate
STAB
NaBH4./
CH3CO2H
(1:1)
NaBH4/
CH3CO2H
(excess)
SMAB
NaBH4/
CH3CO2H
(6.5:1)
NaBH4/
RCO2H
(excess)
NaBH4./
CF3CO2H
(excess)
STAB
STRB
STFAB
168
Reduction
ref
Reduction of
aldehydes
Reductive
alkylation of
quinoline and
isoquinoline
Reduction of
amides and
amines
N-alkylation of
aromatic amines
and indoles
Reductive
deoxygenantion of
carbonyl tosyl
hydrazones
Reduction of
nitrimines to
nitramines
Reductive
alkylation of
oximes
Reduction of
carbonols and
ketones to alkanes
208 209
210
211 212
213
214
216
215
NaBH4
/CF3CO2H (1:1)
NaBH4/phthalic
acid (1:1)
NaBH4/thiol
SMFAB
NaH2B
(phthalato)
NaBH4/anilide
(1:1)
NaH3B
anilido)
NaBH4/ NaOH)
NaH3BOH
STAB= NaBH(O2CCH3)3
SMAB= NaBH3(O2CCH3)
STRB= NaBH(O2CR)3
STFAB=NaBH(O2CCF3)3
SMFAB=NaBH3(O2CCF3)
Reduction of
nitriles to amines
Reduction of
nitriles to amines
Reduction of nitro
compounds,
esters, amides and
imide
Reduction of
esters, aldehydes
and ketones, acid
chlorides
Reduction of
esters, nitriles and
nitro compounds
217
218
219
220
221
222223224
225226
References:
1) Wade, R.C.; Sullivan, E.A.; Berschied, Jr, J.R.;
Purccell, K.F. Inorg. Chem. 1970, 9, 2146; Chem.
73, 83350
2) Kreevoy, M.M.; Hutchins, J.E.C. J. Am. Chem.
Soc. 1969, 91, 4329; Chem. Abstr. 71, 54148p
3) Berschied, Jr. J.R.; Purcell, K.F. Inorg. Chem.
1970, 9, 624; Chem. Abstr. 72, 96136j
4) Levine, L.A.; Kreevoy, M.M. J. Am. Chem. Soc.
1972, 94, 3346; Chem. Abstr. 77, 10408t
5) Borch, R.F.; Bernstein, M.D.; Durst, H.D. J. Am.
Chem. Soc. 1971, 93, 2897; Chem. Abstr. 75,
49525n
6) Pfeil, J.L.; Kukolja, S.; Paquette, L.A. J. Org.
Chem. 1981, 46, 827; Chem. Abstr. 94, 139711s
7) Rosen, G.M.; J. Med. Chem. 1974, 17, 358;
Chem. Abstr. 81, 33187
8) Inokoshi, J.; Nakagawa, A.; Tanaka, H. Omura, S.
J. Antibiot 1983, 36, 1713; Chem. Abstr. 100,
97722e
9) Mathis, C.A.; Shulgin, A.T.; Sargent, T. J.
Labelled Cmpd. Radiopharm. 1986, 23, 115;
Chem. Abstr. 105, 225903
169
170
171
172
106) Gribble, G.W.; Nutatitis, C.F. Org. Prep Proc. Int. 1985,
17, 317
107) Gribble, G.W. Reduction in Organic Synthesis, ACS
Symposium Series, 1996, 641, 167
108) Gribble, G.W. Chemtech 1996, 12, 26
109) Gribble, G.W. Chemical Society Reviews 1998, 27, 395
110) Brown, H.C. Mead, E.J. J. Am. Chem. Soc. 1953, 75,
6263; Chem. Abstr. 5705e
111) Brown, H.C. Mead, E.J.; Shoaf, C.F. J. Am. Chem. Soc.
1953, 75, 6263; Chem. Abstr. 51, 3435g
112) Brown, H.C.; Cha, J.S.; Nazer, B. Inorg.Chem. 1984, 23,
2929; Chem. Abstr. 100, 121881a
113) Kriz, O.; Stucklik, J.; Socochor, P.; Stronf, O. Collect.
Czech. Chem. Commun. 1977, 42, 421; Chem. Abstr. 86,
188544h
114) U.S. 3,853,927 1974; Chem. Abstr. 82, 86499x
115) Ger. Offen. 2,137, 273 1972; Chem. Abstr. 77, 22412c
116) Private communication. W.R. Moser, Badger Company,
Inc., Waltham, Mass.
117) Firouzabadi, H.; Adibi, M.; Zeynizadeh, B. Synth.
Commun. 1998, 28, 1257
118) Tamami, B.; Goudarzian, N. J. Chem. Soc., Chem.
Commun. 1994, 1079
173
174
175
176
177
178
IV.
ANALYTICAL
BOROHYDRIDES
PROCEDURES
FOR
Disclaimer:
These methods were developed for internal use by Rohm and
Haas and are provided as an aid to our customers and other
interested parties. While we believe the information
contained herein to be reliable, we assume no liability for its
use. It is suggested that the user validate these procedures
for his/her own specific needs and samples.
Assay Methods
Sodium
borohydride
may
be
determined
gasometically, the hydrogen evolution method (1-5),
or volumetrically (6-9).
Jensen (8) lists four volumetric methods of
assay: acid and base titration (1), the iodate method
(7), a hypochlorite method (6), and a potentiometric
titration with permanganate. Sodium borohydride has
also been determined volumetrically by an iodine
method (2,10), a Chloramine T method (11) and the
argentimetric method of Brown and Boyd (12).
Other methods that have been reported to be
successful include an indirect spectrophotometric
179
180
181
NAD+
Crystal
Violet
readily
available
Rapid,
simple
method
applicable
over a wide
pH range
Rapid,
simple
method
interfere.
Reagent is
expensive and
unstable.
Must be done
in aqueous
solution.
Not
applicable to
caustic
solutions or
where strong
nucleophiles
are present.
Has been
applied to
aqueous and
non-aqueous
systems.
182
W2-W1
-V
B-P
15.17
273 + t
W(1000)
183
20.5
21.0
21.5
22.0
22.5
23.0
23.5
24.0
24.5
25.0
25.5
26.0
26.5
27.0
27.5
28.0
28.5
29.0
29.5
30.0
30.5
31.0
21.0
21.6
22.2
22.8
23.4
24.1
24.7
25.4
26.0
26.7
27.5
28.2
29.0
29.7
30.5
31.3
32.2
33.0
33.9
34.8
35.7
36.7
184
0.9980
0.9978
0.9976
0.9973
31.5
32.0
32.5
33.0
33.5
34.0
34.5
35.0
37.7
38.7
39.7
40.0
41.8
42.9
44.0
45.2
0.9971
0.9968
0.9965
0.9963
0.9960
0.9957
0.9954
Figure 13
0.9951
0.9947
0.9944
0.9941
3.
4.
5.
B. Reagents
6.
1.
2.
185
Volume of KIO3, mL x N
Volume of Na2S2O3, mL
186
187
Volume of iodate to
be added (mL)
30
35
40
45
3.
Trace NaBH4 Assay-Hydrogen Evolution
Apparatus
4.
See Figure 14
1.
2.
Procedure:
1. In order to expel all the air from measuring
burette (B)- the leveling bulb is raised while
stopcock is open. A small amount of
confining liquid is expelled to insure absence
of air, and stopcock S is then closed. The
5.
6.
7.
8.
188
Calculation
% NaBH4 = (V2-V1) x (B-3-P)* x 15.17
1000 x (273+t) x W
ppm NaBH4 = % NaBH4 x 104
V2 = The volume of gas evolved when sample is reacted, mL
V1 = The volume of gas evolved when blank is used, mL
B = Recorded barometric pressure in mm of Hg.
P = The vapor pressure in mm of the confining solution at the
temperature t. See Figure 15.
t = Recorded room temperature in oC
W = Sample weight in grams.
*3 mm are subtracted from the observed barometric pressure
to correct for the difference in expansion of the mercury and
the brass scale at different temperatures. Exact corrections
can be found in any chemical handbook.
Figure 14
189
Figure 15
190
4.
5.
B. Procedures:
1. Weigh a 100-gram sample to the nearest 0.0001 g
and transfer it to a 500 mL iodine flask with 1N
NaOH
2. Add 50-75 mL of H2O (two layers developorganic and an aqueous layer if the sample is
organic).
3. Add equivalent amount of 0.025 N KIO3 (1 mL
0.025 N= 0.00012 g NaBH4) plus 10 mL in
excess.
4. Add 2 g of potassium iodide and 10 mL of 6N
H2SO4 for every 10 mL of 1N NaOH present.
5. Titrate to yellow end point with 0.01 N Na2S2O3,
shaking vigorously while titrating.
6. Add 5 mL of starch and continue titration to clear
end point.
7. Calculation:
191
192
9.
193
5.
C. Calibration
1. Immediately before use, prepare a reagent
mixture of 50 mL of 0.05M NBC and 850
mL of 0.05 THAM buffer. Dispense 85 mL
of this mixture into each of six 100-mL
volumetric flask.
2. Add 8 mL of 0.05M KOH to each flask.
3. Add 0.0, 1.0, 2.0, 3.0, 4.0 and 5.0 mL of the
NaBH4 working solution (20, 40, 60, 80, 100
g NaBH4) to each flask, dilute to volume
with 0.05 M KOH and mix well.
4. Zero the spectrophotometer at 360 nm using
the blank (no NaBH4) solution in the 1.0 cm
reference and sample cells.
5. After 10 minutes measure the absorbance of
each of the standards at 360 nm.
6. Prepare a calibration curve by plotting
absorbance versus amount of NaBH4.
D. Procedure
1. Dispense 85 mL of the THAM/NBC mixture (see C
1) into each of two 100 mL volumetric flasks.
2. Add 8 mL of 0.05 M KOH to each flask.
3. Add up to 5 mL of the sample containing NaBH4 to a
100-mL volumetric flask. Add 5 mL of sample
matrix containing no NaBH4 (blank sample) to a
second 100-mL flask.
4. Dilute the contents of the flasks to 100 mL with 0.05
M KOH.
5. Measure the absorbance of each solution at 360 nm
after 10 minutes.
E. Calculations
NaBH4 concentration (ppm) = (S-B)( C )(D)
W
S = absorbance of NaBH4 treated sample
B = absorbance of blank
C= slope of calibration curve, g NaBH4/ absorbance unit
D = dilution factor, if any
W = Weight of sample in g
194
2.
3.
4.
5.
195
C. Calculations
1. Calculate the concentration of SBH in the
sample as follows:
References:
1) Davis, W.D.; Mason, L.S.; Stegeman, G. J. Am.
Chem. Soc. 1949, 71, 2775; Chem. Abstr. 43, 7805d
2) Morton Thiokol, inc. Ventron Products, Unpublished
standard methods
3) Krynitsky, J.A.; Johnson, J.E.; Carhart, H.W. Anal.
Chem. 1948, 20, 311; Chem. Abtsr. 42, 40941
4) Fatt, I.; Tashima, M. Alkai Metal Dispersions,
D.Van Nostrand Co. , Inc., Princeton, Newy Jersey,
1961, 98
5) Jensen, E.H. A Study on Sodium Borohydride Nyt
Nordisk Forlag Arnold Busck, Copenhagen 1954, 49
6) Chaikin, S.W. Anal. Chem. 1953, 25, 831; Chem.
Abstr. 47, 7371g
7) Lyttle, D.A.; Jensen, E.H.; Struck, W.A. Anal. Chem.
1953, 24, 1843
8) Jensen, E.H. A Study on Sodium Borohydride Nyt
Nordisk Forlag Arnold Busck, Copenhagen 1954, 49
9) Harzdorf, C.F. Anal. Chem. 1965, 210, 12; Chem.
Abstr. 63, 16f
10) Skoblionok, R.F.; Mochalov, K.N.; Berner, B.G. Zh.
Anal. Khim. 1968, 23, 1518; Chem. Abstr. 70, 16832d
ppm NaBH4 = F
Sample wt, g
Volume of CV+,
ml used for
sample titration
Suggested
Sample
Weight, g
Expected
Volume of
Titrant, mL
3
1.5
0.75
0.4
Up to 42.6
21.3-42.6
21.3-42.6
22.7-45.4
200-500
500-1000
1000-2000
1.5
0.75
0.4
17.0-42.6
21.3-42.6
22.7-45.4
Recommended
CV+
Concentration
0.019g CV+/L
0.19g CV+/L
196
197
V. AVAILABILITY
198
199
Dry
Dry borohydride products are corrosive to eyes,
skin and respiratory tract. They will cause irritation or
chemical burns if left in contact with moist skin or
respiratory tract. Therefore, the use of personal
protective equipment is required upon handling. The
level of equipment required can vary depending on the
expected level of exposure. We recommend :
Chemical goggles
Dust mask and/or a full face shield
Rubber gloves
Coveralls
Rubber boots or closed leather footwear
When the potential for exposure is significant, we
recommend wearing in addition to the above:
Apron or chemical resistant suit
A NIOSH-approved respirator for corrosive dusts
in place of dusk mask
Solution
Sodium borohydride
solutions
contain
sodium
borohydride stabilized with sodium hydroxide. These products
are strongly alkaline and corrosive. They can be handled with
the same personal protective equipment used when handling
50 % caustic. We recommend the following personal
protective equipment when handling the solution form:
Chemical splash goggles and a full face shield
Impervious rubber gloves
Coveralls
Rubber boots with pants over boots
(Note : Sodium borohydride solutions are very corrosive to leather)
200
Dry
Eye contact
Immediately flush eyes with copious amounts of water
for at least 15 minutes, including under the eyelids.
Then seek immediate medical attention.
Skin Contact
Immediately flush affected area with copious amounts of
water for at least 15 minutes. For larger exposures, use
an emergency shower. Remove contaminated clothing
and shoe. Cleanse skin with soap and water, including
hair and under fingernails. Then seek immediate medical
attention.
Inhalation
Remove to fresh air. If symptoms develop, seek
immediate medical attention. If not breathing, give
artificial respiration.
Ingestion
Powder/Granules: Rinse mouth with water and give
another cupful of water to drink. Do not give carbonated
Solution
Eye Contact
Immediately flush eyes with copious amounts of water for at least
15 minutes, including under the eyelids. Then seek immediate
medical attention.
Skin Contact
Immediately flush affected areas with copious amounts of water
for at least 15 minutes. For large exposure, use an emergency
shower. Remove contaminated clothing and shoes. Cleanse skin
with soap and water, including hair and under fingernails. Seek
immediate medical attention. Professionally wash clothing before
re-use.
Inhalation
If mist is inhaled, move to fresh air. Rinse mouth with water. If
symptoms develop, seek immediate medical attention. If not
breathing, give artificial respiration.
Ingestion
Give several glasses of water to drink. Do not give
carbonated drinks.
Do not induce vomiting, seek
immediate medical attention.
Note to physician: Highly alkaline materials can
cause extensive and deep penetrating tissue damage.
There is danger of hemorrhage and perforation if lavage is
performed. No attempt should be made to neutralize the
base with a weak acid.
201
VIII REACTIVITY
Dry
Dry borohydride products will react violently or
explosively in contact with concentrated oxidizers.
They will also react vigorously in contact with
concentrated acids or under acidic conditions,
generating heat and hydrogen gas.
Solutions
containing borohydride will also react to release
hydrogen in the presence of transition metal salts or
finely divided metallic precipitates.
Dry borohydride products will ignite from a free flame
due to hydrogen formation formed by decomposition
and will continue to burn as hydrogen is evolved. Dry
borohydride products also react with moisture in the
air, leading to caking. The moisture will slowly react
with the borohydride to liberate hydrogen gas.
Some organic solvents, such as acetone and methanol,
will react vigorously with borohydride.
Other
materials can generate heat and liberate hydrogen
when high concentrations of borohydride are
dissolved or slurried in these materials. Some known
Solution
NaBH4 solutions will react violently or explosively in contact
with concentrated oxidizers. They will also react vigorously in
contact with strong acids or under acidic conditions,
generating heat and hydrogen gas. Solutions containing
borohydride will also react to release hydrogen in contact with
transition metal salts or finely divided metallic precipitates.
Sodium borohydride solution will also react violently with
aluminum due to the sodium hydroxide present in the solution.
In addition, material as sensitive polymerization under alkaline
conditions, such as acrylonitirle and ethylene oxide, may
polymerize upon contact with sodium borohydride solution.
This solution is also incompatible with ammonia also.
General Consideration
In all cases where borohydride products are used, some H2
generation is expected. In many cases, H2 can be safely vented
to the outside of the building. H2 should not be allowed to
collect in a closed area.
202
203
surface. Disturbing the surface too soon can cause the hot
material to reignite.
Dry
Dry borohydride products are flammable solids and
are classified by the U.S. DOT as Division 4.3Dangerous when wet and the NFPA as a class 1 dust.
Fires involving dry sodium borohydride products
should be controlled with dry chemical extinguishers:
recommended dry chemical agents are sodium
bicarbonate based, monoammonium phosphate based
or equivalent. Do not use water, carbon dioxide or
halogen type fire extinguishers. Sand, dolomite or
lime should also be available in case the dry chemical
agent is insufficient or in windy conditions.
Firefighters and others who may be exposed to the
products of combustion should be equipped with
NIOSH-approved positive pressure self-contained
breathing apparatus (SCBS) and full protective
clothing.
Once the fire is extinguished, add additional
smothering agents such as dolomite, dry sand or lime.
Allow the material to cool before disturbing the
*For Online Consulting Only
Solution
Sodium borohydride solution is nonflammable.
Any
flammability is due to hydrogen generation upon
decomposition.
Under normal storage conditions, it is
extremely stable, decomposing less than 0.01% per year. To
prevent pressure buildup, 10% free volume is required for all
closed containers, under these conditions, containers will
normally generate less then 1 psig per year.
204
Dry
In the U.S., spills and wastes of dry sodium
borohydride products are regulated by the U.S. EPAs
Resource Conservation and Recovery ACT (RCRA)
as a hazardous waste with the code D003-reactive and
D001-Ignitable. Check with local regulations and
guidelines for additional requirements.
When dry borohydride products are spilled, clean-up
personnel must wear appropriate personal protective
equipment. Use non-sparking tools or explosion proof
equipment to shovel or vacuum material into an
appropriate container for disposal as hazardous waste.
After removing the spill from the floor, the area
should be rinsed with water, and the rinse water
collected for disposal.
Solution
In the U.S. spills and wastes of borohydride solution
products are regulated by the U.S. EPAs Resource
Conservation and Recovery Act (RCRA) as a
205
206
XI. TOXICITY
Dry
Dry sodium borohydride powder and caplets have
an acute dermal LD50 on dry skin of 4000 8000 mg
/kg and are not skin sensitizers. Toxicity is increased
in the presence of moisture and can result in severe
irritation and skin burns.
The acute oral LD50 of sodium borohydride
powder or caplets is 69-mg/kg. This product is
considered toxic under FHSA classifications.
The acute oral LD50 of potassium borohydride
powder is 160-mg/kg. This product is considered
toxic under FHSA classifications.
Solution
Solution of sodium borohydride in 50 % caustic has a
dermal LD50 of 100-500 mg/Kg and is considered moderately
toxic. This is primarily attributed to caustic soda, which can
cause skin burns and irritation.
The acute oral LD50 of the SWS solution is 500-1000
mg/kg. This product is considered toxic under FHSA
classifications.
Sodium borate, the product form the reaction or
decomposition of sodium borohydride, is considered slightly
toxic orally (LD50; 2000-4000mg /kg) and nontoxic dermally
(LD50 8000 mg/kg).
207
Solution
208
209
XIII. SHIPPING
Dry
Solution
Packing Group:I
Packaging Group: II
Label: Dangerous when wet
Label: Corrosive
210
Disclaimer:
To the best of our knowledge the information
contained herein is correct. All products may present
unknown health hazards and should be used with
caution. Although certain hazards are described
herein, we cannot guarantee that these are the only
hazards which exists.
Final determination of
suitability of the product is the sole responsibility of
the user. Users of the products should satisfy
themselves that thee conditions and methods of use
assure that the product is used safely.
NO
REPRESENTAIONS OR WARRANTIES, EITHER
EXPRESSED
OR
IMPLIED,
OF
MERCHANTABILITY,
FITNESS
FOR
A
PARTICULAR PURPOSE OR ANY OTHER NATURE
ARE MADE HERE UNDER WITH REPECT TO THE
NFORMATION CONTAINED HEREIN OR THE
PRODUCT TO WHICH THE INFROMATION
REFERS.
Nothing herein is intended as a
recommendation to use our products so as to infringe
any patents. We assume no liability for customers
violation of patents or other rights. The customer
211
Please feel free to send us your questions via venpure@rohmhaas.com, or contact one of our offices :
in America:
Rohm and Haas Company
S&PA
60 Willow Street
Phone: 1-978-557-1832
Fax: 1-978-557-1879
in Asia:
Rohm and Haas China, Inc.
23rd Floor, Hitech Plaza
No. 488 S. Wu Ning Road
Shanghai, China
Phone: +86 21 6230 6366
Fax: +86 21 6230 6377
in Europe:
Rohm and Haas France S.A.
la tour de Lyon
185, rue de Bercy
F-75579 Paris
Phone: +33-1 4002 5210
Fax : +33-1 4002 5441
212