Arenesulfonylation of dl-serine, l-proline, l-threonine, and dl-methionine in systems 1,4-dioxane-water and propan-2-ol-water

Article abstract of DOI:10.1007/s11172-010-0186-0

Kinetics of interaction of dl-serine, l-proline, l-threonine, and dl-methionine with 3-nitrobenzenesulfonyl chloride in water (40%)-1,4-dioxane and water (40%)-isopropanol mixed solvents was studied spectrophotometrically at 298 K. The main reactive form of α-amino acids is shown to be anionic. Under conditions of arenesulfonylation, the basicity of α-amino acids is crucial in determining the reaction rate. Arenesulfonylation rate constants are 20-50 times lower than the constants of N-acylation of the same α-amino acids with benzoyl chloride and 10⁴-10⁵ times higher than the rate constants of their reactions with benzoic acid 4-nitrophenyl ester.

Full text of DOI:10.1007/s11172-010-0186-0

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 922—926, May, 2010
922
Arenesulfonylation of DLꢀserine, Lꢀproline, Lꢀthreonine,
and DLꢀmethionine in systems 1,4ꢀdioxane—water
and propanꢀ2ꢀol—water
N. V. Kalinina, T. P. Kustova, and L. B. Kochetova
Ivanovo State University,
39 ul. Ermaka, 153025 Ivanovo, Russian Federation.
Eꢀmail: kalinina_nv52@mail.ru
Kinetics of interaction of DLꢀserine, Lꢀproline, Lꢀthreonine, and DLꢀmethionine with
3ꢀnitrobenzenesulfonyl chloride in water (40%)—1,4ꢀdioxane and water (40%)—isopropanol
mixed solvents was studied spectrophotometrically at 298 K. The main reactive form of
αꢀamino acids is shown to be anionic. Under conditions of arenesulfonylation, the basicity
of αꢀamino acids is crucial in determining the reaction rate. Arenesulfonylation rate constants
are 20—50 times lower than the constants of Nꢀacylation of the same αꢀamino acids with
benzoyl chloride and 104—105 times higher than the rate constants of their reactions
with benzoic acid 4ꢀnitrophenyl ester.
Key words: amino acids, kinetics, Nꢀacylation, arenesulfonylation, benzoic acid, solvent,
ab initio calculations.
Studying the sulfamide bond formation by αꢀamino
lems of insolubility of αꢀamino acids in organic solvents
acids is essential for both an understanding of the mechaꢀ
nisms of reactions occurring in biosystems and choosing
optimal synthetic conditions for sulfamides, especially in
view of the rather sparse available data on synthetically
viable routes to produce acylamino acids.1
and strong hydrolysis of sulfonyl chloride in water (that
suppresses acylation).
Experimental
An interest in the principles of the N—S bond formaꢀ
tion in biological objects is due to the important role
of sulfonic acid derivatives in inhibition of a range of
enzymes. Furthermore, the sulfonation of the amino group
of amino acids is known to be used as a protection against
formation of the αꢀcarbonꢀcentered radicals. Nitrogenꢀ
and sulfurꢀcontaining organic compounds are widely emꢀ
ployed in QSAR (quantitative structure—activity relationꢀ
ship) studies that makes the knowledge of amino acid
arenesulfonylation kinetics useful for optimization of the
synthesis of biologically active sulfonylamides by convenꢀ
tional as well as combinatorial methods.
Previously,2,3 the kinetic studies have been performed
for the reactions of glycine, DLꢀαꢀalanine, and DLꢀvaline
with 3ꢀnitrobenzenesulfonic acid chloroanhydride in
isopropanol—water and 1,4ꢀdioxane—water solvent
systems.
αꢀAmino acids: DLꢀserine (chemically pure grade), Lꢀproline
(chemically pure grade), DLꢀmethionine (analytical grade), and
DLꢀthreonine (pure grade) were dried at 150 °C and used without
further purification. 3ꢀNitrobenzenesulfonyl chloride (pure
grade) was recrystallized from hexane—isopropanol (9 : 1) with
activated charcoal. 1,4ꢀDioxane (chemically pure grade) was
dried over KOH and distilled on a column at atmospheric
pressure in the presence of metal sodium. Isopropanol (chemiꢀ
cally pure grade) was distilled on a column at atmospheric
pressure. Sodium acetate (analytical grade) was recrystallized
from water. Physicochemical constants of the purified reagents
were in agreement with the literature data.4 Acetic acid (chemiꢀ
cally pure grade) was used as purchased. All aqueous solutions
were prepared in doubly distilled water.
The course of the reaction was monitored spectrophotoꢀ
meterically by changes in 3ꢀNBSC concentration at 242 nm
using a SFꢀ46 spectrophotometer equipped with a digital
Shchꢀ1312 voltmeter. Kinetic experiments were carried out as
described in Ref. 2. The value of pH of the solution was
maintained constant using the acetate buffer; pH of the working
solutions was measured with an Iꢀ160M ionomer (with an
ESꢀ10603 pH glass electrode and ESrꢀ10103 reference electrode).
The Hꢀfunction of a glass electrode was checked by calibration
against perchloric acid solutions.
Here we describe the results of the kinetic studies
of reactions of DLꢀserine, Lꢀproline, DLꢀthreonine, and
DLꢀmethionine with 3ꢀnitrobenzenesulfonyl chloride
(3ꢀNBSC) in the mixtures of 1,4ꢀdioxane and isoproꢀ
panol with water (40%) at 298 К. The waterꢀorganic mixed
solvents were chosen with the aim to overcome the probꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 900—904, May, 2010.
1066ꢀ5285/10/5905ꢀ0922 © 2010 Springer Science+Business Media, Inc.

Arenesulfonylation of αꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
923
T•103 (conv. units)
Results and Discussion
1200
In water and in waterꢀorganic solutions, αꢀamino
acids can adopt four forms depending on pH, viz.,
cationic, anionic, zwitterionic, and uncharged, with only
two ones (molecular and anionic) reactive towards
Nꢀacylating reagents as containing nonprotonated
amino groups.5 3ꢀNBSC can react with the active forms
of αꢀamino acids and water contained in a waterꢀorganic
solvent via three parallel routes (R is amino acid radical):
800
NH2CH(R)COOH + 3ꢀO2NC6H4SO2Cl
100
200
300
400 τ/s
3ꢀO2NC6H4SO2NHCH(R)COOH + HCl,
(1)
(2)
Fig. 1. Transmittance of solution (T) vs. time (τ) for reaction of
Lꢀproline with 3ꢀNBSC in dioxane—water (40%) mixture
at 298 К, Caa = 0.0048 mol L–1, kapp = (8.60 0.06)•10–3 s–1
T values are given in conventional units (voltage readings
of a digital voltmeter in mV) since for determining kapp by
Guggenheim method the absolute T values need not be
known.
.
NH2CH(R)COO– + 3ꢀO2NC6H4SO2Cl
3ꢀO2NC6H4SO2NHCH(R)COO– + HCl,
H2O + 3ꢀO2NC6H4SO2Cl
3ꢀO2NC6H4SO3H + HCl. (3)
Table 1. Effective rate constants (kapp) of reactions of αꢀamino
acids with 3ꢀNBSC at 298 К*
The rate of the solvolysis of sulfonyl chloride by the
organic components of the solvents used in the experiꢀ
ments is negligibly small compared to those of reacꢀ
tions (1)—(3) (see Ref. 6) and thus can be ignored.
In accordance with reactions (1)—(3), when the amino
acid concentration (Caa) is 2—3 orders of magnitude higher
than the sulfonyl chloride concentration (Csc), the Csc
dynamics in the kinetic experiment will obey the relation
Dioxane—H2O (40%)
Caa/mol L–1 kapp•103/s–1
Isopropanol—H2O (40%)
Caa/mol L–1
kapp•103/s–1
DLꢀMet
0.0010
0.0030
0.0040
0.0050
0.0060
0.0080
0.0090
10.25
10.39
10.43
10.48
10.52
10.70
10.78
0.0010
0.0040
0.0050
0.0070
0.0090
0—
2.52
2.65
2.73
2.83
2.98
0—
–(dCsc/dτ) = [kh + (k0α0 + k_α_)Caa]Csc,
(4)
where α0 and α_ are the mole fractions of uncharged
and anionic αꢀamino acid forms, respectively; Caa is the
total concentration of all αꢀamino acid forms in solution;
k0 and k_ are the acylation rate constants for uncharged
and anionic forms of αꢀamino acid, respectively; kh is the
rate constant of hydrolysis of 3ꢀNBSC. The apparent firstꢀ
order rate constant (kapp) is expressed as
0—
0—
DLꢀSer
0.0010
0.0060
0.0070
0.0080
0.0100
0.—
7.78
8.29
8.4
8.43
8.7
0.0010
0.0020
0.0030
0.0040
0.0050
0.0070
3.32
3.36
3.38
3.40
3.43
3.51
kapp = kh + (k0α0 + k_α_)Caa
.
(5)
0—
LꢀPro
The kapp values were derived from kinetic data by use
of the Guggenheim equation:
0.0032
0.0048
0.0056
0.0064
0.0080
0—
6.19
8.60
8.67
9.02
11.2
0—
0.0008
0.0016
0.0048
0.0056
0.0064
0.0072
2.05
2.08
2.31
2.38
2.52
2.64
,
(6)
DLꢀThr
where T1 and T2 are the transmittance coefficients of the
solution at time τ1 and τ2, respectively; τ2 = τ1 + Δ (Δ is a
constant); T0 and T∞ are the transmittance coefficients of
the solution before beginning and after completion of the
reaction.
The left hand side of Eq. (6) is a linear function of τ1
that allows estimation of the effective rate constants kapp
by least squares without determining T0 and T∞.
0.0010
0.0020
0.0040
0.0060
0.0070
0—
9.32
9.39
9.51
9.72
9.81
0—
0.0010
0.0030
0.0040
0.0050
0.0060
0.0070
0.0100
3.13
3.30
3.31
3.37
3.40
3.46
3.55
0—
0—
* Caa is the starting concentration of amino acid.

924
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Kalinina et al.
Table 2. HOMO energies (ЕHOMO) of anionic
and molecular forms of amino acids and LUMO
energies (ЕLUMO) of acylating agent molecules
The rate constant values were derived from 60—100
measurements of solution transmittance. Their accuracy
was determined assessing statistical significance at 95%
level. An example of thus obtained kinetic curve is given
in Figure 1. The kapp values obtained from the experimenꢀ
tal kinetic data are summarized in Table 1.
It was previously shown5,7 for αꢀamino acid acylation
with benzoyl chloride that the uncharged form does not
contribute significantly to the effective reaction rate
because of k_α_ >> k0α0. Under conditions of our experiꢀ
ment (pH 6.0—7.0), the mole fraction of the anionic
αꢀamino acid form (α_) in the studied waterꢀorganic
media is one or two orders of magnitude higher than that
of the molecular form (α0).5,8 The reactivities of the
anionic and molecular αꢀamino acid forms can be qualiꢀ
tatively compared with the aid of quantum chemical calꢀ
culations.
Compound
Anion
Molecule
–ЕHOMO/eV
Amino acid
DLꢀSer
5.56
5.02
5.39
5.38
10.92
10.22
10.54
9.10
LꢀPro
LꢀThr
DLꢀMet
Acylating agent
Benzoyl chloride
3ꢀNBSC
ЕLUMO/eV
—
—
1.90
0.75
Under the conditions of kinetic experiment, CH+ is of
the order of 10–7—10–8 mol L–1, and Ka for αꢀamino
II
acids considered is 10–10—10–11 mol L–1 (see Ref. 5),
The acylation reactions of amines and amino acids
are known to proceed under orbital control,5 which means
the interaction between the HOMO of amine and LUMO
of the acylating agent is the rateꢀlimiting step. The enerꢀ
gies of the interacting LUMO and HOMO orbitals of
αꢀamino acid molecules and anions as well as of acylating
agent molecules calculated for fully optimized geometries
using the HyperChem 7.52 program9 on the HF/6ꢀ31G*
level of theory are collected in Table 2.
hence Ka value in Eq. (8) can be neglected:
II
α
– = Ka /CH+
,
(9)
II
to obtain
keff = k_Ka /CH+
,
(10)
II
which means that the acylation rate constants for αꢀamino
acid anionic form (k_) can be found as
The energy difference between the HOMO and LUMO
level (HOMO—LUMO gap) ΔЕ = ЕHOMO – ЕLUMO for
the αꢀamino acid anions interacting with benzoyl chloꢀ
ride and 3ꢀNBSC is substantially lower than for their
uncharged forms (see Table 2), which accounts for the
higher reactivity to Nꢀacylation of the anionic form comꢀ
pared to molecular form. The above data imply that in the
reactions considered, in common with reactions of αꢀ
amino acids with benzoyl chloride, k_α_ >> k0α0, so that
Eq. (5) can be reduced to give
k_ = keffCH+/Ka
.
(11)
II
The k_ values for reactions of αꢀamino acids with
3ꢀNBSC derived from Eq. (11), along with the experiꢀ
mental CH+ values and Ka of a protonated αꢀamino acid
amino group in water—dIiIoxane and water—isopropanol
media (40% water)5 are collected in Table 3.
From the data of Table 3 it follows that the reactivity
of the studied αꢀamino acids in water—dioxane and waꢀ
ter—isopropanol mixed solvents increases in a series
kapp = kh + (k_α_)Caa
.
(7)
DLꢀMet < DLꢀSer, DLꢀThr << LꢀPro.
Validity of this equation would require the apparent
rate constant kapp to be the linear function of initial amino
acid concentration Caa with a slope equal to the effective
rate constant keff = k_α_. Eq (7) is valid for all reactions
studied (see Table 1). Effective rate constants for the acyꢀ
lation of αꢀamino acids by 3ꢀNBSC (keff) derived from
this equation and its linear correlation coefficients (r) are
given in Table 3.
Table 3. Kinetic characteristics of reactions of αꢀamino acids
with 3ꢀNBSC
αꢀAmino СH+•107
acid
pKa
keff
k_
r
II
/mol L–1
L mol–1 s–1
Dioxane—H2O (40%)
In a number of works (e.g., Ref. 5, 7) it was shown that
the mole fraction of the anionic form (α–) can be repreꢀ
sented as
DLꢀMet
DLꢀSer
LꢀPro
2.11
1.41
1.41
1.80
10.16
10.42
11.59
10.41
0.064
0.100
0.96
196
370
52880
378
0.991
0.996
0.971
0.994
DLꢀThr
0.082
α
– = Ka /(CH+ + Ka ),
(8)
Isopropanol—H2O (40%)
II
II
DLꢀMet
DLꢀSer
LꢀPro
8.86
7.45
21.41
7.45
9.57
10.02
11.17
9.92
0.048
0.029
0.0917 29040
0.032 201
158
228
0.993
0.992
0.971
0.991
where CH+ is the concentration of H+ ions in solution, and
Ka is the second thermodynamic dissociation constant of
αꢀIaI mino acid in a given solvent.
DLꢀThr

Arenesulfonylation of αꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
925
It should be noted that this series coincides with the
basicity sequence for αꢀamino acids in both waterꢀorꢀ
ganic solvents (see Table 3). The rate of arenesulfonylation
of Lꢀproline is significantly higher compared to reactions
of other αꢀamino acids with 3ꢀNBSC, which is due to its
higher basicity as well as to specific structural features.
Higher reactivity of Lꢀproline compared to other αꢀamino
acids was found in a number of reactions, in particular, in
the reactions of αꢀamino acids with benzoic acid chloroꢀ
anhydride, and with its substituted phenyl esters as well.5,10
The logarithms of the rate constants of reaction (2) are
The rate constants of reaction (2) in aqueous dioxane
are 20—50 times lower than the rate constants of Nꢀacyꢀ
lation of the same αꢀamino acids with benzoyl chloride
under similar conditions. At the same time, areneꢀ
sulfonylation rate constants for the studied αꢀamino acids
in aqueous isopropanol, k_ are 4—5 orders of magnitude
higher than the rate constants of their reactions with
4ꢀnitrophenyl benzoate in the same solvent.5 This is in
agreement with the literature data on the relative reactivꢀ
ity of arenesulfonyl chlorides, chloroanhydrides, and
aromatic carboxylic acid esters in Nꢀacylation reactions.5
The logarithms of arenesulfonylation rate constants of
αꢀamino acids in aqueous dioxane and in aqueous isoproꢀ
panol (logk_) are related linearly to the logarithms of the
corresponding rate constants of their acylation with
benzoyl chloride in aqueous dioxane (logkbc) and with
4ꢀnitrophenyl benzoate in aqueous isopropanol (logkes):
proportional to pKa values in dioxane—water medium
II
(40% water);5 the corresponding line plotted using the k_
rate constants of reactions of αꢀamino acids with 3ꢀNBSC
obtained previously under the similar conditions2,3 is
shown in Fig. 2. The similar linear relation holds for
aqueous isopropanol.
There exists a linear relationship between the logaꢀ
rithms of the rate constants of reactions of αꢀamino acids
with 3ꢀNBSC in aqueous isopropanol (logkips) and in
aqueous dioxane (logkdo) (determined herein as well as
previously2,3):
logk_ = (4.47 0.10) + (0.78 0.05)•logkes,
(13)
logk_ = (0.14 0.21) + (0.74 0.05)•logkbc
.
(14)
These dependences are consistent with the concept of
rate controlling basicity in Nꢀacylation of amino acids
and suggest that the key feature for the reactivity of
αꢀamino acids in nucleophilic substitution reactions is
the ability of amino nitrogen to the nucleophilic attack of
electrophilic center, i.e., the carbonyl carbon atom and
sulfonyl sulfur atom.
In conclusion, the basicity of a protonated amino group
appears to be a key factor that determines the rate of
arenesulfonylation of αꢀamino acids along with the speꢀ
cific solvation of the amino acid anions by components
of waterꢀorganic solvents.
logkips = –(0.102 0.131) + (0.970 0.041)•logkdo
. (12)
An explanation of this proportionality is that the
basicity of the amino group controls the rate of Nꢀacylaꢀ
tion of αꢀamino acids. The arenesulfonylation rate conꢀ
stants for αꢀamino acids (k_) in aqueous dioxane are
higher than in aqueous isopropanol, which is attributable
to higher pKa values in aqueous dioxane (see Table 3).
However, theIIreaction rate may also be affected by speꢀ
cific solvation of αꢀamino acid anions and the transition
state by solvent components.4
This work was financially supported by the Ministry
of Education and Science of the Russian Federation
(Project RNP 2.2.1.1.2820).
log(k_)
5.0
Pro
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II

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Received November 17, 2008;
in revised form July 27, 2009