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Kinetic determination of pKa in 2′-hydroxychalcones
00404039,?33$6.00 + .OO kI8~On h?SS h‘,
TeuahcdronLcttcrs.Vol. 34. No. 29. pp. 4615-4618.1993 Printedin Great Britain
Kinetic Determination of pKa in 2’-Hydroxychalcones fb~ia El. Blanco, Nora B. Debattih,
Juan M. Luco and Ferdinando
H. Fer&ti*
Department of Chemistry, San his National University 5700 San Lois, Argentina
Abstract: A kinetic model that enables the determination of pKa of 2’(OH)-chrlcone in 60% (w/w) ethanol-water, 32T, pH 9-10 and ionic shengtb 0.001 is developed. Experimental data arc obtained by UVMS and HPLC techniIpS.
The spcctrometric
correlations
on the basicity of substituted
studies
of KBH+ with
parameters and magnitudes bioactivity
have already
involved
the
the Brown
and Okamoto
chalcones
constants4
in highly acid media’”
are widely
related to simple flavonoid structure, microbiological been determined.5.8
distribution
cyclohexane(cy):ethanol-water
of
In the present (1)
t’(OH)-chalcone
(01-w), its coupling
and
flavanone
Thermodynamic
and chemical reactivity and
work, experiments
with specific
of isomers
known.
and the
were carried
out which
2’(OH)-4-(OCH3)-chalcone basic catalysis
(2)
of cyclization’
(3) and 4’(OCHj)-flavanone
in
of these
substances
in 01-w and the distribution
(4) in the
mentioned
phases. Rate equations were also developed that were used along with partition methods (KR) to
determine pKa values of 1 and 2. The compounds
used were obtained by Claisen-Schmidtlo
in cy:ol-w (60% w/w), spectroscopically The kinetic measurements
determined
and Reickel-MBlle&’
at 32T are:
1: 5.11,
2: 2.94,
procedures.
KR values
3: 2.60 and
4: 1.43.
on the systems (40 ml of chalcone solution in cy with 40 ml of 0.001 M KCI in
01-w 60% w/w, taken to the desired pH with 0.1 M NaOH), were carried out at 32*C by HPLC. The equilibria
established
and the reactions taking place in the systems studied are shown in Scheme
2. In the first place, there is a distribution subsequent
acid
Z’(OH)-chalcone flavanone
dissociation
from cy to the 01-w 60% w/w phase, with a
of the substance. Step 3 includes
a number
of changes
A ring rotation with respect to the Cl-C7 simple bond and the formation
enolate C ring (the interconversion
medium is a subject of continuing Steps 4, 5 and 6 respectively enolization
of chalcone
investigation
reaction Z’(OH)-chalcones with results and conclusion
refer to conjugated
and flavanone distribution
w
acid-base
in cy:ol-w 60% w/w.
4615
equilibrium
flavanones
such
as the
of the isomeric in an alkaline
not always in agreement).‘2-z4
of the flavanone
enol, flavanone
4616
Scheme 1 Equilibria and Reactions of the Analyzed Systems Process
SbP 1*
C(CY)=
C(w)
K~c=NJlc~/lc]w
Eql
c’(w) + H30+
Kac=r-lwlm
&2
C(w) + I320 *
2”’
kl C-(w) =
grd
E’(w)
Cyclization Reaction
E(w) + Hz0
KeE=lE- llw-wl
Eq3
kz 4fh
E-(w) + HsO+ C
5’h
E(w) =
F(w)
KEF=[EI/F~
Eq4
dh
F(w) =
WY)
K~~=Flcy/mw
&J
MCY : chaicone moiarity in chaiconate ankms, hydroahun respectively; mcy : flavanone isomeric flavanone ; Kac and librium constant of fiavanone Considering -(d[C’lw/dt)
cy ; [CJw, [Clw, [IPJ, PTJw, [Elw and FJw: molar& of chalcone, ions, enoiate onions, enoi and flavaoone in phase 01-w (60% w/w), molarity in cy ; Km and KRF : partitbn constants of chakone and &E : ackl dissocietion constants of chakone and enol ; KEF : equienolization; kl and h : specifk rates invoived in the reaction.
the reaction proposed in Step 3, its rate can be defined as: = kl.[C-jw - kz.[E‘lw
Making use of equilibrium
Eq6
relations 2 and 3, the following expression can be obtained from the rate equation:
{KeC/(KRc.CH+I)}.(-dMcyldt) = = k~.&c.Mcy/(KRc.&l)According
to the stoichiometry
~~~E.KEF.FIcY/(/(KRF.[H+~)
& 7
of the process presented in Scheme I,the mass balance can be established
MT = [Cky +[qcy/KRc + KdClcy/(KRc@l)+
&E.KEF.FJcY/WRF[H?I)
+ KEF.CFICY/KRF + IFIcY/KRF+ LFlcy Using this balance relation,it [C]cy. Upon
&8
is possible to reformulate Eq 7 and express it only as a function of time and
separation of variables and subsequent integration, the following is obtained
[Clcy = (B.[Glcy-A)/B.exp{-(B.KRC.lH+]/Ksc).t~ + A/B being ‘A’
t: and
as:
time ‘B’,
and
[Colcy:
defined
by
chalcone
Eqs
10
molarity and
II
,
in are
&9 cy constants
for
t=O.
The
characteristic
amounts of
the
4617
set pH, temperature and ionic strength values.
system at the previously
A = ~~.K&.KEF.FIT/ /{ KRe.W+l.(l+ ~KEP/(KRP.[H+~)+(~+KEF)/KRF)) B = kl.Kd(KRc.[H+I)+
EqlO
~~.K&KEF.(~+K~(KRc.[H+I)+VKRC)/
/{ KRF.U@I.(~+K&CEF/(KRF.[H%+
(~+KEF)/KRF))
Eq11
If the various constants of Eq 9 are indicated as ZI =
expression
(B.Kolc~- NIB
Eq 12
Z2 = B.KRc.@I&c
Eq 13
z3 = A/B
Eq I4
9 can be stated as Eq IS
[CJcy = Zi.exp( -Zz.t) + Z3 It is clear that the kinetic study of the 2’(OH)chaicone be carried out measuring
6
and & by Eq 25. The A and B constants are subsequently 14 and rearranging
flavanone isomerixation
the [C]cy changes in time and evaluating
terms conveniently,
the empirical
reaction in 01-w can
kinetic parameters
calculated using Eqs 12-Z4. Combining
the following expression
Zt, Z2
Eqs 20 to
is obtained
Z2.{1 - Z3.(l+l/KRC)/[aT) = Eq 16
= kl + (KpC%RC).{ 22.23/(MT.m+I)) The graphic representation
of this equation enables the calculation of the acid dissociation
chaicone under consideration chaicone cyclixation
(IGc), measuring the slope of the straight line obtained.
specific rate value (kt) is obtained from the corresponding
constants
of the
In the same way, the
intercept. The pH data used
in the plotting were obtained using the following equation pH = 4.238+ 0.4927pH (01-w60% w/w) This relationwas experimentally
established
in the pH 7 to pH 10 interval,
proposed by Van Uitert et ai.15-z6 The values of&c w/w,
32O C,
pH
9-10
2’(0H)-4-(OCH3)-chaicone K&(l) K&(2)
and
strength
following
the methodology
constants and of specific isomerixation O.OOl), determined
for
rates (01-w 60%
Z’(OH)-chaicone
(1)
and
(2), are the following
= 5.06 1o-9 = 1.59 lo-to
‘Ihe ordering obtained,
ionic
Eq 17
hr (1) = 4.67 1O-2(mid) kl (2) = 7.46 lO-2 (min”)
pKaC(1) = 8.30 < pKaC(2) = 9.80is in agreement with the higher
of 2’(0H)-4-(OCH3)-chaicone atom in 2’(0H)-chaicone.
carboniiic
oxygen,
Determinations
in
carried
relation out
to by
that other
presented authorslz18
nucieophiiicity
by the using
equivalent different
4618
methods and experimental Finally, considered
operating conditions, are in reasonable agreement with our results. *
the kinetic methodology
to be very convenient
proposed
for the determination
It is known that this fact makes it difftcult to apply conventional frequently
of pKa of 2’-hydroxychalcones
to overcome the marked unstability of such substances techniques
is
in alkaline medium.
and procedutes,z9~20
which are
used to determine acidity constants of various compounds.
REFERENCES
*
Catedra de Quimica - Fisica II, Departamento
1.
Noyce, D.S.; Jorgenson
2.
Tsukerman, S.V.; Kutulya, L.A.; Lavrushin, V.F.; Tyau, N.M. Russ. .I. Phys. Chem., 1968,42(8),1015.
Farmacia. Univetsidad
de Quimica. Fact&ad de Qufmica, Bioquimica
National de San Luis. Chacabuco y Pedemera. M.J.
J. Am Chem. Sot., 1%2,84,
y
5700. San Luis - Argentina.
4312-19.
Actu Chim. (Budupest), 1977, 94(l), 67-74.
3.
David, E.R.; Sxab6, G.B.; Rakosi, M.; Litkei, G.
4.
Brown, H.C.; Okamoto, K. J. Am. Chem. Sot., 1957, 79, 1913.
5.
Debattista,
6.
Pappano, N.B.; Blanco, SE.; Debattista, N.B.; Ferretti, F.H.
N.B.; Borkowski, E.J.; Pappano, N.B.; Kavka J.; Ferretti, F.H.
An. Asoc. Qufm. Argent.,
19% ,7 (2), 179-87.
Rev. Lat-umer. Microbial., 1987,29,
367-73. 7.
Debattista,
N.B.; Ferretti, F.H.; Pappano, N.B.; Blanco, S.E.
Rev. Latinoumer. Qufm., 1989,20(Z),
36-40. 8.
Blanco, S.E.; Tosetti, M.I.S.; Segovia, R.F.; Ferretti, F.H.
Rev. Microbiof., Sun Pablo, 1990,
21(2), 17582. 9.
Furlong, J.J.P.; Ferretti, F.H.; Pappano, N.B.; Debattista, N.B.; Borkowski, E.J.; Kavka J.,
An.QuGn.,
199-204.
1985,81(3),
The Fkwonoidr ; Harbone, J.B.; Mabry, T.J.;
10.
Wagner, H.; Farkas, L.: Synthesis of FIavonoids. In
11.
Reickel, L.; Miiller, K.
12.
Furlong, J.J.P.; Nudelman, N.S.
J.Chem.Soc. Perkin Trans. II, 1988, (7), 1213. J. Phys. Org. Chem.,1991, 4, 263.
Mabry, H. Eds.; Academic Pres: NewYork, Part 1, 1975, p. 131.
Ber., 1941, 748, 1741-42.
13.
Nudelman,
14.
Arcus, V.L.; Simpson, C.; Main, L. J.Chem.Reseurch (S), 1992, 80-81.
N.S.; Furlong, J.J.P.
15.
Van Uitert, LG.; Haas, C.G.
J. Am. Chem Soc.,1953, 75,451.
16.
Van Uitert, LG.; Femelius, W.C.
17.
Kakkar, S.N.; Khadikar, P.V.
18.
Swamy, S.J.; Lingaiah, P.
19.
Cookson, RF.
20.
Albert, A.; Serjeant, E.P.
JAmC’hem. SOC.,1954, 76,5887.
J.Indiun ChemSoc., 1977, 54, 667-69.
Indian J. Chem., 1978, 16A, 723-24.
Chem. Rev., 1974,74(l), 5-28. The Determination of fonizution Constants, Chapman and Hall: New York,
3rd ed., 1984
(Received in USA 23 March 1993; accepted 26 May 1993)
TeuahcdronLcttcrs.Vol. 34. No. 29. pp. 4615-4618.1993 Printedin Great Britain
Kinetic Determination of pKa in 2’-Hydroxychalcones fb~ia El. Blanco, Nora B. Debattih,
Juan M. Luco and Ferdinando
H. Fer&ti*
Department of Chemistry, San his National University 5700 San Lois, Argentina
Abstract: A kinetic model that enables the determination of pKa of 2’(OH)-chrlcone in 60% (w/w) ethanol-water, 32T, pH 9-10 and ionic shengtb 0.001 is developed. Experimental data arc obtained by UVMS and HPLC techniIpS.
The spcctrometric
correlations
on the basicity of substituted
studies
of KBH+ with
parameters and magnitudes bioactivity
have already
involved
the
the Brown
and Okamoto
chalcones
constants4
in highly acid media’”
are widely
related to simple flavonoid structure, microbiological been determined.5.8
distribution
cyclohexane(cy):ethanol-water
of
In the present (1)
t’(OH)-chalcone
(01-w), its coupling
and
flavanone
Thermodynamic
and chemical reactivity and
work, experiments
with specific
of isomers
known.
and the
were carried
out which
2’(OH)-4-(OCH3)-chalcone basic catalysis
(2)
of cyclization’
(3) and 4’(OCHj)-flavanone
in
of these
substances
in 01-w and the distribution
(4) in the
mentioned
phases. Rate equations were also developed that were used along with partition methods (KR) to
determine pKa values of 1 and 2. The compounds
used were obtained by Claisen-Schmidtlo
in cy:ol-w (60% w/w), spectroscopically The kinetic measurements
determined
and Reickel-MBlle&’
at 32T are:
1: 5.11,
2: 2.94,
procedures.
KR values
3: 2.60 and
4: 1.43.
on the systems (40 ml of chalcone solution in cy with 40 ml of 0.001 M KCI in
01-w 60% w/w, taken to the desired pH with 0.1 M NaOH), were carried out at 32*C by HPLC. The equilibria
established
and the reactions taking place in the systems studied are shown in Scheme
2. In the first place, there is a distribution subsequent
acid
Z’(OH)-chalcone flavanone
dissociation
from cy to the 01-w 60% w/w phase, with a
of the substance. Step 3 includes
a number
of changes
A ring rotation with respect to the Cl-C7 simple bond and the formation
enolate C ring (the interconversion
medium is a subject of continuing Steps 4, 5 and 6 respectively enolization
of chalcone
investigation
reaction Z’(OH)-chalcones with results and conclusion
refer to conjugated
and flavanone distribution
w
acid-base
in cy:ol-w 60% w/w.
4615
equilibrium
flavanones
such
as the
of the isomeric in an alkaline
not always in agreement).‘2-z4
of the flavanone
enol, flavanone
4616
Scheme 1 Equilibria and Reactions of the Analyzed Systems Process
SbP 1*
C(CY)=
C(w)
K~c=NJlc~/lc]w
Eql
c’(w) + H30+
Kac=r-lwlm
&2
C(w) + I320 *
2”’
kl C-(w) =
grd
E’(w)
Cyclization Reaction
E(w) + Hz0
KeE=lE- llw-wl
Eq3
kz 4fh
E-(w) + HsO+ C
5’h
E(w) =
F(w)
KEF=[EI/F~
Eq4
dh
F(w) =
WY)
K~~=Flcy/mw
&J
MCY : chaicone moiarity in chaiconate ankms, hydroahun respectively; mcy : flavanone isomeric flavanone ; Kac and librium constant of fiavanone Considering -(d[C’lw/dt)
cy ; [CJw, [Clw, [IPJ, PTJw, [Elw and FJw: molar& of chalcone, ions, enoiate onions, enoi and flavaoone in phase 01-w (60% w/w), molarity in cy ; Km and KRF : partitbn constants of chakone and &E : ackl dissocietion constants of chakone and enol ; KEF : equienolization; kl and h : specifk rates invoived in the reaction.
the reaction proposed in Step 3, its rate can be defined as: = kl.[C-jw - kz.[E‘lw
Making use of equilibrium
Eq6
relations 2 and 3, the following expression can be obtained from the rate equation:
{KeC/(KRc.CH+I)}.(-dMcyldt) = = k~.&c.Mcy/(KRc.&l)According
to the stoichiometry
~~~E.KEF.FIcY/(/(KRF.[H+~)
& 7
of the process presented in Scheme I,the mass balance can be established
MT = [Cky +[qcy/KRc + KdClcy/(KRc@l)+
&E.KEF.FJcY/WRF[H?I)
+ KEF.CFICY/KRF + IFIcY/KRF+ LFlcy Using this balance relation,it [C]cy. Upon
&8
is possible to reformulate Eq 7 and express it only as a function of time and
separation of variables and subsequent integration, the following is obtained
[Clcy = (B.[Glcy-A)/B.exp{-(B.KRC.lH+]/Ksc).t~ + A/B being ‘A’
t: and
as:
time ‘B’,
and
[Colcy:
defined
by
chalcone
Eqs
10
molarity and
II
,
in are
&9 cy constants
for
t=O.
The
characteristic
amounts of
the
4617
set pH, temperature and ionic strength values.
system at the previously
A = ~~.K&.KEF.FIT/ /{ KRe.W+l.(l+ ~KEP/(KRP.[H+~)+(~+KEF)/KRF)) B = kl.Kd(KRc.[H+I)+
EqlO
~~.K&KEF.(~+K~(KRc.[H+I)+VKRC)/
/{ KRF.U@I.(~+K&CEF/(KRF.[H%+
(~+KEF)/KRF))
Eq11
If the various constants of Eq 9 are indicated as ZI =
expression
(B.Kolc~- NIB
Eq 12
Z2 = B.KRc.@I&c
Eq 13
z3 = A/B
Eq I4
9 can be stated as Eq IS
[CJcy = Zi.exp( -Zz.t) + Z3 It is clear that the kinetic study of the 2’(OH)chaicone be carried out measuring
6
and & by Eq 25. The A and B constants are subsequently 14 and rearranging
flavanone isomerixation
the [C]cy changes in time and evaluating
terms conveniently,
the empirical
reaction in 01-w can
kinetic parameters
calculated using Eqs 12-Z4. Combining
the following expression
Zt, Z2
Eqs 20 to
is obtained
Z2.{1 - Z3.(l+l/KRC)/[aT) = Eq 16
= kl + (KpC%RC).{ 22.23/(MT.m+I)) The graphic representation
of this equation enables the calculation of the acid dissociation
chaicone under consideration chaicone cyclixation
(IGc), measuring the slope of the straight line obtained.
specific rate value (kt) is obtained from the corresponding
constants
of the
In the same way, the
intercept. The pH data used
in the plotting were obtained using the following equation pH = 4.238+ 0.4927pH (01-w60% w/w) This relationwas experimentally
established
in the pH 7 to pH 10 interval,
proposed by Van Uitert et ai.15-z6 The values of&c w/w,
32O C,
pH
9-10
2’(0H)-4-(OCH3)-chaicone K&(l) K&(2)
and
strength
following
the methodology
constants and of specific isomerixation O.OOl), determined
for
rates (01-w 60%
Z’(OH)-chaicone
(1)
and
(2), are the following
= 5.06 1o-9 = 1.59 lo-to
‘Ihe ordering obtained,
ionic
Eq 17
hr (1) = 4.67 1O-2(mid) kl (2) = 7.46 lO-2 (min”)
pKaC(1) = 8.30 < pKaC(2) = 9.80is in agreement with the higher
of 2’(0H)-4-(OCH3)-chaicone atom in 2’(0H)-chaicone.
carboniiic
oxygen,
Determinations
in
carried
relation out
to by
that other
presented authorslz18
nucieophiiicity
by the using
equivalent different
4618
methods and experimental Finally, considered
operating conditions, are in reasonable agreement with our results. *
the kinetic methodology
to be very convenient
proposed
for the determination
It is known that this fact makes it difftcult to apply conventional frequently
of pKa of 2’-hydroxychalcones
to overcome the marked unstability of such substances techniques
is
in alkaline medium.
and procedutes,z9~20
which are
used to determine acidity constants of various compounds.
REFERENCES
*
Catedra de Quimica - Fisica II, Departamento
1.
Noyce, D.S.; Jorgenson
2.
Tsukerman, S.V.; Kutulya, L.A.; Lavrushin, V.F.; Tyau, N.M. Russ. .I. Phys. Chem., 1968,42(8),1015.
Farmacia. Univetsidad
de Quimica. Fact&ad de Qufmica, Bioquimica
National de San Luis. Chacabuco y Pedemera. M.J.
J. Am Chem. Sot., 1%2,84,
y
5700. San Luis - Argentina.
4312-19.
Actu Chim. (Budupest), 1977, 94(l), 67-74.
3.
David, E.R.; Sxab6, G.B.; Rakosi, M.; Litkei, G.
4.
Brown, H.C.; Okamoto, K. J. Am. Chem. Sot., 1957, 79, 1913.
5.
Debattista,
6.
Pappano, N.B.; Blanco, SE.; Debattista, N.B.; Ferretti, F.H.
N.B.; Borkowski, E.J.; Pappano, N.B.; Kavka J.; Ferretti, F.H.
An. Asoc. Qufm. Argent.,
19% ,7 (2), 179-87.
Rev. Lat-umer. Microbial., 1987,29,
367-73. 7.
Debattista,
N.B.; Ferretti, F.H.; Pappano, N.B.; Blanco, S.E.
Rev. Latinoumer. Qufm., 1989,20(Z),
36-40. 8.
Blanco, S.E.; Tosetti, M.I.S.; Segovia, R.F.; Ferretti, F.H.
Rev. Microbiof., Sun Pablo, 1990,
21(2), 17582. 9.
Furlong, J.J.P.; Ferretti, F.H.; Pappano, N.B.; Debattista, N.B.; Borkowski, E.J.; Kavka J.,
An.QuGn.,
199-204.
1985,81(3),
The Fkwonoidr ; Harbone, J.B.; Mabry, T.J.;
10.
Wagner, H.; Farkas, L.: Synthesis of FIavonoids. In
11.
Reickel, L.; Miiller, K.
12.
Furlong, J.J.P.; Nudelman, N.S.
J.Chem.Soc. Perkin Trans. II, 1988, (7), 1213. J. Phys. Org. Chem.,1991, 4, 263.
Mabry, H. Eds.; Academic Pres: NewYork, Part 1, 1975, p. 131.
Ber., 1941, 748, 1741-42.
13.
Nudelman,
14.
Arcus, V.L.; Simpson, C.; Main, L. J.Chem.Reseurch (S), 1992, 80-81.
N.S.; Furlong, J.J.P.
15.
Van Uitert, LG.; Haas, C.G.
J. Am. Chem Soc.,1953, 75,451.
16.
Van Uitert, LG.; Femelius, W.C.
17.
Kakkar, S.N.; Khadikar, P.V.
18.
Swamy, S.J.; Lingaiah, P.
19.
Cookson, RF.
20.
Albert, A.; Serjeant, E.P.
JAmC’hem. SOC.,1954, 76,5887.
J.Indiun ChemSoc., 1977, 54, 667-69.
Indian J. Chem., 1978, 16A, 723-24.
Chem. Rev., 1974,74(l), 5-28. The Determination of fonizution Constants, Chapman and Hall: New York,
3rd ed., 1984
(Received in USA 23 March 1993; accepted 26 May 1993)