Equilibria of formation and dehydration of the carbinolamine intermediate in the reaction of benzaldehyde with hydrazine

Article abstract of DOI:10.1016/j.tet.2007.04.034

Measurement of polarographic limiting currents at equilibria made it possible at pH 3-7 to simultaneously determine concentrations of benzaldehyde, of its hydrazone and of the carbinolamine derivative. The dependence of concentration of carbinolamine at equilibrium on pH indicated presence of its di-, mono-, and unprotonated forms. Acid dissociation constants of the formation (pK_a¹≈3.2) of the diprotonated form and of the dissociation of the monoprotonated form of carbinolamine (pK_a²≈4.7) were estimated. The equilibrium constants of formation (K₁) and dehydration (K₂) of the carbinolamine intermediate were determined.

Full text of DOI:10.1016/j.tet.2007.04.034

Tetrahedron 63 (2007) 5450–5454
Equilibria of formation and dehydration of the carbinolamine
intermediate in the reaction of benzaldehyde with hydrazine
y
*
Melek S. Baymak and Petr Zuman
Department of Chemistry, Clarkson University, Potsdam, NY 13699-5810, USA
Received 23 March 2007; revised 10 April 2007; accepted 12 April 2007
Available online 20 April 2007
Abstract—Measurement of polarographic limiting currents at equilibria made it possible at pH 3–7 to simultaneously determine concentra-
tions of benzaldehyde, of its hydrazone and of the carbinolamine derivative. The dependence of concentration of carbinolamine at equilibrium
on pH indicated presence of its di-, mono-, and unprotonated forms. Acid dissociation constants of the formation (pK1az3.2) of the diproto-
nated form and of the dissociation of the monoprotonated form of carbinolamine (pK2az4.7) were estimated. The equilibrium constants of
formation (K1) and dehydration (K2) of the carbinolamine intermediate were determined.
Ó 2007 Published by Elsevier Ltd.
O
O-
1. Introduction
NH+3
CH +
CH
H2N
NH+2 NH+3
K1
Literature dealing with kinetics of reaction of carbonyl com-
pounds with nucleophiles such as hydroxylamine, semicarb-
azone and its congeners, and hydrazine and its derivatives is
voluminous.1–7 These reactions were assumed to involve
two equilibria, with a carbinolamine as intermediate (1):
+ H+
OH
CH
NH+2 NH+3
OH
CH
+
-
H
NH NH+3
pK1 = 3.7
a
OH
C
O
RNH2
+
C
ð1Þ
+
NR
C
H2O
pK2 = 4.7
+
NHR
-
H
a
- H2O
K2
OH
CH
NH
At pH 2–7, where hydrazine is predominantly present in
a monoprotonated form, the reaction has to involve several
acid–base equilibria (Scheme 1). Little is known about the
position and role of these equilibria. The evidence reported4
for the presence of carbinolamine in such reactions was
only qualitative and obtained in unbuffered solutions. The
existence of such intermediate was concluded based on
a rapid decrease of the carbonyl band in the IR spectrum.
This was observed in a reaction mixture containing 0.5 M
furfural dissolved in D2O in the presence of 2.0 M hydroxyl-
amine. This relatively fast reaction was followed in the used
unbuffered system by a slower increase of this band with
time.
NH2
N
H
C
NH2
Scheme 1. The reaction mechanism between benzaldehyde and hydrazine.
In a similar experimental approach, the UVabsorption in the
250–290 nm range was followed during the reaction of benz-
aldehyde (in the presence of 25% ethanol) or furfural with an
excess of hydroxylamine.4 A rapid decrease in absorbance in
this wavelength range was attributed to the formation of car-
binolamine. The following slow increase of the measured
absorbance with time was attributed to the formation of
the oxime. Reported spectra4 indicate an overlap of absorp-
tion bands of all three aromatic compounds present—
the parent carbonyl compound, the carbinolamine, and the
resulting oxime.
Keywords: Benzaldehyde hydrazone; Formation and dehydration of car-
binolamine; Equilibria; Polarography.
* Corresponding author. Tel.: +1 315 268 2340; fax: +1 315 268 6610;
This demonstrates the limited suitability of spectrophoto-
metry for evaluation of equilibrium constants involved.
Because of this situation and the absence of buffers to con-
trol the pH during these reactions, the few reported values
for experimental equilibrium constants K01¼[C(OH)NHR]/
e-mail: zumanp@clarkson.edu
Present address: Department of Chemistry, Marmara University, Goztepe,
y
€
_
Istanbul, Turkey.
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.04.034

M. S. Baymak, P. Zuman / Tetrahedron 63 (2007) 5450–5454
5451
[CO][RNH2] and K02¼[C]NR][H2O]/[C(OH)NHR] are not
reliable, because the role of the acid–base equilibrium con-
stants has not been taken into consideration. Moreover, no
attempt has been made to investigate the role of pH on equi-
libria involved in Scheme 1.
cell, together with a dropping mercury electrode and a refer-
ence electrode. To these two electrodes is applied a voltage,
gradually increasing by about 0.1 V/min. Currents passing
through the investigated solution are recorded as a function
of the applied voltage. In the presence of a reducible or an
easily oxidized species, the current increases with increasing
voltage. The plot of the current as a function of the applied
voltage shows an increase of current in the potential region
where the species is reduced or oxidized. At a sufficiently
high voltage, the current ceases to increase and reaches a
limiting value.
In later communications from the Jencks’ group8,9 some
equilibria between carbonyl compounds and hydroxylamine
or semicarbazide have been followed in buffered solutions.
The measurements have been carried out at a single pH
and only the overall equilibrium constants K0¼[>C]NR]/
[>C]O][RNH2] were reported.
Resulting stepwise curve (resembling the plots of integrated
areas in NMR) is called a polarographic wave. The potential
at the inflection point of such curve, where the current rea-
ches one half of its limiting value, is called the half-wave
potential. Its value is characteristic for the nature of the
reduced or oxidized species in the given solution. The differ-
ence between the current before the wave raise and the top of
the step is called ‘limiting current’. Such currents are often
controlled by the diffusion of the electroactive species to
the electrode and are a linear function of concentration (sim-
ilarly as an absorbance at a given wavelength).
In this contribution, the advantage has been taken from the
possibility of simultaneous determination of the unreacted
benzaldehyde and the hydrazone formed. This was possible
based on measurements of limiting currents of polarographic
i–E curves.
Currently, the most frequently used technique for investiga-
tions of kinetics and equilibria involving organic compounds
is spectrophotometry in the UV–visible region. This tech-
nique offers in most cases useful information concerning
the kinetics of reactions involved. For investigation of equi-
libria, an application of this technique offers straightforward
information, provided that absorption maxima of starting
materials, of products and sometimes of intermediates are
well separated. Frequently overlaps occur, which can be
solved only using time-consuming deconvolution ap-
proaches. The usage of another spectroscopic technique,
namely NMR, is often limited for reactions in D2O by the
insufficient solubility of the starting materials or products.
If two species are present in the solution, such as benzalde-
hyde and its hydrazone, two waves are observed, if the
reduction potentials of the two species differ by more than
about 0.1 V (Fig. 1). The limiting currents of the two species
are additive. Measurements of two (or more) limiting cur-
rents, which are a linear function of concentration, enable
simultaneous determination of two (or more) electroactive
species present in the solution. This makes it possible to
determine concentrations of starting materials and products
(and sometimes even intermediates) in a much less time-
consuming fashion than a deconvolution of spectra.
In DC polarography, used in this study, the investigated so-
lution is placed in a supporting electrolyte in an electrolytic
Figure 1. Polarographic curves of benzaldehyde in the presence of hydrazine at equilibrium. The concentration of the amine increases from right to left.

5452
M. S. Baymak, P. Zuman / Tetrahedron 63 (2007) 5450–5454
0.00020
0.00010
0.00000
The above condition is fulfilled in reaction mixtures contain-
ing benzaldehyde and its hydrazone. The majority of reduc-
tions of azomethine derivatives occur at more positive
potentials than the reduction of the parent carbonyl com-
pound.10 The limiting current of the first wave in Figure 1,
which is more positive by about 0.25 V and corresponds to
a two-electro reduction of the azomethine bond in the prod-
uct, increases with increasing concentration of the amine.
The limiting current of the second, more negative wave,
which corresponds to the two-electron reduction of the for-
myl group, decreases. Measurements of the limiting currents
of the two waves thus enable a simultaneous determination
of both species in the given reaction mixture.
2. Results and discussion
In the investigated pH range benzaldehyde is reduced in
a single two-electron wave or two one-electron waves to
alcohol,11 whereas benzaldehyde hydrazone is reduced, sim-
ilarly as other hydrazones,12,13 in a single four-electron wave
to benzylamine. Limiting currents of the waves of these two
compounds are a linear function of concentration and indi-
vidual concentrations were determined using calibration
curves. Due to a different number of transferred electrons,
a direct comparison of limiting currents would be in this
case misleading.
0
30
t (min)
60
Figure 2. Time dependence of concentration of benzaldehyde, benzalde-
hyde hydrazone, and their sum at pH 4.15. Initial benzaldehyde concentra-
tion was 2ꢀ10ꢁ4 M, that of hydrazine 2ꢀ10ꢁ3 M. (A) Benzaldehyde
hydrazone, (-) benzaldehyde, (:) the sum of concentrations of benzalde-
hyde and of benzaldehyde hydrazone. Theoretical curves for first-order
kinetics were plotted together with experimental points.
From the difference of the sum of equilibrium concen-
trations of benzaldehyde [PhCHO]e and of its hydrazone
[PhCH]NNH2]e subtracted from the initial concentra-
tion of [PhCHO]o, it was at each pH possible to calculate
the equilibrium concentration of the carbinolamine [PhCH-
(OH)NHNH2]e, using expression [PhCH(OH)NHNH2]e¼
[PhCHO]o–([PhCHO]e+[PhCH]NNH2]e).
the reaction as well as at equilibrium. The rate of formation
of carbinolamine at pH 4.15 is too fast to be followed in this
way, but the investigation of kinetics at other pH values and
temperatures is under investigation. In the reaction of hydr-
azine with terephthalaldehyde it was possible using variations
of polarographic i–E curves to follow concentration changes
of two carbinolamines –4–CH(OH)NHNH2–C6H4–CHO
and CH(OH)NHNH2–C6H4–CH]NNH2 with time.17
The possibility of using polarographic limiting currents for
following formation of carbinolamine in the course of hy-
drolysis of benzylidine aniline has been pointed out early.14
In that communication, which remained undeservedly ob-
scure, the authors did not apply their results for the determi-
nation of equilibrium constants of formation and cleavage of
carbinolamine nor their pH dependence.
The equilibrium concentration of benzaldehyde in the pres-
ence of a 10-fold excess of hydrazine decreases with increas-
ing pH (Fig. 3), whereas that of benzaldehyde hydrazone
increases. The equilibrium concentration of the carbinol-
amine increases at pH higher than about 2.5, reaches a max-
imum at about pH 4.2 and decreases up to about pH 5.5.
Between pH 5.5 and 7.0 the equilibrium concentration of
the carbinolamine remains constant. This shape of the pH
dependence of the equilibrium concentration indicates that
carbinolamine is present in three forms—a diprotonated
one, a monoprotonated one, and an unprotonated one. The
equilibrium concentration of the diprotonated form remains
negligible, that of the monoprotonated one is highest, and
that of the unprotonated form is somewhat lower.
The hydrazine is in aqueous media present in diprotonated,
monoprotonated, and unprotonated forms. For the two disso-
ciations, pKa values of 0.27 and 8.2 have been reported.15,16
To simplify the data treatment, the reaction of benzaldehyde
in this investigation was followed between pH 2.0 and 7.0
where the monoprotonated form of hydrazine predominates.
Reactions were followed in the presence of 10-fold excess of
hydrazine over benzaldehyde. Under such conditions, the
formation of azine is negligible.
To estimate the equilibrium constant of the reaction involv-
ing the monoprotonated form of the carbinolamine, the pH
dependence of the equilibrium concentration of the mono-
protonated carbinolamine was approximated by two dissoci-
ation curves (Fig. 4), which show that the two acid–base
equilibria involving the monoprotonated form of carbinol-
amine are approximately pK1az3.7 and pKa2z4.7.
To find conditions under which the equilibrium at each pH
value was established, the decrease in concentration of benz-
aldehyde and increase in concentration of the hydrazone
formed with time were followed (Fig. 2). At pH higher
than about 2.5 the sum of concentration of benzaldehyde
and its hydrazone was lower than the analytical concentra-
tion of benzaldehyde introduced into solution (Fig. 2). The
difference between the sum and initial concentration pres-
ents the concentration of carbinolamine at any time during
Different approaches have to be used to estimate the equili-
brium constants involving carbinolamine formation in

M. S. Baymak, P. Zuman / Tetrahedron 63 (2007) 5450–5454
5453
0.00020
0.00015
0.00010
0.00005
0.00000
3.7 and about 5.5 both mono and unprotonated forms are
present.
The sequence of reactions is depicted in Scheme 1. Defining
K1a¼[PhCH(OH)NHNH3+][H+]/[PhCH(OH)NH2+NH+3] and
K2a¼[PhCH(OH)NHNH2][H+]/[PhCH(OH)NHNH+3]
and
equilibrium constant for the carbinol formation K1¼SIM
[H+]2/(Ka1Ka2+K1a[H+]+[H+]2)[PhCHO][NH2NH+3] and the
equilibrium constant of dehydration of the carbinolamine
K2¼[PhCH]NNH2](K2a+[H+])/SIMK2a where the deter-
mined analytical concentration of the intermediate is defined
as SIM¼[PhCH(OH)NH+2NH3+]+[PhCH(OH)NHNH+3]+[Ph-
CH(OH)NHNH2], it was possible to calculate the values of
equilibrium constant K1 for the addition reaction yielding
the carbinolamine and equilibrium constant K2 for the elim-
ination of water from carbinolamine at individual pH values
(Table 1).
As the analytical concentration of the carbinolamine (SIM
)
was obtained as a difference between two large values, the
accuracy of values of SIM is limited. This, together with
possible contribution of some azine formation, may be re-
sponsible for the trend in calculated values of K1.
2
3
4
5
6
7
pH
Figure 3. Dependences of equilibrium concentrations of benzaldehyde,
benzaldehyde hydrazone, and carbinolamine intermediate on pH in solu-
tions containing 2ꢀ10ꢁ4 M benzaldehyde and 2ꢀ10ꢁ3 M hydrazine. (A)
Benzaldehyde, (:) benzaldehyde hydrazone, and (-) carbinolamine inter-
mediate.
The basicity of the Oꢁ group in the primary addition product
PhCH(Oꢁ)NH2+NH+3 is so strong that its protonation will
not play a role within the studied pH range 2–7. The depen-
dence of concentration of carbinolamine at pH<4 indicates
that its monoprotonated form is generated by a dissocia-
tion (at pH<4). This rules out the possibility that the con-
version of PhCH(Oꢁ)NH2+NH3+ into PhCH(OH)NHNH+3
would take place by an intramolecular hydrogen ion transfer.
Such transfer would be, namely, pH independent and the
concentration of the monoprotonated form would remain
pH independent at pH lower than about 4. No informa-
tion is available about the process involved in the dehydra-
tion. It is currently not possible to decide, if the
elimination of water takes place in two steps—e.g., by pro-
tonation of the OH group with a subsequent dissociation of
PhCH]NH+NH2, by initial elimination of the OHꢁ ion or
by an intramolecular proton transfer, followed by the elimi-
nation of water.
different pH regions. At pH lower than about 3, the equili-
brium concentration of carbinolamine, which is practically
completely present in a diprotonated form, is negligibly
low. In the given pH range, the concentration of the mono-
protonated form is extremely low and cannot be followed.
As the equilibrium between the diprotonated form and the
starting material is shifted in favor of the parent aldehyde,
the reaction can be considered to go directly from the start-
ing materials to the product.
At pH between about 3.7 and 4.7 the predominant form of
the carbinolamine is the monoprotonated one. Between pH
The difference between pK1a¼3.2 used in calculation of
constants K1 and K2 in Table 1 and pK1a¼3.7 used for
a good fit in Figure 4 is within experimental error in both
approaches. The observed dependence of the concentration
Table 1. Equilibrium constants of addition of hydrazine to benzaldehyde
(K1) and of the dehydration of carbinolamine yielding benzaldehyde hydr-
azone (K2) obtained at different pH values
pH
K1
9.1
15.2
22.4
—
—
—
—
K2
3.15
3.65
4.15
5.15
5.75
6.2
—
—
18.6
14.7
17.7
16.4
16.1
6.7
Figure 4. Dependence of concentration of carbinolamine in a solution con-
taining 0.1 mM benzaldehyde and 1ꢀ10ꢁ3 M hydrazine on pH. Experimen-
tal points (size indicates experimental error) and theoretical curves for
pK1a¼3.7 and pK2a¼4.7.
Average
15.6ꢂ6.6
16.7ꢂ1.5
Benzaldehyde (1ꢀ10ꢁ4 M) and hydrazine (1ꢀ10ꢁ3 M) in phosphate and
acetate buffers at 20 ꢃC. pKa1 used was 3.2 and that for pK2a was 4.7.

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M. S. Baymak, P. Zuman / Tetrahedron 63 (2007) 5450–5454
of the carbinolamine intermediate on pH and the possi-
bility of finding the equilibrium constants of both the forma-
tion of this intermediate and of its elimination might be
proved useful in re-interpretation of the mechanism of
formation of addition compounds of some carbonyl
compounds.
4.3. Procedures
Polarographic experiments were carried out by using a total
of 10 mL buffer solution with concentrations of the benz-
aldehyde and hydrazine in ratios suitable for individual equi-
libria. For a preliminary investigation of kinetics for testing
the establishment of the equilibria were used reaction mix-
tures containing 2ꢀ10ꢁ4 M benzaldehyde and 2ꢀ10ꢁ3 M
hydrazine. For the investigation of the equilibria, 2ꢀ
10ꢁ4 M benzaldehyde was reacted with hydrazine with con-
centrations varying between 2ꢀ10ꢁ4 and 2ꢀ10ꢁ2 M. Such
an excess of hydrazine was to achieve a suitable conversion
of the benzaldehyde to the product at the given pH. The
conversions of polarographic limiting currents into concen-
trations for benzaldehyde and the reaction product, needed
in evaluation of equilibrium constants, were achieved by
using calibration curves for these species recorded under
identical experimental conditions as those used in investiga-
tions of equilibria. The concentration of the free hydrazine
was calculated by subtracting the product concentration
from the initial hydrazine concentration and the concentra-
tion of intermediate was calculated by subtracting the sum
of equilibrium concentrations of the product and benzalde-
hyde from the initial concentration of benzaldehyde.
3. Conclusion
Based on measurements of polarographic limiting currents
of separate waves of benzaldehyde and its hydrazone, it was
possible to follow changes in concentration of the intermedi-
ate carbinolamine at equilibria in the reaction between benz-
aldehyde and hydrazine as a function of pH. The variations
of the equilibrium concentrations of the carbinolamine
with pH indicated that the equilibrium concentration of
carbinolamine is limited by two acid–base equilibria. The
equilibrium between the diprotonated form of the carbinol-
amine and the starting materials is shifted in favor of the
benzaldehyde and the monoprotonated form of hydrazine.
The equilibrium between the unprotonated form of the car-
binolamine and hydrazone is strongly shifted in favor of
the product. Only the monoprotonated form of the carbinol-
amine exists in reaction mixtures containing a 10-fold excess
of hydrazine in measurable equilibrium concentrations in
the presence of the starting materials and the product
(Scheme 1). This reaction scheme offers more detailed infor-
mation, enabling a better understanding of the mechanism of
this reaction. It represents a starting point for investigation of
kinetics of this reaction, which is in process. For benzene
derivatives bearing another electroactive group acting as
a substituent, it is possible to follow concentration changes
of carbinolamines directly, as has been recently demon-
strated for the reaction of hydrazine with terephthal-
aldhyde,17 where the second formyl group or hydrazone
group act as substituents.
Acknowledgements
The financial support of M.S.B. by Marmara University,
Istanbul, Turkey is gratefully acknowledged.
References and notes
1. Jencks, W. P. Catalysis in Chemistry and Enzymology;
McGraw-Hill: New York, NY, 1969.
2. Reeves, R. L. The Chemistry of the Carbon–Nitrogen Double
Bond; Patai, S., Ed.; Interscience: New York, NY, 1966;
pp 567–614.
4. Experimental
3. Ogata, Y.; Kawasaki, A. The Chemistry of the Carbonyl Group;
Zabicky, J., Ed.; Interscience: New York, NY, 1970; Vol. 2,
pp 42–55.
4.1. Electrochemical instrumentation
4. Jencks, W. P. J. Am. Chem. Soc. 1959, 81, 475.
5. Do Amaral, L.; Bastos, M. P. J. Org. Chem. 1971, 36, 3412.
6. Broghente, I. M. C.;Yunes, R. A. J. Braz.Chem. Soc. 1997,8, 549.
7. Zuman, P. Arkivoc 2002, 540–591R.
8. Sander, E. G.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 6154.
9. Sayer, J. M.; Peskin, M.; Jencks, W. P. J. Am. Chem. Soc. 1973,
95, 4277.
Current–voltage curves were recorded by using a polaro-
graph as well as capillary electrodes with characteristics of
m¼2.0 mg/s, t1¼3.0 s at h¼64 cm. A two-electrode electro-
lytic cell is used with a saturated calomel electrode (SCE)
separated by a liquid junction (Kalousek cell).
4.2. Chemicals
10. Zuman, P. Collect. Czech. Chem. Commun. 1950, 15, 839.
11. Zuman, P. Electroanalysis 2006, 18, 131.
12. Baymak, M. S.; Celik, H.; Lund, H.; Zuman, P. J. Electroanal.
Chem. 2006, 589, 7.
13. Baymak, M. S.; Celik, H.; Lund, H.; Zuman, P. J. Electroanal.
Chem. 2005, 581, 284.
14. Kastening, B.; Holleck, L.; Melkonian, G. A. Z. Elektrochem.
1956, 60, 130.
15. Yui, N. Rikagaku Kenkyusho Iho 1941, 20, 256; Chem. Abstr.
1941, 35, 46606.
The chemicals used for the preparation of simple phosphate,
acetate, bicine, and borate buffers were of analytical quality
and supplied by Baker and Fisher Sci. Company. Benzalde-
hyde and hydrazine sulfate were supplied by J.T. Baker
Chemical Co. (Phillipsburg, NJ). All chemicals were used
without further purification. Stock solutions (0.01 M) of
the studied aldehydes were prepared in acetonitrile and
stored in the dark for up to 3 days, and 0.01 M and 0.1 M
stock solutions of hydrazine sulfate were prepared freshly
in water.
16. Perin, D. D. Pure Appl. Chem. 1969, 20, 133.
17. Baymak, M. S.; Zuman, P. Tetrahedron Lett. 2006, 47, 7991.