Azo bond hydrogenation with hydrazine, R-NHNH2, and hydrazobenzene

Article abstract of DOI:10.1016/j.tetlet.2008.03.083

Hydrogenation of azo bonds with hydrazine, mono-substituted hydrazine, and hydrazobenzene was studied with selected diazene compounds under oxygen-free conditions. The reactions proceed rapidly and in high yield in several solvents, utilizing all N-H protons. While the reduction process is accompanied by the evolution of nitrogen gas in the case of N₂H₄, the intermediacy of diimide could not be confirmed by standard trapping experiments.

Full text of DOI:10.1016/j.tetlet.2008.03.083

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Tetrahedron Letters 49 (2008) 3234–3237
Azo bond hydrogenation with hydrazine,
R–NHNH , and hydrazobenzene
2
a
b
b,
b
*
William M. Koppes , Jesse S. Moran , Jimmie C. Oxley , James L. Smith
a
Naval Surface Warfare Center, Indian Head Division, Indian Head, MD, United States
b
Department of Chemistry, University of Rhode Island, Kingston, RI, United States
Received 29 February 2008; revised 14 March 2008; accepted 18 March 2008
Available online 21 March 2008
Abstract
Hydrogenation of azo bonds with hydrazine, mono-substituted hydrazine, and hydrazobenzene was studied with selected diazene
compounds under oxygen-free conditions. The reactions proceed rapidly and in high yield in several solvents, utilizing all N–H protons.
While the reduction process is accompanied by the evolution of nitrogen gas in the case of N
be confirmed by standard trapping experiments.
2 4
H , the intermediacy of diimide could not
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
conditions, the reduction appears to occur by a pathway
different from that commonly accepted for olefins. An effi-
cient reduction is observed with a minimum quantity of
hydrazine, whereas the common practice is to use a substan-
tial excess of hydrazine or hydrazine derivatives. An excess
of reducing reagent is used because of the disproportion-
ation of the intermediate diimide, which is assumed to be
The direct reduction of unsaturated bonds in certain
carbonyl and nitro functionalities with hydrazine is an
established technique.
non-polar, unsaturated bonds in olefins is achieved by the
decomposition of hydrazine derivatives to diimide (or di-
azene, HN@NH). In the presence of oxygen or hydrogen
peroxide, and with metal salt (e.g., Cu ) catalysis, hydr-
azine also reduces olefins.
formation rather than a direct reduction by hydrazine.
In a recent communication, an apparent direct reduction
of azo compounds with hydrazine is reported. The proce-
dure utilizes hydrazine in approximately a 100:1 ratio to the
azo compound. The reactions are done in ethanol at 60 °C
with no mention of an attempt to exclude exposure to air. In
connection with a program to synthesize energetic triazinyl
diazenes, we also observed their reduction to hydrazo com-
pounds in the course of using hydrazine to displace leaving
groups at the 4,6 positions of the triazine rings linked by azo
1
,2a
The indirect reduction of the
3
3
the actual reducing agent. Our experiments with less than
2
+
a molar equivalent of hydrazine suggest that all the hydro-
gens from hydrazine are efficiently utilized. These anaerobic
experiments appear to involve a direct reduction with
hydrazine, whereas the previous report of azo bond reduc-
tion with hydrazine likely involved an indirect reduction
through the diimide intermediate.
4
–8
This is attributed to diimide
9
1
0
2. Results
We investigated the reduction reaction with triazinyl
diazenes having structural variations, which revealed vary-
ing degrees of reactivity, as well as azo compounds with
attached alkyl, phenyl, and carbonyl functional groups
11
bonds. We present here the first investigation of the
hydrogenation of azo compounds by hydrazine with the
exclusion of oxygen or other oxidizing agents. Under these
(Fig. 1). Diazenes that were relatively electron deficient
were rapidly reduced in the presence or absence of oxygen,
whereas exposure to air was required for the reduction of
azobenzene. The effect of using substituted hydrazines as
*
Corresponding author. Tel./fax: +1 401 874 2103.
E-mail address: joxley@chm.uri.edu (J. C. Oxley).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.083

W. M. Koppes et al. / Tetrahedron Letters 49 (2008) 3234–3237
3235
MeO
N
OMe
N
H
2
N
N
OMe H
2
N
N
N
NH
N
2
2
Cl
NH
2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
1
2
3
4
N
O
MeO
Cl
OMe MeO
Cl
NH
2
H
2
NH
H
2
N
Cl
N
N
N
N
O
H
2
N
O
O
N
N
N
N
N
N
O
O
O
NH2
5
6
7
NH2
2
H N
8
Cl
Cl
O
N
O
N
O
N
N
NC
N
N
CN
N
N
N
N
9
10
1
1
Fig. 1. Synthesized and commercial diazenes used in this study.
reducing agents was also investigated. Although this has
not been previously reported, we found that phenylhydr-
azine, for example, was also an effective reducing agent
electron-deficient azo bond in 1 results in decolorization
in minutes at ambient temperature to give a 92% yield of
the reduced product. Azobenzene does not react in 18 h,
or after 6 h of heating at 60 °C (Table 1). Compounds 2
and 4, with 1 M equiv of hydrazine, displayed selective
reduction of the diazene and no displacement of the chloro
or methoxy substituents. Compound 3 was the least reac-
tive of the triazinyl diazenes, which may be chiefly attribut-
able to the deactivating amino groups, but its low solubility
would also contribute to the rate of reduction. Compound
5 showed very rapid elimination of its deep red color on the
addition of hydrazine at À10 °C. The reduction of the azo
bond took place without the displacement of the
chloro substituents. Diethyl azodicarboxylate 6 also was
reduced rapidly and in high yield. This reduction was
(
Table 1). Hydrazine, substituted hydrazines, and hydrazo-
benzene react rapidly under anaerobic conditions with
electron-deficient azo compounds to convert the colored
azo compounds to colorless hydrazo products, accompa-
nied the evolution of gas. The headspace gases produced
from the reaction of 1 and hydrazine or phenylhydrazine,
when analyzed by gas chromatography/mass spectrometry
(
GC/MS), confirmed that the effervescence observed was
due to the production of nitrogen.
Our reduction experiments were conducted primarily in
acetonitrile, but the use of chloroform, alcohols, and tolu-
ene afforded the same outcome. Several experiments were
conducted in ethanol as a comparison to the reductions
observed in 1895 and again in 1957, but the reaction
1
0
12,13
reported by Wang. The hydrazine reagent was in some
cases pre-dissolved in acetonitrile to enhance its mixing
with chloroform solutions of an azo substrate. Several
experiments with 1, 6, and 7, done in the absence of ultra-
violet light, did not affect the outcome, implying a reaction
initiating from a transient cis-diazene is not a requirement.
The reduction was accompanied by a rapid loss of the
initial color and the evolution of a gas. The color loss is
the expected as a result of loss of the p-bond connection
between the substituents of the diazene. Depending on
the compound, complete reaction was achieved in seconds
to many hours. The rate of reduction could not in all the
cases be reliably linked to the activation of the azo bond
due to the electron-withdrawing properties of the func-
tional group or ring system to which it was bonded because
some of the reactants were only marginally soluble in the
chosen solvent. The reaction rate, as qualitatively observed
by effervescence, remained unchanged when the hydrazine
reagent was stoichiometrically limited. The reduction of
diazenes achieved full conversion, even when the reaction
took several hours, with only one-half an equivalent of
hydrazine. Diimide lacks the stability to achieve this
specifics were not detailed.
Azodicarbonamide 7 also
reacted with hydrazine efficiently and quickly to yield
biurea. The rate was somewhat slower than 6. The related
cyclic amide 8 presented the shortest reaction time of all the
compounds studied. It is the only compound in this study
which contains a highly activated azo bond in the cis
conformation.
The elimination of oxygen prevents azobenzene, 9, from
reacting with hydrazine. Azobenzene was unreactive with
20 and 100 M equiv of hydrazine, in both ethanol and
acetonitrile without atmospheric oxygen, even at elevated
temperatures. When the azobenzene reaction is exposed to
the atmosphere, it proceeds, and with increasing rate with
greater hydrazine concentration. A considerable excess of
hydrazine is required to complete the reaction in a few
hours, but the reduction of azobenzenes does not require
1
0
heating in ethanol as done in a previous report. (Contra-
dictory to our findings and those of Wang, Pasha reported
that diazene cleavage rather than the reduction that
1
4
occurred under similar conditions. ) Under anaerobic con-
ditions azoisobutyronitrile, 10, and azo(bis-aminofurozan),
11, are resistant to hydrazine reduction.
3
efficiency over long reaction times.
We found that hydrazobenzene could be quickly and
efficiently oxidized to azobenzene while reducing diazene
compounds. The yield was similar to our other experi-
ments, and the azobenzene produced was also recovered.
The comparison of the homogeneous reductions of azo-
benzene 9 and tetramethoxy-substituted triazinyl diazene 1
does show a dramatic difference in reactivity. The more

3236
W. M. Koppes et al. / Tetrahedron Letters 49 (2008) 3234–3237
Table 1
of possible simultaneous direct and indirect reduction path-
Summary of the reduction reactions
ways. The autoxidation of hydrazine with oxygen occurs to
some degree without catalysis by metal ions, but hydrazine
oxidation in synthetically useful procedures is usually done
ID
Hydrazine reagent
NH NH
M equiv
Solvent
Yield (%)
Time
1
2
2
1
1
ACN
EtOH
ACN
92
97
90
90
93
83
63
94
75
94
94
94
98
100
20 m
4 h
2
b
in the presence of catalysts. It was initially assumed that
diimide was the active species in the reduction of the di-
azenes. However, the elimination of oxygen did not stop
the reduction. Furthermore, the stoichiometry suggested
that all four hydrogens from hydrazine are available for
delivery. These observations led us to believe the published
diimide mechanism was not solely operative. To probe for
the evidence of diimide generated in situ by the action of
the highly electron-deficient azo linkage, the reaction was
conducted in the presence of an olefin. However, our di-
azene reactions conducted with cis- or trans-stilbene or
diphenylacetylene were unaffected even when severe molar
excesses were employed. Additionally, the reduction of
acetonitrile solvent was not observed offering no evidence
0.5
0.5
0.5
20 m
10 m
10 m
10 m
20 m
15 m
20 m
15 h
15 h
2 h
7 d
18 h
2 m
2 m
10 m
5 m
CHCl
EtOH
3
Me–NHNH
Ph–NHNH
2
0.66
0.5
1
0.66
1
1
1
1
1
CHCl
ACN
ACN
CHCl
ACN
3
2
HOEt–NHNH
Ph–NHNH–Ph
2
3
EtOH
ACN
ACN
ACN
ACN
ACN
ACN
Toluene
ACN
ACN
ACN
ACN
ACN
ACN
2
3
4
5
NH
NH
NH
NH
NH
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
NH
2
2
2
2
2
2
a
1
0.5
1
n/a
87
100
99
89
88
74
86
98
98
98
87
95
81
95
99
96
NR
97
6
1
4
0
.5
1 m
1 m
for a diimide intermediate. Wang’s conditions (hydr-
8
Me–NHNH
Ph–NHNH
Ph–NHNH–Ph
NH NH
2
0.66
0.66
1
azinous ethanol) including a labile olefin, effectively yield
2
30 m
1 h
1.5 h
18 h
8 h
4 h
8 h
2 h
the saturated product indicating in situ diimide generation.
An insertion mechanism was considered as a possible
route to the overall reduction. Although such a mechanism
would be indistinguishable from the reduction when using
hydrazine, a two-step insertion and then the ejection of the
original linkage are less plausible with substituted hydr-
azines. Reacting substituted hydrazines with 1, 6, or 7 pro-
7
2
2
1
0
0
.5
.5
CHCl
ACN
ACN
ACN
3
Me–NHNH
Ph–NHNH
HOEt–NHNH
2
0.66
1
0.66
2
2
0
1
.66
EtOH
ACN
ACN
EtOH
EtOH
EtOH
ACN
15 h
<1 m
1 m
duced the reduced product and effervescence (N ), but no
8
9
NH
2
NH
2
2
0
.5
substituted triazinyl hydrazines that would indicate an
insertion of hydrazine into the C–N bond. When phenyl-
hydrazine was used as the reducing agent, azobenzene,
benzene, nitrogen, and biphenyl were identified by GC/
MS. While these match the expected decay products result-
ing from the oxidation of phenylhydrazine to phenyldi-
b
NH
NH
2
NH
NH
2
100
100
3 d
2
2
/O
2
3.5 h
24 d
18 h
1
0
1
94
NH
NH
NH
2
NH
2
NH
2
NH
2
2
2
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
c,d
6 h
1
1
1
EtOH
EtOH
ACN
18 h
c
15
6 h
azene (Ph–N@NH), we were unable to obtain any UV
/O
2
18 h
evidence for a phenyldiazene intermediate. Unlike diimide,
phenylhydrazine or hydroxyethylhydrazine, when oxidized
to substituted diazenes (R–N@NH), show no reaction with
c
2 d
Ph–NHNH
2
2 h
c,d
18 h
18 h
18 h
7 d
6
1
1
0
NH
2
NH
2
1
1
1
ACN
ACN
ACN
olefins, and delivery of the final hydrogen is not ade-
c
quately described by the published mechanisms. Neverthe-
less, even in aprotic solvents, reactions with 2/3rd M equiv
fully reduced our diazenes even when the reaction took
several hours.
1
a
b
c
NH
2
NH
2
Excess hydrazine causes rapid polymerization.
Subsequent venting to air gave 94% in 2 h.
Reactions performed at 60 °C.
d
The azobenzene experiments suggest that the effective-
ness of oxygen in promoting the reduction is greater than
would be expected if it is proceeding through the simple
oxidation of hydrazine to diimide. The admission of air
to a solution that was standing for three days without reac-
tion resulted in the isolation of hydrazobenzene in 94%
yield after 2 h exposure. This efficiency in the apparent
air oxidation of hydrazine indicates that the azo-bond in
azobenzene has an activating effect on hydrazine that facil-
itates its oxidation to form the diimide (shown to be only
slowly generated in air/hydrazine mixes without the help
of catalysts). In notably electron poor diazenes, the
activation is such that oxygen is not a requirement to yield
a reductive species. However, our experiments show that a
Subsequent venting to air gave NR.
However, the color loss of the diazene was masked by the
color of azobenzene, and no effervescence was observed. It
was therefore difficult to qualitatively measure the reaction
progress, and the reaction times reported may not reflect
the time necessary for full conversion.
3
. Discussion
The possible role of oxygen in the hydrazine reductions
that we initially observed in our triazinyl diazene synthesis
reactions led us to use anaerobic conditions in investigating
these reactions so that we could eliminate the complication

W. M. Koppes et al. / Tetrahedron Letters 49 (2008) 3234–3237
3237
diimide species, if generated, is not available to susceptible
olefins (stilbenes) in the reaction mixture.
unchanging. The resulting hydrazo compounds were
typically of lesser solubility and presented themselves as a
white precipitate. The solvent was removed under high vac-
uum and the product isolated. In the cases where the prod-
uct was highly insoluble, the dry solid was reconstituted with
solvent (25 mL) and immediately filtered to retrieve the solid
product. Reactions deviating from this general workup are
described as necessary. Properties were compared to litera-
ture spectra or authentic samples. Nuclear magnetic reso-
nance and melting-point were primarily used for the
analysis of the products but at such times when GC/MS
was feasible, it was also implemented and the retention time
and fragmentation matched with authentic samples.
4
. Conclusions
We have shown that all N–H hydrogens of hydrazine and
several substituted hydrazines (methyl-, hydroxyethyl-, and
phenyl-hydrazine) and hydrazobenzene are efficiently
delivered to highly electron poor diazenes under mild condi-
tions, in a variety of solvents. No evidence was found for di-
imide generated in situ. The difference in reactivity between
these diazenes and azoarenes in the absence of oxygen, cou-
pled with stoichiometry observed when using substituted
hydrazines, indicates a previously unstudied mechanism.
While we have discussed the role of hydrazine as a
reducing agent, we should also consider our observations
in terms of the behavior of diazenes as oxidizing agents.
Such reactivity has been observed by Yoneda when using
Acknowledgments
J.M. was supported in part by NSWC Indian Head
under the Student Career Experience Program. The
authors thank Dr. William Rosen and Evan Bernier of
the University of Rhode Island for their discussions and
instrumental expertise.
6
as a hydrogen-abstractor, but a mechanism was not pos-
1
6,17
tulated nor the role of oxygen adequately examined.
Several papers have reported that 8 can be used to remove
1
8,19
non-adjacent C–H hydrogens.
We observed a stark dif-
ference between highly electron poor diazenes, requiring no
external oxygen for their reaction with hydrazines, and the
more electron-rich azoarenes which required the reaction
to be conducted under oxygen atmosphere. Indeed, the
results suggest some hierarchy of reactivity when compar-
ing olefins, azoarenes, and electron-poor diazenes. This
continuum may include a change in mechanism which
has yet to be recognized and suggests unstudied chemistry
surrounding the azo functionality. It may be that further
studies will find that highly electron-poor diazenes may
be used as green oxidizers, offering the advantages of atom
efficiency, facile workup, and mild reaction conditions.
Supplementary data
Experimental details and spectral data for unpublished
compounds. Instrument settings for chromatographic
experiments. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2008.03.083.
References and notes
1
2
. Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis;
Wiley & Sons: New York, 1995; Vol. 4.
. (a) Schmidt, E. W. Hydrazine and its Derivatives. Preparation,
Properties, Applications, 2nd ed.; Wiley & Sons: New York, 2001,
pp 442–445; (b) Schmidt, E. W. Hydrazine and its Derivatives.
Preparation, Properties, Applications, 2nd ed.; Wiley & Sons: New
York, 2001, pp 473–485.
5
. Experimental
A round-bottom flask fitted with a rubber septa was
3
. Pasto, D. J.; Taylor, R. T. In Organic Reactions; Paquette, L. A., Ed.;
Wiley & Sons: New York, 1991; Vol. 40, pp 91–95.
charged with the starting azo compound (0.25–0.1 g) dis-
solved or suspended in a solvent (25 mL) and appropriate
stir bar. The reaction mixture was sonicated for 10 min
and then placed on a vacuum line. The reaction was
freeze–thaw degassed three times with multiple backfills of
inert gas. The reaction mixtures for all the compounds
except (10) were highly colored. During the third warming
of the reaction, after all the solvent ice had melted, the
hydrazine compound was added via syringe. The tempera-
ture at this point was estimated to be somewhat below the
room temperature, but the reaction flask was equilibrated
to room temperature in only a few minutes. The hydrazine
monohydrate was delivered via syringe from a sonicated
4
5
. Aylward, F.; Sawistowska, M. Chem. Ind. 1961, 433–434.
. Aylward, F.; Sawistowska, M. Chem. Ind. 1961, 404.
6. Aylward, F.; Sawistowska, M. Chem. Ind. 1962, 484–491.
7
. Corey, E. J.; Mock, W. L.; Pasto, D. J. Tetrahedron Lett. 1961, 11,
47–352.
3
8
9
. vanTamelen, E. E. J. Am. Chem. Soc. 1961, 83, 4302.
. Miller, C. E. J. Chem. Educ. 1965, 42, 254–259.
1
0. Zhang, C.-R.; Wang, Y.-L. Synth. Commun. 2003, 33, 4205–4208.
11. Koppes, W. M.; Rosenberg, D. M.; Vos, B. W.; Oxley, J. C.; Moran,
J. S. 230th ACS National Meeting, Washington, DC, 2005.
1
1
1
2. Curtius, T.; Heidenreich, K. J. Prakt. Chem. 1895, 52, 454–489.
3. Reed, R. A. Chem. Prod. 1957, 20, 271–274.
4. Pasha, M. A.; Nanjundaswamy, H. M. Synth. Commun. 2005, 35,
8
97–900.
15. Huang, P.-K. C.; Kosower, E. M. J. Am. Chem. Soc. 1968, 90, 2367–
376.
1
M solution in matching solvent where applicable. In some
2
cases, the hydrazine monohydrate was delivered neat in
microliter quantities via a gastight syringe in one portion.
The reaction proceeded with effervescence over minutes to
many hours. The mixture was allowed to stir under the inert
gas until the loss of color indicated the reaction complete or
16. Yoneda, F.; Suzuki, K.; Nitta, Y. J. Am. Chem. Soc. 1966, 88, 2328.
17. Yoneda, F.; Suzuki, K.; Nitta, Y. J. Org. Chem. 1967, 32, 727.
18. Christoforou, A.; Nicolaou, G.; Elemes, Y. Tetrahedron Lett. 2006,
4
7, 9211–9213.
19. Klindert, T.; Seitz, G. Synth. Commun. 1996, 26, 2587–2596.