Spectrophotometric and polarographic studies on the kinetics of hydrolysis of N-(6-methyl-5-nitropyridin-2-yl methylidene)-N′-(substituted thiazol-2-yl)hydrazines

Article abstract of DOI:10.1002/jccs.200100159

The kinetics of the hydrolysis of hydrazpne derived from nitropyridine 2-carboxaldehyde and 2-hydrazino-4-substituted thiazoles la-e in 10% (v/v) DMF-buffer mixture has been investigated by applying two independent and different techniques viz UV-spectrop

Full text of DOI:10.1002/jccs.200100159

JournaloftheChineseChemicalSociety, 2001, 48, 1081-1086
1081
Spectrophotometric and Polarographic Studies on the Kinetics of
HydrolysisofN-(6-methyl-5-nitropyridin-2-ylmethylidene)-N -(substituted
thiazol-2-yl)hydrazines
Abobakr M. El-Nady
ChemistryDepartment,FacultyofScience,AssiutUniversity,Assiut,Egypt
The ki net ics of the hy dro ly sis of hydrazone de rived from nitropyridine 2-carboxaldehyde and 2-hydrazino-
4-substitutedthiazolesIa-ein10%(v/v)DMF-buffermixturehasbeeninvestigatedbyapplyingtwoindependent
and dif fer ent tech niques viz UV-spectrophotometry and dif fer en tial pulse, polarography (DPP).Thehydrolysis
hasbeenfoundtofollowgeneralacid-basecatalysis.Mechanismforthehydrolysisinacidic me dium has been pos-
tulated.Theobservedrateconstants,activationandthermodynamicparametersforthehydrolysishavebeencalcu-
lated. The ef fects of pH, mo lec u lar struc ture, tem per a ture and change in per cent age of wa ter in the DMF-buffer
mixtureontherateofhydrolysishavebeendiscussed.
INTRODUCTION
EXPERIMENTAL
Materials
(6-Methyl-5-nitropyridine-2-yl methylidene)-4-(sub-
sti tuted thiazol-2-yl)hydrazines (Ia-e) were pre pared and pu ri-
fied by the con ven tional method.19 The pu rity of the com-
poundswascheckedbyelementalanalysisandm.p.determi-
nation.
Hydrazinocompoundsandhydrazones1,2 have been ex-
tensivelystudiedfortheirpotentialityastherapeuticagents
for the treat ment of hy per ten sion and CNS de pres sion. Sev-
eralresearchprojectsweredirectedtostudythehydrolysisof
hydrazone de rived from aliphatic and ar o matic amines.3-14
The prep a ra tion of heterocyclic hydrazines and hydrazides
hasreceivedconsiderableattentionsinceiproniazidedemon-
stratedinvitroactivity.15,16 However, aliteraturesurveyre-
vealed the ab sence of hy dro ly sis of hydrazone de rived from
biologicallyactivenitropyridine17,18 and 4-substituted amino-
thiazole. The re sult ing hy dra zones have more po tent mono-
amineoxidaseinhibitoryactivity. 19
Thestructuresofthecompoundsunderinvestigation
arerepresentedasfollows:
O N
2
R
N
CH = N - NH
H C
3
N
S
Thepresentinvestigationisconcernedwiththehydro-
lysis kinetics of (6-methyl-5-nitropyridine-2-yl methyl i-
dene)-4-(substitutedthiazol-2-yl)hydrazinesinacidicbuffer
so lu tions. Such type of in ves ti ga tion has been fol lowed by
spectrophotometric(UV-spectra)anddifferentialpulsepo-
lar o graphic (DPP) tech niques. Thus, the eval u a tion of re ac-
tionrate,activationenergyandthermodynamicparameters
( G*, H* and S*) for the hy dro ly sis pro cess with the two
in de pend ent tech niques, i.e. UV-spectra and DPP, can give
additionalinformationontheeffectofpolarsubstituentson
the rate of hy dro ly sis. More over our aim is to ex plore the po-
ten ti al i ties of UV-spectrophotometry for stud ies on the hy-
drolysisprocessofthecompoundsinvestigatedincompari-
son with DPP.
I
(a) R = C6H4-OCH3(p) (b) R = C6H4-CH3(p) (c) R =
-C6H5 (d) R = C6H4-Cl(p) (e) R = C6H4-NO2(p)
Stock 10-3 M so lu tions of the hydrazone com pounds
were pre pared in DMF. The mod i fied uni ver sal buffer se ries
of Britton and Rob in son20 has a dual func tion: one as a sup-
port ing elec tro lyte in polarographic mea sure ments and the
other as a hy dro ly sis me dium. The mea sured val ues of pH’s
were ob tained us ing a dig i tal Ra di om e ter pH (M 64). The
pH-meter ac cu racy lies within 0.005 units.

1082 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
El-Nady
Instrumentation
RESULTS AND DISCUSSION
ElectronicspectrawerescannedonaCECILCE599re-
cordingspectrophotometerequippedwithatemperaturecon-
trolled cell holder and matched 1 cm quartz cell. The tem per-
a ture in the cell holder was con trolled by means of a Julabo
FP 40 ther mo stat with an ac cu racy of 0.01 °C where tem-
peratureofthesamplewasmeasureddirectlyinthecellwith-
in the wave length range 250-550 nm.
Dif fer en tial pulse polarograms were ob tained with a
PAR 174 A polarographic an a lyzer equipped with a PAR 1.72
drop time and electrode as sem bly. Polarograms were re-
corded with an ad vanced X-Y re corded (HP 7045 A). A ther-
mo stated Metrohm cell with a three elec trode sys tem was
used.
ThehydrolysisofIa-e de riv a tives in 10% (v/v) DMF-
buffermixtureshasbeenstudiedspectrophotometrically.UV
absorptionoftheinvestigatedcompoundsexhibitabsorption
bands lo cated at (283-410 nm), a phe nom ena which can be in-
ter preted as charge trans fer (CT) bands for the hydrazone
compoundsinvestigated.23 It was found that in acidic buffer
so lu tions the ab sorp tion of the CT band de creases while a
new band ap pears at lon ger wave length. This new band is due
totheabsorptionofoneofthehydrolysedproducts(Figs. 1A
and 1B).
Spectrophotometric Rate Measurements
The ki netic runs of the in ves ti gated com pounds were
per formed in 10% (v/v) DMF-buffer mix tures at 30 °C. Af ter
be ing prop erly thermostated at the re quired tem per a ture,
aliquots (9 mL) of buffer were trans ferred to a test tube con-
tain ing (1 mL) of 5 10-4 M I a-e. The mix ture was then shaken
vig or ously and trans ferred to 1 cm quartz cell, and the change
in UV ab sorp tion at the se lected wave length was re corded.
ThedisappearanceofIa-e was fol lowed to ~65-85% com ple-
tion.
Polarographic Rate Mea sure ments
Fig. 1A. Timedependenceofabsorptionspectraof5
10-5 M Ic derivativeat30°C. (pH2.25). 1)
10; 2) 15; 3) 20; 4) 25; 5) 32; 6) 40; and 7)
50 min.
TheUniversalbuffersolution(20mL)containingDMF
10% (v/v) was placed in the polarographic cell and deaerated
withnitrogen.After30min.oftemperatureequilibrationthe
re quired vol ume of the in ves ti gated com pounds was added
rapidly, andthedecayofthedifferentialpulsepolarographic
beakwasrecordedatdifferenttimeintervals.Thehydrolysis
productsdonotexhibitanyreductioncurrentinthepotential
range in which the re duc tion of the in ves ti gated com pounds
occurs.
Thereactionismonitoredspectrophotometricallyor
polarographically un der pseudo first-order con di tion by fol-
low ing the dis ap pear ance of Ia-e. The rate con stants were
com puted from the vari a tion of absorbance (A) and/or beak
height ( A)withtime. Thedataweregraphicallyrepresented
as log A or log Ip vs. time. Straight lines were ob tained with a
correlationcoefficientclosetounity,whichindicatesthatthe
hydrolysisstrictlyfollowsfirst-orderkinetics.Foreveryrun
the rate con stant was ob tained from the slope of the least
squares re fined lin ear plot. The re ported rate con stant is the
mean of at least four rep li cate runs. Ac ti va tion pa ram e ters
were ob tained from Arrhenius plots and the ap pro pri ate ki-
neticequations.
Fig. 1B. Timedependenceofabsorptionspectraof5
10-5 M Ie derivativeat30°C. (pH2.25). 1)
10; 2) 18; 3) 25; 4) 33; 5) 42; 6) 50; and 7)
60 min.

KineticsofHydrolysisofHydrazone
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1083
Thedifferentialpulsecurrentsofadifferentsubstitute
Ia-e hasalsobeenrecordedasafunctionofpotentialinuniver-
sal buffer so lu tions con tain ing 10% (v/v) DMF. Ib and Ie de-
riv a tives are shown in (Figs. 2A and 2B). The dif fer en tial
pulsepeakisrelatedtothereductionofthehydrazonemoiety
(-CH=N-NH-)whichinacidicmediaundergoesatotallyirre-
versibleelectrodereactionwithatotaluptakeof4-electrons
and 4-protons per mol e cule.21,22 In this con text it was found
that, inacidicbuffersolutions, thereductionpeak, whichcor-
re sponds to the re duc tion of the C=N bond, de creases with
time (Fig. 2A and 2B) while a sec ond dif fer en tial peak ap-
pears at more neg a tive po ten tials. Closer in spec tion of the
sec ond peak shows the co in ci dence of Ep of this peak with
that cor re spond ing to the re duc tion of the al de hyde. This in-
di cates that the sec ond peak must be at trib uted to the re duc-
tion of al de hyde formed by hy dro ly sis of the in ves ti gated
compoundsintotheirmainconstituents.Hydrolysisisdueto
the lo cal iza tion of elec trons on the “N” atom of the azo-
methinecenteraccordingtothefollowinggeneralreaction:
O N
2
R
O
N
C
2
3
R
N
H O
+
H
N
2
+
CHO
CH = N- NH
H
C
Fig. 2A. Time de pend ence of dif fer en tial pulse po-
lar ograms of 5 10-5 M Icderivativeat30
°C. (pH 2.25). 1) 10; 2) 16; 3) 22; 4) 30; 5)
38; 6) 45; and 7) 55 min.
3
N
H N-NH
H
S
N
2
S
A com par a tive ki netic study of the in ves ti gated com-
pounds was car ried out with UV spec tros copy and DDP. The
dis ap pear ance of the absorbance of the CT band or of the
DDPpeakwasrecordedatdifferenttimeintervals.Thedecay
of Ia-e de riv a tives in acidic me dium (pH 2.25-5.05) is of first
or der (Figs. 3 and 4).
The ob served first or der rate con stants are plot ted as a
func tion of pH for all com pounds un der in ves ti ga tion. The
pH-rate con stant pro file shows that the rate con stant de-
creases grad u ally with in creas ing the pH. At pH < 2.25 the
rateofhydrolysisbecomesindependentonthepH(Fig.5).
How ever, in neu tral me dia (pH > 5.05) the hy dro ly sis
processwasnotobservedandhasnomeasurablevalues.Such
behaviourcanbeobservedunderconditionsinwhichthesub-
strate ex ists as a free base and can un dergo at tack by pro tons,
sothatageneralacid-basecatalysismechanismispostulated
inSchemeIforthehydrolysisofcompoundsunderinvestiga-
tion in uni ver sal buffer acidic me dia which is sim i lar to the
mechanismproposedbymanyworkersforsimilarsystems.24-26
Such mech a nism in volves the con ver sion of the hydrazone
com pound to its con ju gate acid (-CH=NH-NH-) in a rapid
pre-equilibrium step fol lowed by the slow at tack of H2O mol-
e cule (Scheme I).
Fig. 2B. Time de pend ence of dif fer en tial pulse po-
larograms of 5 10-5 M Iederivativeat30
°C. (pH 2.25). 1) 10; 2) 18; 3) 27; 4) 35; 5)
43; 6) 52; and 7) 65 min.
The rate of the hy dro ly sis re ac tion fol lows the equa-
tions,

1084 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
El-Nady
Scheme I
O
H
N
C
2
3
R
N
K
1
+ HA
CH = N - NH
N
S
I
O
N
2
R
N
..... (1)
-
+
+ A
CH= NH - NH
H
C
3
N
S
II
R
N
k
-
2
....
A.... H ... O ... CH NH - NH
+ A
II + H O
2
slow
S
H
N
CH
3
T.S.
Fig. 3. First-order plots of log A vs t (min) at dif fer-
ent tem per a tures for the hy dro ly sis of Ic de-
riv a tive at pH 2.25. a) 20 °C, b) 25 °C, c) 30
°C, d) 35 °C and e) 40 °C.
NO
2
O
N
2
R
N
+ HA
CH - NH - NH
H
C
3
N
S
OH
III
k
3
O
N
C
2
R
N
+
.........
(3)
CH-NH - NH
H
3
2
N
S
-
O
IV
k
4
R
O N
N
2
NH - NH
...... (4)
+
2
S
H
C
CHO
3
N
d(II)
dt
= k2 [II] [A] = k2 K1 [I] [HA],
= Kobs. [I] [HA].
Fig. 4. First-order plots of log ip vs t (min) at dif fer-
ent tem per a tures for the hy dro ly sis of Ic de-
riv a tive at pH 2.25. a) 20 °C, b) 25 °C, c) 30
°C, d) 35 °C and e) 40 °C.
d(II)
dt
Uponincreasingthepercentageofwatercontentduring
thehydrolysisprocessofthecompoundsunderinvestigation,
one can ob serve an in crease in the rate con stant val ues where
theactivationenergyvaluesshowaremarkabledecrease(Ta-
ble 1).
Fur ther more, it was found that the ob served rate con-
stantincreaseswithincreasingelectrondonatingpower(Ta-
ble 2) in the thiazole moi ety con firm ing that the at tack of wa-
ter on the protonated hydrazone rep re sents the rate de ter min-
ing step. On the other hand elec tron with draw ing group (Id
and Ie) de crease kobs andincreasetheenergyofactivation.
Activationparameterswereobtainedfromtheplotof
logarithmoftheobservedrateconstantversusthereciprocal
ofabsolutetemperature.Thermodynamicparametersofacti-
va tion ( G*, H* and S*) were cal cu lated from the ap pro-
Fig. 5. Ef fect of pH on the first-order rate con stant
valueofhydrolysisof5 10-5 M of Ia-Ie at 30
°C.

Ki net ics of Hydrolysis of Hydrazone
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1085
Table 2. Specific Rate Constants for the Hydrolysis of Ia-e at pH
2.25, 10% (v/v) DMF-buffer Solutions Calculated from
UV-spectra and DPP Measurements at 30 °C
Table 1. Effect of Percentages of Water in the DMF-buffer
Solution Mixtures on the Values of the Observed Rate
Constants for the Hydrolysis of Ic at pH = 2.25 and
30 °C Calculated from UV-spectra and DDP
UV-spectra
103 k, min-1
DPP
103 k, min-1
No
R
UV-spectra
103 k, min-1
DPP
103 k, min-1
% water
Ia
Ib
Ic
Id
Ie
C6H4OCH3(p)
C6H4CH3(p)
C6H5
C6H4Cl(p)
C6H4NO2(p)
21.6 1.2
17.1 0.9
12.9 0.6
8.7 0.4
5.3 0.2
22.1 1.4
18.2 1.1
13.6 0.7
9.3 0.6
4.7 0.3
90
80
70
60
12.9 0.6
11.1 0.7
7.6 0.4
4.2 0.2
13.6 0.7
10.4 0.8
8.3 0.6
3.7 0.3
Table 3. Activation Energies and Thermodynamic Activation Parameters for the Hydrolysis of Ia-e at
pH 2.25, 10% (v/v) DMF-buffer Solutions Calculated from UV-spectra DDP at 30 °C
UV-spectra
DPP
Ea*
Kcal
mol-1
G*
Kcal
mol-1
H*
- S*
cal
Ea*
Kcal
mol-1
G*
Kcal
H*
Kcal
mol-1
- S*
cal
Compounds
Kcal
mol-1
mol-1 k-1
mol-1
mol-1 k-1
Ia
Ib
Ic
Id
Ie
11.1
12.4
13.7
16.1
19.5
21.0
21.4
21.7
22.9
25.0
10.5
11.8
13.1
15.5
18.9
34.7
31.8
28.4
24.4
20.1
10.5
12.8
14.2
15.8
20.4
20.8
21.7
22.0
22.2
25.3
9.9
36.1
31.5
27.8
23.0
18.2
12.2
13.6
15.2
19.8
ACKNOWLEDGEMENT
pri ate equa tions de rived from tran si tion state the ory and are
giveninTable3.Theparametersindicatethatthehydrolysis
is de creased with in creas ing the pH of the hy dro ly sis me-
dium, but en hanced by an in creas ing do nat ing power of the
substituent. Thevaluesofentropyofactivation S*indicate
a de pend ence on both the pH and the type of substituent in the
thiazolemoiety. Oncomparingthevaluesof S* at the same
pH,itbecomesapparentthatIe derivativehasthelowestacti-
vationentropythantheotherderivatives(Ia-d).
I kindly thank Dr. Hoda Y. Hassan, De part ment of Phar-
maceutical Medicinal Chemistry, Faculty of Pharmacy,
AssiutUniversityforprovidingthecompoundsunderinves-
tigation.
Received April 19, 2001.
This cor re la tion is due to the strong with draw ing char-
ac ter of the ni tro substituent which in turn makes the ac ti-
vated com plex less ran domly linked to sol vent mol e cules.
This be hav iour is in agree ment with the change of rate con-
stant and Ea*values.
Inconclusion, suchcomparativekineticstudiesonthe
hydrolysisofsomesubstitutedpyridinethiazolehydrazones
em pha size that more com pre hen sive and de tailed in for ma-
tion on the hy dro ly sis of the com pounds in ves ti gated is at-
tainablebythecombinedapplicationofthetwomethodsuti-
lized, i.e. UV-spectrophotometry and DPP tak ing into con-
siderationtheirrespectivesensitivitytochargetransferand
tofaradicreductionresponse.
Key Words
Kinetic studies; Hydrolysis; Nitro-2-pyridine
carboxaldehyde-2-thiozolyl hydrazones;
UV-spectrophotometry and differential pulse; Po-
larograph (DPP).
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