Kinetics and mechanism of the dehydration reaction of sarcosine to a bislactame through diacyclperoxide intermediate in strong acidic medium

Article abstract of DOI:10.1002/kin.20441

The influence of substitution on the amine functional group of glycine in the permanganic oxidation of such an α-amino acid in moderately concentrated sulfuric acid medium has been investigated. Reaction products analysis has revealed that contrary to the usual α-amino acid oxidation product, which is an aldehyde species, a valuable compound, namely 1,4-dimethylpiperazine-2,5-dione, has been obtained as the main product via a cheap, simple, efficient, and novel method. Sarcosine has been chosen as a substituted derivative of glycine, and the kinetics and mechanism of its permanganic oxidation have been investigated using a spectrophotometric technique. Conclusive evidence has proven delayed autocatalytic activity for Mn(II) in this reaction, analogous to some α-amino acids. It has been revealed that such activity can show up when a certain concentration ratio of Mn(II) to sarcosine is built up in the medium, which we call the "critical ratio." The magnitude of the latter ratio depends on the sulfuric acid concentration. Considering the "delayed autocatalytic behavior" of Mn(II) ions, rate equations satisfying observations for both catalytic and noncatalytic routes have been presented. The reaction shows first-order dependence on permanganate ions and sarcosine concentrations in both catalytic and noncatalytic pathways, and apparent first-order dependence on Mn ²⁺ ions in catalytic pathways. The correspondence of pseudo-order rate constants of the catalytic and noncatalytic pathways to Arrhenius and Eyring laws has verified "critical ratio" as well as "delayed autocatalytic behavior" concepts. The activation parameters associated with both pathways have been computed and discussed. Mechanisms for both catalytic and noncatalytic routes involving radical intermediates as well as a product having a diketopiperazine skeleton have been reported for the first time.

Full text of DOI:10.1002/kin.20441

Kinetics and Mechanism of
the Dehydration Reaction of
Sarcosine to a Bislactame
through Diacyclperoxide
Intermediate in Strong
Acidic Medium
HOMAYOON BAHRAMI,1,2 MEHDI D. DAVARI,1 MARYAM KESHAVARI,1 MANSOUR ZAHEDI,1
AYOOB BAZGIR,1 ALI A. MOOSAVI-MOVAHEDI2
1Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, Evin, P.O. Box 19395-4716,
Tehran 19839-6313, Iran
2Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Received 12 November 2008; accepted 23 May 2009
DOI 10.1002/kin.20441
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: The influence of substitution on the amine functional group of glycine in the per-
manganic oxidation of such an α-amino acid in moderately concentrated sulfuric acid medium
has been investigated. Reaction products analysis has revealed that contrary to the usual
α-amino acid oxidation product, which is an aldehyde species, a valuable compound, namely
1,4-dimethylpiperazine-2,5-dione, has been obtained as the main product via a cheap, simple,
efficient, and novel method. Sarcosine has been chosen as a substituted derivative of glycine,
and the kinetics and mechanism of its permanganic oxidation have been investigated using a
spectrophotometric technique. Conclusive evidence has proven delayed autocatalytic activity
for Mn(II) in this reaction, analogous to some α-amino acids. It has been revealed that such
activity can show up when a certain concentration ratio of Mn(II) to sarcosine is built up in the
medium, which we call the “critical ratio.” The magnitude of the latter ratio depends on the
sulfuric acid concentration. Considering the “delayed autocatalytic behavior” of Mn(II) ions,
rate equations satisfying observations for both catalytic and noncatalytic routes have been
presented. The reaction shows first-order dependence on permanganate ions and sarcosine
concentrations in both catalytic and noncatalytic pathways, and apparent first-order depen-
dence on Mn2+ ions in catalytic pathways. The correspondence of pseudo-order rate constants
Correspondence to: Mansour Zahedi; e-mail: m-zahedi@cc.sbu.
ac.ir.
Contract grant sponsor: Research Council of Shahid Beheshti
University.
c
ꢀ
2009 Wiley Periodicals, Inc.

690
BAHRAMI ET AL.
of the catalytic and noncatalytic pathways to Arrhenius and Eyring laws has verified “critical ra-
tio” as well as “delayed autocatalytic behavior” concepts. The activation parameters associated
with both pathways have been computed and discussed. Mechanisms for both catalytic and
noncatalytic routes involving radical intermediates as well as a product having a diketopiper-
azine skeleton have been reported for the first time. ꢀ 2009 Wiley Periodicals, Inc. Int J Chem
C
Kinet 41: 689–703, 2009
agent, whereas in a recent work it is shown that such
autocatalytic activity is accompanied by a delay and it
shows up just after a critical ratio of Mn(II) to amino
acid is built up, depending on the nature of the amino
acid used [17].
As an attempt to investigate the effect of amine’s
substitution of an α-amino acid in permanganate oxida-
tion, we have chosen sarcosine. Besides the importance
of the kinetic and mechanism study of such a process,
product analysis has revealed that permanganic oxida-
tion of sarcosine can be regarded as a novel method for
the synthesis of a valuable diketopiperazine skeleton.
The advantages of such synthesis can be stated as hav-
ing a smooth condition, water as solvent, high yield,
and a single-step procedure.
INTRODUCTION
Monomeric sarcosine oxidase (MSOX) and N-
methyltryptophan oxidase (MTOX) catalyze similar
oxidative reactions with various secondary or tertiary
amino acids. MSOX catalyzes oxidative demethyla-
tion of sarcosine (N-methylglycine) and other sec-
ondary amino acids such as L-proline, to yield glycine,
formaldehyde, and hydrogen peroxide. Sarcosine is a
common soil metabolite that can act as the sole source
of carbon and energy for many microorganisms. De-
spite the sequence similarity with MSOX, sarcosine is
a very poor substrate for N-methyltryptophan oxidase
(MTOX), which exhibits a preference for aromatic or
large aliphatic N-methylated amino acids [1–4].
A new survey shows that diketopiperazines (DKPs)
are very important and attractive synthetic targets be-
cause of their wide range of interesting biological ac-
tivity and their presence in a wide variety of natural
products [5–7]. Synthetically, DKPs have been used as
a starting material for the preparation of enantiomer-
ically pure compounds, as chiral auxiliaries in asym-
metric synthesis such as the asymmetric Diels–Alder
reaction [8–10]. DKPs have also been shown to cat-
alyze some additional organic reactions [11–14].
The synthesis of this class of compounds has already
been reported. Several methods have been reported for
the synthesis of DKPs. However, these methods suf-
fer from several limitations. They require harsh con-
ditions, volatile unfriendly organic solvents, long re-
action times, and low yields [11–14]. Owing to the
above reasons and as a part of our ongoing research
program on oxidation of amino acids [15–17], we have
developed a simple approach for producing this im-
portant class of diketopiperazine-2 (Scheme 1). A lit-
erature survey shows that the kinetics and mechanism
of oxidation of amino acid in moderately concentrated
acid medium have been extensively studied [15–31]. In
most of these studies, the reaction has been considered
as a process that follows a perfect second-order kinet-
ics at constant [H+] without any autocatalytic effect.
There are two reports of a “double stage” process in
which every stage is shown to have kinetics identical to
a pseudo-first-order reaction [27,31]. In our previous
studies [15,16], we have reported the presence of the
autocatalytic effect in which Mn2+ is the autocatalytic
EXPERIMENTAL
Materials
All the reagents were from Merck or Fluka. All
reagents were of analytical grade, and their solutions
were prepared by dissolving the requisite amount of
samples in tridistilled, deionized, and boiled water. All
weighting was performed by a Shimadzu AW220 elec-
tronic balance ( 0.0001 g). The preparation and anal-
ysis of the stock solutions and process for kinetic runs
were the same as described earlier [15–17]. The per-
manganate solutions were prepared and tested by the
Vogel method [32].
Kinetic Measurements
The kinetic progress of reaction was followed by
measuring the absorbance of the permanganate ions
at 525 nm (maximum wavelength for permanganate
ions in a strong acid solution) with a thermostated
(Shimadzu TB-85, 0.1 K) Shimadzu (1605 model)
UV–vis spectrophotometer within the temperature
range of 25–65◦C. It was verified that there is no in-
terference from other reagents at this wavelength. The
molar absorption coefficient for permanganate of 2.26
× 103 dm3 mol−1 cm−1 was obtained and was used
in all kinetic measurements presented in this work.
Sarcosine was used in an excess amount relative to
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KINETICS AND MECHANISM OF THE DEHYDRATION REACTION OF SARCOSINE TO A BISLACTAME
691
O
Procedure for Direct Synthesis of Product
A solution of sarcosine (0.222 g, 2.5 mmol), KMnO4
(0.078 g, 0.5 mmol), concentrated H2SO4 (98%)
(3.16 mol dm−3), was stirred for 8 h until the solution
of KMnO4 became colorless. At the end of the reac-
tion, the solution was neutralized with barium hydrox-
ide. The neutralization process must be done slowly
for 2 h, so that the heat of the neutralization reaction
does not affect the product. The organic phase is sub-
sequently distilled under vacuum condition. The sole
organic product was approved by a single spot on TLC.
The residual was extracted with chloroform and was
crystallized with chloroform and n-hexane. The yield
calculated amounts to 80%. An analysis of the product
gave the following results:
OH
N
KMnO4
O
Concentrated H2SO4
N
NH
2
1
O
Scheme 1
permanganate. To follow up the reaction, TLC was car-
ried out on precoated plates, and spots were detected
by UV light. The melting point was taken on an elec-
trothermal 9200 point apparatus and left uncorrected.
The IR spectra were obtained in potassium bromide
pellets with a Shimadzu IR-470 spectrometer. The 1H
NMR and 13C NMR spectra were taken by a Bruker
Avance DPX300 spectrometer in CDCl3, and chemi-
cal shifts are in ppm relative to CDCl3. A Shimadzu
QP-1100EX mass spectrometer with electron impact
ionization mode was used to measure the MS data.
1,4-Dimethylpiperazine-2,5-dione: White crystals;
mp 143–145◦C; IR (KBr) 2961 (C H, aliphatic), 1657
1
(C O), 1334 (CO N), 1015 (C N) cm−1; H NMR
(300 MHz, CDCl3) δ: 2.98 (6H, s, 2CH3), 3.48 (4H, s,
2CH2), 13C NMR (75 MHz, CDCl3) δ: 33.27 (CH3),
51.63 (CH2), 163.08 (CON); MS (m/z): 143 (M + H,
85), 142 (M, 75), 113 (M-24, 46), 85, 57 (100).
1H NMR is ordered as follow: proton numbers, mul-
tiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet), and group.
Products Analysis
The study reveals that the 13C NMR spectrum has
three types of carbons, whereas the MS spectrum ver-
ifies that the compound mass is equal to the proposed
product. As an assurance, it was observed that when an
oxidizing agent, namely permanganate, was removed
from the medium, no cyclization could occur, meaning
that sulfuric acid alone cannot lead to the product and
permanganate presence is obligatory. As another test
of confidence, the reaction was performed with Mn(II)
when KMnO4 was absent, and as a result no observable
product was detected.
To analyze and identify the reaction products, oxida-
tion of sarcosine was performed at constant tempera-
ture in acidic medium. In the course of reaction, the
solution’s color changed from violet to colorless, in-
dicating Mn2+ ion generation as the major manganese
moiety. Oxygen gas was generated during the reac-
tion, and a conclusive flame test confirmed O2 gener-
ation. After completion of the reaction, the products
were isolated and identified using IR, H NMR, 13C
1
NMR, and MS spectra as well as melting points. The
main product (1,4-dimethylpiperazine-2,5-dione) that
was isolated is a dimer of two sarcosine molecules
having a diketopiperazine skeleton, which is reported
for the first time. It is noteworthy that, as expected, no
CO2 gas was detected as a product of the reaction, due
to the presence of two carbonyl groups in the major
product. Despite the usual synthetic routes for produc-
ing this important class of 2,5-diketopiperazines [11–
14], a simple single step oxidation process in aqueous
medium, high yield, mild conditions has afforded the
mentioned product. Thus, a significant result of this
paper is to replace environmentally unfriendly organic
solvents with environmentally friendly H2O, to omit
organic solvents, and to increase reaction rates and
product yields. This cyclization process is presented in
Scheme 1.
Reaction Stoichiometry
Reaction mixtures containing various ratios of sar-
cosine to MnO−4 were mixed in the presence of
3.16 mol dm−3 H2SO4 and then equilibrated for 24 h at
room temperature. Estimation of the unreacted MnO4−
showed that 1 mol of MnO−4 consumed 5 mol of amino
acid to produce 2.5 mol of 1,4-dimethylpiperazine-
2,5-dione as the major product [29]. In view of these
results and taking into account that the final prod-
uct of permanganate reduction in an acid medium
and in a large excess of reducing species is the
Mn+2 ion [18,20,28,33], the following equation was
obtained:
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692
BAHRAMI ET AL.
O
N
+ 13H2O + 2Mn2+ + 5/2O2
(1)
2MnO + 10
5
CH3NH2CH2COO + 6H
4
N
O
ident that the Mn(VII) is reduced to various states in
acidic, alkaline, and neutral media. Furthermore, the
mechanism by which this multivalent oxidant oxidizes
a substrate depends not only on the substrate but also
on the medium [34] used for the study. In a strongly
acidic medium, the stable reaction product is the Mn2+
ion. From previous studies [35–43], it is known that
MnO2 absorbs in the 400–650 nm region, so the ab-
sorption profiles suggest that MnO2 is not a reaction
product. Furthermore, since no rise and fall in absorp-
tion is observed at 418 nm, it is concluded that MnO2
does not intervene as a possible oxidizing agent unless
it is short lived. Furthermore, the maximum absorp-
tion wavelengths for Mn(IV) and Mn(III) ions lie in
the 400–460 nm region. It has been reported that per-
manganate absorption at the maximum wavelength of
the aforementioned species is about 0.458 and 0.108
of its absorption at 525 nm (permanganate λmax) [44].
Thus, if Mn(IV) and Mn(III) species existed as stable
moieties in the reaction medium, the absorption profile
of permanganate with time must have changed from
what was observed in Fig. 1 in order to contain the
Acrylonitrile Addition
The reaction mixture was mixed with acrylonitrile
monomer and was kept for 2 h in an inert atmosphere.
The presence of free radicals as intermediates was con-
firmed by polymerization, both in the presence and in
the absence of manganese sulfate(II). The blank exper-
iments of either MnO−4 or sarcosine alone with acry-
lonitrile did not induce polymerization under the same
conditions as those induced with reaction mixtures.
Initially added acrylonitrile decreases the rate, indicat-
ing the free radical intervention, which is the case in
earlier work [15–31].
RESULTS AND DISCUSSION
Rate Equation
Figure 1 illustrates the permanganate absorption vs.
wavelength curves for sarcosine oxidation, obtained
at 10 min intervals as the reaction proceeded. In the
course of the permanganate oxidation process, it is ev-
1
0.8
0.6
0.4
0.2
0
400
450
500
550
λ (nm)
600
650
700
Figure 1 Spectral changes in the oxidation of sarcosine with permanganate ions. [KMnO4] = 4.0 × 10−4 mol dm−3, [Sar] =
0.05 mol dm−3, [H2SO4] = 3.16 mol dm−3, T = 323 K, and scanning time intervals = 10 min. [Color figure can be viewed in
the online issue, which is available at www.interscience.wiley.com.]
International Journal of Chemical Kinetics DOI 10.1002/kin

KINETICS AND MECHANISM OF THE DEHYDRATION REACTION OF SARCOSINE TO A BISLACTAME
693
0.0005
0.0004
0.0003
0.0002
0.0001
0
0
60
120
180
Time (min)
Figure 2 Concentration changes vs. time plot. [KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3, [Sar] =
0.05 mol dm−3, T = 318 K.
former ion absorption features. It is worth mentioning
here that for Mn(III) to be generated as a product of the
direct reaction between permanganate and Mn(II), an
acidic medium with a pH of about 1–2 is required [45].
Also it has been reported that for Mn(III) to become
stable in the latter medium, species such as C2O42−
[46] and P2O47− [47] are necessary. Therefore, it is
concluded that under our present conditions, Mn(IV)
and Mn(III) ions can neither be yielded via the direct
permanganate-Mn(II) reaction, nor they are stable even
if they are generated by the amino acid–permanganate
reaction.
In Fig. 2, a typical permanganate concentration
change vs. time plot has been shown. Since Fig. 2 does
not appear to be a perfect sigmoidal profile, it might be
judged that an autocatalysis reaction has not occurred,
which may lead to erroneous results. However, taking a
closer look at the rate–time plot of Fig. 3, a bell-shaped
0.000024
0.000018
0.000012
0.000006
0
0
40
80
120
160
Time (min)
Figure 3 Reaction rate vs. time plot. [KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3, [Sar] = 0.05 mol dm−3
,
T = 318 K.
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694
BAHRAMI ET AL.
0.00008
[Mn(II) = 0.0004 M
[Mn(II) = 0.0008 M
[Mn(II) = 0.0012 M
[Mn(II) = 0.0016 M
0.00006
0.00004
0.00002
0
0
40
80
120
160
Time (min)
Figure 4 Effect of the added initial concentration of Mn2+ ions on the reaction rate–time plots. [Sar] = 0.05 mol dm−3
,
[KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3, T = 303 K.
curve can be seen after 35% of the reaction progres-
sion. Such an observation is clear evidence of a delayed
autocatalytic behavior for this reaction as has been re-
ported elsewhere [17].
According to the above discussion, the following
rate equation is proposed for sarcosine oxidation until
the autocatalytic behavior of Mn2+ emerges:
d[MnO−4 ]
−
= k1ꢁ [MnO−4 ]
(2)
Figure 4 illustrates the rate of permanganate con-
centration change vs. time curves in the order of
increasing initial concentration of Mn(II). Considering
Fig. 4, it is obvious that the reaction’s half life has been
decreased by adding increasing amounts of Mn2+. In
addition, the increasing rate portion (bell shaped) of
these curves is gradually annihilated, while the Mn2+
concentration has been increased to 0.0016 M. Thus,
from above observations it could be concluded that
Mn2+ is the autocatalytic agent. As has been reported
before [17] and is evidenced from Figs. 3 and 4, for
Mn2+ to show such “delayed autocatalytic character-
istic,” it should acquire a certain concentration, which
we call “critical concentration.” It should be noted that
some experiments were carried out with all reactants,
namely KMnO4, Mn(II), and H2SO4, while amino acid
was absent. The result was that the permanganate rate
of consumption was much slower than when sarcosine
was present. This observation confirms that perman-
ganate consumption can be due to the amino acid ox-
idation rather than direct permanganate reaction with
Mn(II), which is known to be very slow. Thus regard-
ing the product analysis section, generation of 1,4-
dimethylpiperazine-2,5-dione can be understood only
by a direct reaction between sarcosine and perman-
ganate, which is catalyzed by Mn(II) ions as shown
above.
dt
As the reaction progresses, the following equation for
sarcosine is yielded:
d[MnO−4 ]
−
= k1ꢁ [MnO4−] + k2ꢁ [MnO−4 ][Mn2+] (3)
dt
where k1ꢁ and k2ꢁ are pseudo-order rate constants for the
noncatalytic and catalytic processes, respectively. The
sarcosine concentration, which is always kept in large
excess, and the constant sulfuric acid concentration in
each experiment are included in these pseudo-order
rate constants. The integrated form of the equations
gives
a
ln
= k1ꢁ t
(4)
(5)
(a − x)
k1ꢁ /k2ꢁ + x
a − x
k2ꢁ a
k1ꢁ
ln
= (k1ꢁ + k2ꢁ a)t − ln
where a represents the initial concentration of per-
manganate and x is the amount of permanganate ion
consumed in time t.
Initial anticipation of k1ꢁ for sarcosine has been
made by fitting the early portion of the rate data to
a first-order rate equation. This is because there is no
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KINETICS AND MECHANISM OF THE DEHYDRATION REACTION OF SARCOSINE TO A BISLACTAME
695
Table I Rate Constants for the Catalyzed and
Table II Rate Constants for the Catalyzed and
Uncatalyzed Processes at Different Temperatures
Uncatalyzed Processes Accompanied by Thresholds (%)
for the Appearance of the Autocatalysis Behavior at
Different Concentrations of Sarcosine
T (K)
k1ꢁ × 105 (s−1
)
k2ꢁ × 100 (dm3 mol−1 s−1
)
298
303
308
313
318
323
328
333
338
1.52
2.07
3.28
4.5
6.11
9.01
13.49
21.85
33.54
6.75
14.42
27.69
43.98
71.33
106.68
155.66
241.07
403.99
Reaction
Progress
(%)
[Sar]
k1ꢁ × 105
k2ꢁ × 100
(mol dm−3
)
(s−1
)
(dm3 mol−1 s−1
)
0.03
0.04
0.05
0.06
0.07
0.09
4.29
5.88
7.33
10.11
11.53
15.49
40.56
53.25
71.33
89.98
102.56
132.57
17
23
32
34
37
38
[KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3
,
[Sar] = 0.05 mol dm−3. Estimated errors on each of k1ꢁ are 1%–2%
[KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3
,
and k2ꢁ are 0.5%–1%.
T = 318 K.
certain critical concentrations of Mn2+. Note that es-
timated errors on k1ꢁ and k2ꢁ are 1%–2% and 0.5%–1%
throughout all experiments, respectively.
catalytic effect in the early stages of the reaction. Hav-
ing anticipated preliminary values of k1ꢁ and k2ꢁ , Eq. (5)
has been used for the simultaneous determination of
the kinetic data of the reaction rate increase region,
by taking advantage of iterative methods [15–17,35–
43,48–53], and such data are summarized in Table I.
Figure 5 demonstrates the typical results of the fitting
process of the rate data for sarcosine at various temper-
atures and under the same conditions. Almost perfect
fits to the data in Fig. 5 (R2 values of 0.9991–0.9993)
not only corroborate the validity of the applied kinet-
ics method but also confirm the autocatalytic effect of
the Mn2+ species and point to such delayed activity at
Dependence of Reaction Rate on [Sar]
Figure 6a illustrates rate–time curves of the reaction
in different concentrations of sarcosine. Considering
Fig. 6, it is clear that onset of the autocatalytic activity is
further delayed if sarcosine concentration is increased.
Such a fact can be justified by referring to the data
of Table II. It can, therefore, be concluded that the
initiation of autocatalytic activity depends not only on
1.6
T = 308 K
R2 = 0.9991
T = 313 K
R2 = 0.9991
T = 303 K
R2 = 0.9993
T = 318 K
R2 = 0.9992
1.2
0.8
0.4
0
T = 323 K
R2 = 0.9991
T = 298 K
R2 = 0.9991
T = 338 K
R2 = 0.9994
0
50
100
150
200
250
300
350
400
450
500
Time (min)
Figure 5 Integrated rate-law plots for the oxidation of sarcosine by potassium permanganate at various temperatures. [Sar] =
0.05 mol dm−3, [KMnO4] = 4.0 ×10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3
International Journal of Chemical Kinetics DOI 10.1002/kin
.

696
BAHRAMI ET AL.
[Sarcosine] = 0.03
[Sarcosine] = 0.05
0.00003
0.00002
0.00001
0
0
50
100
150
200
250
300
Time (min)
(a)
1.6
1.2
0.8
0.4
Noncatalytic pathway
Catalytic pathway
′
k2
′
k1
0
0.02
0.04
0.06
0.08
0.1
[Sar] (mol dm )
(b)
Figure 6 Effect of sarcosine concentration on (a) the reaction rate–time plots and (b) the catalyzed and uncatalyzed
pseudo-order rate constants. [KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol dm−3, T = 318 K; k1ꢁ (s−1),
k2ꢁ (dm3 mol−1 −1).
s
the Mn2+ concentration but also on that of sarcosine.
Thus, the delayed autocatalytic effect can occur only
at certain concentrations of Mn2+ to sarcosine, namely
the “critical ratio.”
The pseudo-order rate constants obtained at various
sarcosine concentrations are shown in Fig. 6b. Plots of
ln(k1ꢁ ) and ln(k2ꢁ ) against ln[Sar] (not shown) confirm
that the reaction order can be considered to be equal
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697
Table III Rate Constants for the Catalyzed and
Uncatalyzed Processes Accompanied by Thresholds (%)
for Appearance of Autocatalysis Behavior at Different
Concentrations of Sulfuric Acid
Table IV Rate Constants for the Catalyzed and
Uncatalyzed Processes at Different Concentrations of
KMnO4
[KMnO4]
(mol dm−3
k1ꢁ × 105
k2ꢁ × 100
k1ꢁ × 105
k2ꢁ ×100
Reaction
Progress (%)
)
(s−1
)
(dm3 mol−1 s−1
)
[H2SO4]
(mol dm−3
)
(s−1
)
(dm3 mol−1 s−1
)
0.0004
0.00054
4.50
3.68
43.98
38.80
2.11
3.16
4.21
5.27
6.32
6.19
4.50
5.13
5.32
15.83
57.15
43.98
36.04
30.28
. . .
15
35
53
54
. . .
[H2SO4] = 3.16 mol dm−3, [Sar] = 0.05 mol dm−3, T = 313 K.
Activation Parameters
[KMnO4] = 4.0 × 10−4 mol dm−3, [Sar] = 0.05 mol dm−3
,
T = 313 K.
Pseudo-order rate constants k1ꢁ and k2ꢁ at various tem-
peratures employing Eq. (5) and at similar conditions
with respect to sarcosine, sulfuric acid, and perman-
ganate concentrations have been determined and sum-
marized in Table I. Figures 8 and 9 demonstrate the
agreement of both k1ꢁ and k2ꢁ with the Arrhenius and
Eyring equations, showing linear relations with R2 co-
efficients ranging from 0.991 to 0.996. Such obser-
vation is a justification of the method applied in the
kinetic study of sarcosine oxidation. The activation
parameters energy, enthalpy, and entropy have been
obtained and are reported in Table V. Thermodynamic
parameters presented in this table reveal that although
the catalytic pathway requires more activation energy,
the reaction rate for this pathway is more than that of
the noncatalytic pathway due to large positive activa-
tion entropy. Such a fact can be further justified by
calculating the activation Gibbs free energy mean val-
ues (T = 298–338 K) for catalytic and noncatalytic
to 1 with respect to sarcosine for both catalytic and
noncatalytic pathways [29].
Dependence of the Reaction Rate on the
Sulfuric Acid Concentration
The effect of [H+] has been investigated by means of
a series of experiments carried out at various sulfuric
acid concentrations. Figure 7a is a rate–time illustration
for sarcosine oxidation at various sulfuric acid concen-
trations. A trend of theses curves indicates that as the
acid concentration is raised, delay in autocatalytic be-
havior in the oxidation process has been increased. At
high concentration of acid (about 6 mol dm−3), the
autocatalytic effect has totally been destroyed. Such a
fact can also be justified by referring to the data given
in Table III. Figure 7b depicts k1ꢁ and k2ꢁ changes vs. the
sulfuric acid concentration. As this figure indicates, k1ꢁ
increases when the acid concentration is raised. The
3–3.5 mol dm−3 concentration region of sulfuric acid
shows the least variation for k1ꢁ . Thus, this concentra-
tion region was determined to be the most appropriate
region for the rest of our kinetic studies. In addition, it
is apparent from the same figure that k2ꢁ decreases with
the increase in the sulfuric acid concentration. Overall,
it can be stated that the autocatalytic behavior of Mn2+
in the oxidation process also depends on the sulfuric
acid concentration.
pathways, being equal to 79.18 and 103.38 kJ mol−1
respectively.
,
Reaction Mechanism
In agreement with the experimental results, two sep-
arate mechanisms for the catalyzed and uncatalyzed
pathways are proposed to describe the reaction path-
way. Since the existence of intermediate free radicals
was confirmed, their involvement in the reaction mech-
anism has also been considered.
Table V Activation Parameters
Ea
ꢀH#
ꢀS#
Dependence of the Reaction Rate
on [MnO−4 ]
Reaction Routes
(kJ mol−1) (kJ mol−1) (J mol−1 K)
Catalyzed processes
Uncatalyzed processes 64 ( 2)
82 ( 2)a 79 ( 2) −0.6( 8)
61 ( 2) −132( 7)
The effect of permanganate concentration is summa-
rized in Table IV. By paying attention to Table IV, it
is obvious that k1ꢁ and k2ꢁ values are decreased with
increasing initial permanganate concentration.
[H2SO4] = 3.16 mol dm−3, [KMnO4] = 4.0 × 10−4 mol dm−3
,
[Sar] = 0.05 mol dm−3, T = 298–318 K.
a Values in parenthesis are estimated errors on each parameter.
International Journal of Chemical Kinetics DOI 10.1002/kin

698
BAHRAMI ET AL.
0.00006
[Solsuric acid] = 2.1 M
[Solsuric acid] = 3.16 M
[Solsuric acid] = 4.21 M
[Solsuric acid] = 6.32 M
0.00005
0.00004
0.00003
0.00002
0.00001
0
0
50
100
150
200
250
Time (min)
(a)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
′
k1
′
k2
0
2
3
4
5
6
7
[Sulfuric acid] (mol dm )
(b)
Figure 7 Effect of the sulfuric acid concentration on (a) the reaction rate–time plots and (b) the catalyzed and uncat-
alyzed pseudo-order rate constants. [KMnO4] = 4.0 × 10−4 mol dm−3, [Sar] = 0.05 mol dm−3, T = 313 K; k1ꢁ (s−1),
k2ꢁ (dm3 mol−1 −1).
s
that H+ may be consumed and later generated in
various steps. With the evidence presented pointing
to no involvement of other manganese ions except
Mn(VII) in the sarcosine oxidation process, the latter
Reaction Mechanism for the Uncatalyzed Process.
All the experiments were performed in moderately
concentrated sulfuric acid media and are considered
as acid-catalyzed reactions. Therefore, it is expected
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KINETICS AND MECHANISM OF THE DEHYDRATION REACTION OF SARCOSINE TO A BISLACTAME
699
6
12+ln k1′
R2 = 0.9917
4
2
ln k′2
R2 = 0.9937
0
0.0029
0.003
0.0031
0.0032
0.0033
0.0034
1/T (K )
Figure 8 Arrhenius plots for the catalyzed and uncatalyzed processes. [KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] =
3.16 mol dm−3, [Sar] = 0.05 mol dm−3
.
ion is the most probable reactive species. The reaction
rate enhancement observed by increasing acid con-
centration suggests the formation of a more powerful
oxidant, namely permanganic acid, by the following
equilibrium:
At the high acid concentration used, protonation of the
zwitterionic form of sarcosine gives
⊕
⊕
ꢂ
K2
ꢀ
ꢁ
CH3NH2CH2COO + H+
CH3NH2CH2COOH
(7)
A mechanism consistent with the observed kinetic data
includes the following steps: In agreement with the
K1
ꢀ
ꢁ
−
MnO−4 + H+
HMnO4
(6)
12+ln(k′1
R2 = 0.9911
ln(k′2
R2 = 0.9932
0.0029
0.003
0.0031
0.0032
0.0033
0.0034
1/T (K )
Figure 9 Eyring plots for the catalyzed and uncatalyzed processes. [KMnO4] = 4.0 × 10−4 mol dm−3, [H2SO4] = 3.16 mol
dm−3, [Sar] = 0.05 mol dm−3
.
International Journal of Chemical Kinetics DOI 10.1002/kin

700
BAHRAMI ET AL.
experimental results, the formation of an addition com-
plex between the permanganic acid and the cationic
form of the sarcosine is proposed [28,29,53].
Knowing the fact that the species Mn(VI) is very un-
stable in strong acidic media, it will be converted into
Mn(II) and Mn(VII) by means of a rapid dispropor-
tionation.
⊕
HMnO4 + CH3NH2CH2COOH
k3
ꢀ
ꢁ
+
X1
(8)
5HMnO−4 + 3H+ −→ 4MnO4− + Mn2+ + 4H2O
k
−3
(16)
This complex may rupture according to the following
equation:
Multiplying Eqs. (6)–(10) by a factor of 10, Eqs. (11)–
(15) by a factor of 5, Eq. (16) by a factor of 2, and then
summing them with each other results in the satisfac-
tion of the overall reaction with the stoichiometry. In
agreement with the above scheme, assuming a steady-
state approximation for X+1 , the rate equation obtained
for the uncatalyzed process is
⊕
ꢂ
X+1 −→ CH3NH2CH2COO• + HMnO4 + H+ (9)
k4
Based on the radical involvement in the reaction mech-
anism, a dimer species is formed by the following steps:
⊕
Fast
CH3NH2CH2COO• −→ CH3NHCH2COO• + H+
(10)
(11)
CH3-NH-CH2-C-O-O-C-CH2-NH-CH3
2CH3NHCH2COO
O
O
(12)
H3C-NH-CH2-C-NH(CH3)-CH2-C-O-O
CH3-NH-CH2- C- O-O-C-CH2-NH-CH3
O
O
O
O
To have an appropriate leaving group, the following
step may be considered:
d[Mn(VII)]
−
= k1ꢁ [MnO−4 ]
(17)
dt
(13)
H3C-NH-CH2-C-NH(CH3)-CH2-C-O-OH
+ H
H3C-NH-CH2-C-NH(CH3)-CH2-C-O-O
O
O
O
O
Owing to an internal rearrangement of the aforemen-
tioned dimer, a product involving the diketopiperazine
skeleton is finally produced.
α0[Sar]t [H+]2
β0(1 + β1[H+] + β2[H+]2) + α1[H+]2[Mn(VII)]
k1ꢁ =
(18)
O
N
(14)
+ H2O2 + H
H3C-NH-CH2-C-NH(CH3)-CH2-C- O-OH
N
O
O
O
Hydrogen peroxide decomposition can be considered
as follows:
α0 = K1K2k3k4
α1 = K1K2k3
β0 = k−3 + k4
H2O2 −→ H2O + 1/2 O2
(15)
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KINETICS AND MECHANISM OF THE DEHYDRATION REACTION OF SARCOSINE TO A BISLACTAME
701
This rate law is in accord with all experimental
results presented in this article, namely the first-order
dependence on Mn2+ ions, permanganate ions, and
sarcosine concentrations and the change in k2ꢁ values
with respect to the initial permanganate concentration.
Owing to the complexity of the proposed mecha-
nism, evaluation of the rate constant values correspond-
ing to the reaction rate-determining steps for both pro-
cesses has not been possible. Thus, the activation pa-
rameters reported are associated with reaction pseudo-
rate constants k1ꢁ and k2ꢁ , and these values cannot be
attributed to any particular reaction step.
β1 = K1 + K2
β2 = K1K2
where [Sar]t represents the total concentration of sar-
cosine and [Mn(VII)] represents the total concentration
of permanganate.
The rate law obtained above corresponds to that
mechanism explaining the observed experimental be-
havior: the first-order reaction with respect to perman-
ganate and sarcosine concentrations, and change in k1ꢁ ,
the uncatalyzed pseudo-order rate constant when the
initial permanganate concentration varies.
CONCLUSIONS
Reaction Mechanism for the Catalyzed Process. Ad-
dition of Mn2+ ions led to an increase in the reaction
rate, while the evidence presented also suggests that an
adduct might be formed between Mn2+ and the proto-
nated sarcosine.
To study the influence of substitution on the amine
functional group of glycine in oxidation of such α-
amino acids, the kinetics of permanganate oxidation
reaction with sarcosine in a moderately concentrated
sulfuric acid medium was investigated using a spec-
trophotometric technique. The present work is con-
cerned with the crucial evidence for the cyclization
of two sarcosine molecules, which is being reported
for the first time. To the best of our knowledge, there
is no report in the literature for the oxidation of this
amino acid and preparation of DKPs via oxidation of a
secondary α-amino acid with KMnO4 in water media.
It is well known that oxidation of primary α-amino
acids with KMnO4 in water produces simple aldehy-
des. Here, by using a secondary α-amino acid instead
and having the same conditions, an interesting product
was encountered, namely 1,4-dimethylpiperazine-2,5-
dione. The well-known and important DKP obtained in
a single step preparation was completely characterized
by IR, mass, 1H NMR, and 13C NMR spectral analyses,
as well as its melting point.
⊕
K5
ꢀ
ꢁ
CH3NH2CH2COON + Mn2+
X32+
(19)
As the rate-determining step, a slow attack of perman-
ganic acid to the above-mentioned complex has been
proposed [48,53].
⊕
X32+ + HMnO4 −→ CH3NH2CH2COO•
k6
+ HMnO−4 + Mn2+ + H+
(20)
The remaining steps, leading to the final products, re-
semble those presented for the uncatalyzed pathway.
Again, multiplying Eqs. (6), (7), (19), (20), (10), by a
factor of 10, Eqs. (11)–(15) by a factor of 5, Eq. (16)
by a factor of 2, and then summing them with each
other results in the overall reaction’s equation with the
correct stoichiometry. Assuming a steady-state approx-
imation for the X32+ complex in the above mechanism,
the following rate equation [53] is derived:
Other major goals of this paper are to replace envi-
ronmentally unfriendly organic solvents with environ-
mentally friendly H2O, to omit organic solvents, and
d[Mn(VII)]
−
= k1ꢁ [MnO4−] + k2ꢁ [MnO4−][Mn2+
]
(21)
dt
β0δ0[Sar]t [H+]2
k2ꢁ =
(22)
β0(1 + β1[H+] + [H+]2) + α1[H+]2[Mn(VII)] + β0δ1[H+][Mn2+] + β0δ2[H+]2[Mn2+
]
δ0 = K1K2K5k6
δ1 = K2K5
δ2 = K1K2K5
where the notation employed in Eq. (17) is
conserved.
to increase reaction rates and product yields. By inves-
tigating rate–time curves, it is concluded that when a
International Journal of Chemical Kinetics DOI 10.1002/kin

702
BAHRAMI ET AL.
determined portion of the reaction time for sarcosine
has passed, a parallel reaction is encountered similar to
that of primary α-amino acids studied in our previous
works. Results show that this process can be consid-
ered as a delayed autocatalytic reaction. By increas-
ing the concentration of Mn(II), speeding the reaction,
and also fitting the kinetics data into appropriate ki-
netics equations, it is determined that this species is
the autocatalytic agent. It has been determined that the
initiation of autocatalytic activity depends not only on
the Mn2+ concentration but also on that of sarcosine.
Thus, the delayed autocatalytic effect can occur only at
a certain concentration of Mn2+ to sarcosine, namely
the “critical ratio.” Moreover, the delayed autocatalytic
phenomenon in such reactions vanishes in concentra-
tions of sulfuric acid that are greater than 6 M. There-
fore, it is appropriate to conclude that the mentioned
phenomenon depends on the amount of sulfuric acid
in the medium.
The pseudo-order rate constants obtained for both
the catalytic and noncatalytic pathways when sarco-
sine was in excess obeyed the Arrhenius and Eyring
relations. The activation parameters associated with
reaction pseudo-rate constants k1ꢁ and k2ꢁ were com-
puted and discussed. It is clear that results obtained in
the present work satisfy the presence of radical inter-
mediates as well as the formation and decomposition
of permanganate–sarcosine and Mn2+–sarcosine com-
plexes in these reactions.
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