Spectroscopy of Hydrothermal Reactions, Part 26: Kinetics of Decarboxylation of Aliphatic Amino Acids and Comparison with the Rates of Racemization

Article abstract of DOI:10.1002/kin.10160

The kinetics of decarboxylation of six α-amino acids (glycine, alanine, aminobutyric acid, valine, leucine, and isoleucine) and β-aminobutyric acid were studied in aqueous solution at 310-330 deg C and 275 bar over the pH₂₅ range 1.5-8.5 by using an in situ FT-IR spectroscopy flow reactor. Based on the rate of formation of CO2, the first-order or pseudo-first-order rate constants were obtained along with the Arrhenius parameters. The decarboxylation rates of amino acids follow the order Gly > Leu ca. Ile ca. Val > Ala > α-Aib > β-Aib. Differences in the concentration between 0.05 and 0.5 m had only a minor effect on the decarboxylation rate. The effect of the position of the amino group on the decarboxylation rate was investigated for α-, β-, and γ-aminobutyric acid and the order was found to be α > β >> γ. Although the pH dependence is complex, the decarboxylation rates of α-amino acids qualitatively have the inverse trend of the racemization rates.

Full text of DOI:10.1002/kin.10160

Spectroscopy
of Hydrothermal Reactions,
Part 26: Kinetics
of Decarboxylation
of Aliphatic Amino Acids
and Comparison with the
Rates of Racemization
JUN LI, THOMAS B. BRILL
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received 18 April 2003; accepted 17 July 2003
DOI 10.1002/kin.10160
ABSTRACT: The kinetics of decarboxylation of six α-amino acids (glycine, alanine, aminobutyric
acid, valine, leucine, and isoleucine) and β-aminobutyric acid were studied in aqueous solution
at 310–330◦C and 275 bar over the pH25 range 1.5–8.5 by using an in situ FT-IR spectroscopy
flow reactor. Based on the rate of formation of CO2, the first-order or pseudo-first-order rate
constants were obtained along with the Arrhenius parameters. The decarboxylation rates of
amino acids follow the order Gly > Leu ≈ Ile ≈ Val > Ala > α-Aib > β-Aib. Differences in
the concentration between 0.05 and 0.5 m had only a minor effect on the decarboxylation rate.
The effect of the position of the amino group on the decarboxylation rate was investigated
for α-, β-, and γ -aminobutyric acid and the order was found to be α > β ꢀ γ . Although the
pH dependence is complex, the decarboxꢁylation rates of α-amino acids qualitatively have the
C
inverse trend of the racemization rates.
602–610, 2003
2003 Wiley Periodicals, Inc. Int J Chem Kinet 35:
ence of mineral assemblies [2], and the ionic strength
[9,13] all affect the rate to some degree. Three pri-
mary decomposition reactions [5] exist for free amino
acids: decarboxylation, deamination, and racemiza-
tion. Racemization [14–23] and deamination [24,25] of
several amino acids occur at lower temperature than is
needed for decarboxylation. Asparagine, aspartic acid,
cysteine, and glutamine are four amino acids known to
deaminate easily [24]. Other reactions can occur, such
INTRODUCTION
Free amino acids slowly decompose in hydrothermal
solutions [1–13]. The hydrogen fugacity [1], the pres-
Correspondence to: Thomas B. Brill; e-mail: brill@udel.edu.
Contract grant sponsor: National Science Foundation.
Contract grant number: CHE-9807370.
2003 Wiley Periodicals, Inc.
c
ꢁ

SPECTROSCOPY OF HYDROTHERMAL REACTIONS
603
as in glutamine and glutamic acid where intramolecular
dehydration to form lactam is an easy route to degrada-
tion[11]. Whenthesidechainofanaminoacidcontains
the hydroxyl group, such as occurs in serine and threo-
nine, the decomposition process involves the competi-
tive reactions: decarboxylation, dehydration, and aldol
cleavage [26].
about the relation between the rates of decarboxylation
and racemization.
EXPERIMENTAL SECTION
All of the amino acids (glycine, alanine, ꢀ-
aminobutyric acid, ꢁ-aminobutyric acid, ꢂ-
aminobutyric acid, valine, leucine, and isoleucine)
were purchased from Sigma-Aldrich and used without
further purification. Milli-Q deionized water was used
to prepare the solutions whose concentrations were
controlled to lie in the range of 0.05–0.5 m. The
amino acid solutions were adjusted to the desired pH
by titrating with aqueous HCl or NaOH, which was
determined with an Orion model 330 pH meter.
The flow reactor FT-IR spectroscopy cell con-
structed from grade 2 titanium with sapphire windows
and gold foil seals has been described in detail else-
where [44,45]. The temperature and pressure were con-
trolled within 1◦C and 1 bar, respectively. The cho-
sen flow rate in the 0.1–1.0 mL/min range was con-
trolled with an accuracy of 1% by the use of an Isco
syringe pump. The flow rate was corrected to account
for the density change with temperature. The residence
time used was 4–20 s, which is much shorter than that
used in batch mode studies. Transmission IR spectra
were recorded at 4 cm−1 resolution using a Nicolet 560
Magna FTIR spectrometer equipped with an MCT-A
detector. Background spectra recorded on pure water
at the same conditions were subtracted from the sam-
ple spectra. Thirty-two spectra were summed at each
condition and the rate data reported herein are the av-
erage of three replicated measurements. Corrosion and
leakage are the two factors that restricted the use of the
flow reactor with more acidic solutions and at higher
temperatures and pressures than those used.
Only the asymmetric stretch of aqueous CO2 cen-
tered at 2343 cm−1 was observed by FT-IR spec-
troscopy in the band pass of sapphire and the pH
range of 1.5–8.5. The band area of CO2 was con-
verted into concentration at each condition by using
the Beer–Lambert Law and the previously determined,
temperature-dependent molar absorptivity of aqueous
CO2 [46]. No absorbance for aqueous CO2 is observed
at more basic conditions than used because of the low
solubility of several of the amino acids (valine, leucine,
and isoleucine) and hydrolysis of the CO2 released by
decarboxylation. The hydrolysis of CO2 [Eqs. (1) and
(2)] [47] in a closed system is strongly dependent on
the solution pH and temperature.
Of all reactions mentioned above, the mechanism
of racemization and the effect of side chains on the
racemization rate are the most studied [14–23]. Fac-
tors that affect the racemization rate are the solution
pH [17,18,21,22], ionic strength [20], buffer concen-
tration [21], and presence of water molecules [15]. The
racemization of amino acids is widely accepted to fol-
low a carbanion mechanism [16]. The rate-determining
step is abstraction of the hydrogen atom from the ꢀ-
carbon, resulting in the formation of a planar carbanion.
Since reprotonation can occur in two ways, the optical
activity of the amino acid can be reversed. Based on
this mechanism, the Taft equation has been success-
fully applied to account for the electronic and steric
effects of alkyl and aryl side chains on the racemiza-
tion rate [14,16,17,21]. The faster racemization rate of
aspartic acid and asparagine was explained to be the
result of intramolecular cyclization [16,27].
The mechanism of decarboxylation can be compli-
cated. Direct decarboxylation of the zwitterions of the
carboxylic acid and carboxylate ion, such as occurs in
aminoacids, hasbeenfound[28–31]. Generally, thede-
carboxylation of aliphatic carboxylic acids is strongly
dependent on the group attached and the bond type
at the ꢁ-position [30–35]. For example, an aromatic
ring acts as an electron sink that dissipates the devel-
oping negative charge on the ꢀ-carbon atom during
the decarboxylation of aromatic acids [35]. A general
water-molecule-catalyzed transition state involving a
six-member ring has been suggested for decarboxy-
lation [34–38]. The decarboxylation of protein amino
acids takes place at high temperatures. However, when
Cl or Br replaces a proton on the amino group, the
amino acid has much lower thermal stability [39–43].
Decomposition occurs at room temperature via a con-
certed fragmentation mechanism to give halogen ions,
imines, and CO2.
Most experimental studies on the hydrothermal sta-
bility of free amino acids have been conducted in the
batch or semibatch mode over long periods of time. In
this paper the rate of formation of CO2 from aliphatic
ꢀ-amino acids were compared at different pH values
using an FT-IR spectroscopy flow reactor. This is a di-
rect measure of the decarboxylation kinetics without
the complications of side reactions. The effects of the
alkyl side chain and amino group position on the decar-
boxylation rate are discussed, along with observations
Ka1
CO2 + H2O ⇐⇒ HCO3− + H+
(1)
(2)
Ka2
HCO3 ⇐⇒ CO32− + H+
−

604
LI AND BRILL
The total CO2 concentration is given by Eqs. (3) and
(4).
ꢀ
ꢁ
[CO2]T = [CO2]obs + [HCO3−] + CO3
(3)
(4)
ꢂ
2−ꢃ
Ka1
Ka1 Ka2
= [CO2]obs 1 +
+
[H+]2
[H+]
When the solution pH values correspond to acidic, neu-
tral, and slightly basic at 25◦C, the hydrolysis of CO2
is negligible and the total CO2 concentration equals the
observed CO2 concentration [47] since the pH values
of both acidic and basic solutions at room temperature
will shift toward neutral at high temperatures. This fact
is illustrated in Fig. 1 where the pH of a 0.5 m aque-
ous alanine solution at room temperature is compared
to that calculated at 320◦C. The trend in the pH is in
agreementwiththedirectmeasurementofthepHofsalt
solutions [48]. The distribution of CO2 species varied
withpH320 asshowninFig. 2. Therequireddissociation
constants for the CO2 species and for alanine at high
temperature were extrapolated from the room temper-
ature values by using the iso-Coulombic method [49]
with the ionization constant [50] and specific volume
[51] of water. The solution pH values at high temper-
atures were calculated from the charge balance equa-
tion [13]. Weighted least-squares regression [52] with
a 95% confidence interval was performed on the rate
data in which the statistical weight was set to be 1/σ2,
where σ is the standard deviation of the variables.
Figure 2 The distribution of aqueous solution CO2 species
at 320◦C.
RESULTS AND DISCUSSION
Aliphatic amino acids produce aliphatic amines and
CO2 upon decarboxylation. On the basis of measure-
ments of the rate of formation of CO2, the decar-
boxylation rate constants can be obtained by plotting
ln([amino acid]0 − [CO2]T) vs. residence time, where
Figure1 ThesolutionpHchangeofa0.5 m alaninesolution
Figure 3 The rate plot for decarboxylation of 0.1 m glycine
at 275 bar showing first-order behavior.
at 320◦C compared to 25◦C.

SPECTROSCOPY OF HYDROTHERMAL REACTIONS
605
[amino acid]0 is the initial concentration of the amino
acid, and [CO2]T is the total CO2 concentration calcu-
lated according to Eq. (4). As discussed above, the total
CO2 concentrationat300–320◦Ccanbereplacedbythe
observed CO2 concentration in the pH25 range of 1.5–
8.5 without loss of accuracy in the calculation of rate
constants. Figure 3 for glycine shows that the decar-
boxylation process followed first-order or pseudo-first-
order kinetics. The observed rate constants are listed
in Table I. The pH dependence of the observed rate
Table I Observed Pseudo-First-Order Rate Constants [k(103 s−1)] of Decarboxylation of Amino Acids at 275 bar and
Different Solution pH25 Values
Glycine (0.1 m)
Temperature (◦C)
1.64
2.0a
2.54
3.14
4.01
5.66 (Nat.)b
8.08
310
320
330
13.99 1.31 23.85 0.95
31.45 0.87 36.84 2.05 116.18 3.89 64.75 2.55 55.44 1.67 61.66 1.79 47.35 1.48
62.12 1.29 67.96 5.00 186.89 5.17 99.49 4.39 95.81 2.69 95.47 2.45 90.79 4.35
57.06 2.32 40.07 1.43 30.61 0.46 37.15 0.80 27.90 0.43
Alanine (0.1 m)
Temperature (◦C)
1.76
2.58
3.46
4.53
5.86 (Nat.)b
4.99 0.16
7.22
8.50
310
320
330
7.55 0.41
5.52 0.12
12.10 0.52
4.30 0.17
5.32 0.24
5.68 0.18
3.53 0.20 15.49 0.50
9.88 0.67
9.83 0.39 10.18 0.35 11.59 0.53 10.41 0.25
30.7 0.95
20.89 0.60 18.36 0.50 18.44 0.50 19.85 0.61 18.73 0.40
ꢀ-Aminobutyric acid (0.25 m)
Temperature (◦C)
1.16
2.51
3.49
4.11
5.68 (Nat.)b
7.59
8.44
310
320
330
6.52 0.28
0.88 0.18 14.58 0.60
2.38 0.08 28.06 0.69
1.77 0.06
4.07 0.06
9.15 0.19
1.66 0.07
4.01 0.22
9.38 0.29 10.85 0.26 10.08 0.28
2.60 0.10
5.65 0.21
1.85 0.07
4.39 0.22
1.43 0.09
4.04 0.25
8.19 0.28
ꢁ-Aminobutyric acid (0.1 m)
Temperature (◦C)
2.50
3.58
4.58
5.44
6.22
7.95 (Nat.)b
9.15
310
320
330
2.54 0.12
4.12 0.37
6.05 0.33
3.42 0.29
5.31 0.29
7.48 0.25
3.52 0.15
5.11 0.22
7.48 0.18
3.54 0.21
5.32 0.13
7.84 0.22
3.02 0.31
4.75 0.15
7.05 0.17
3.46 0.16
5.29 0.15
7.61 0.16
2.78 0.10
4.54 0.11
6.71 0.11
Valine (0.25 m)
Temperature (◦C)
1.55
2.51
3.49
4.38
5.80 (Nat.)
8.65 0.31
7.70
8.20
310
320
330
10.9 0.41
8.59 0.26
7.89 0.32
8.26 0.39
7.05 0.04
4.81 0.22 23.83 0.76
10.58 0.27 47.38 1.27
17.94 0.70 16.74 0.71 16.02 0.47 16.85 0.36 14.82 0.40
29.32 0.77 27.62 0.80 30.56 0.57 27.37 0.76 29.64 0.73
Leucine (0.05 m)
Temperature (◦C)
1.51
2.46
3.15
4.02
5.47 (Nat.) b
7.35
8.50
310
320
330
14.59 1.02
3.19 0.44 28.85 1.17
5.69 0.52 51.34 2.39
11.36 0.44
8.77 0.59 11.51 0.64
9.07 0.54
7.55 0.82
18.85 0.87 17.03 0.44 19.47 0.77 18.17 1.03 12.88 1.41
30.31 1.19 31.39 1.93 30.75 0.86 28.32 1.00 28.60 1.58
Isoleucine (0.05 m)
Temperature (◦C)
1.50
2.45
3.13
3.96
6.03 (Nat.)b
8.08 0.43
7.35
8.52
310
320
330
10.87 0.18
7.51 0.29
7.60 0.66
7.98 0.36
8.15 0.70
1.39 0.57 23.93 0.25
2.33 0.21 39.00 0.40
15.74 0.67 14.80 0.41 16.83 0.75 15.64 0.53 16.26 1.76
30.22 1.06 30.10 1.12 28.89 0.54 29.03 0.68 28.64 0.76
aGlycine hydrochloride.
bNatural pH.

606
LI AND BRILL
Figure 4 The pH dependence of the decarboxylation rate
Figure 6 Comparison of the decarboxylation rate constants
reported for glycine at its natural pH.
of aliphatic amino acids at 320◦C and 275 bar.
constants for all of the amino acids at 320◦C is dis-
played in Fig. 4.
It is clear that the observed rate constants are rela-
tively independent of the solution pH in the range of
3–8.5. On the other hand, the rate constants reach a
maximum when the pH25 is about 2.5, and then de-
crease again as the pH decreases. The maximum rate
constant at pH25 = 2.5 was missed in the former study
[13] of the decarboxylation of alanine because the rate
constant is very sensitive to pH in this range. On the
other hand, in the pH25 range of 3–8.5, the predominant
amino acid form is the zwitterion even at high temper-
atures. The pH changes very little at high temperature
during decarboxylation, because the mixture of amino
acid, alkyl amine, and CO2 due to decarboxylation cre-
ates a buffered system.
The decarboxylation reaction of alanine is the most
studied of the amino acids. The present experimen-
tal results and those of other authors are compared in
Fig. 5 by plotting ln k vs. 1/T . The data of Qian et al.
Table II Arrhenius Parameters of Amino Acids Toward
Decarboxylation
Amino Acid
Ea (kJ mol−1
)
ln A (s−1
)
Glycine
Alanine
138.4 3.9
190.6 7.7
25.25 0.79
34.01 1.49
(30.09 1.99)a
36.81 1.49
17.71 0.85
33.58 0.81
24.84 0.89
(32.77)b
(175.5 8.3)a
207.2 7.4
113.3 4.2
185.9 4.0
142.0 4.4
(189.1)b
ꢀ-Aminobutyric acid
ꢁ-Aminobutyric acid
Valine
Leucine
Isoleucine
180.8 12.3
32.51 2.47
aRegressed based on all reported data except Ref. 6.
bFrom Ref. 12.
Figure 5 Comparison of the decarboxylation rate constants
reported for alanine at its natural pH.

SPECTROSCOPY OF HYDROTHERMAL REACTIONS
607
Figure 7 Comparison of the decarboxylation rate constants
Figure 8 Arrhenius plot of the decarboxylation rates of
of valine, leucine, and isoleucine at their natural pH values.
amino acids.
[6] are not consistent with the other studies. Taking
into account the reactor materials mentioned in liter-
ature, the decarboxylation of alanine appears not to
be particularly dependent on the surface. On the other
hand, there is a large difference among the reported
rates for glycine (Fig. 6). The present rate constants for
glycine are 5–10 times faster than those of Qian et al.
[6], and Snider and Wolfenden [9], and Vallentyne [10]
when the comparison is made at the same temperature.
Qian et al. [6] and Snider and Wolfenden [9] found that
the decarboxylation rate of glycine is slower than that
of alanine, whereas Vallentyne [10] and Quitain et al.
[53] and the present work observe the reverse. Reac-
tor surface materials used for glycine kinetics include
Pyrex glass, quartz glass, stainless steel, and titanium.
The discrepancies in the rate constants for glycine sug-
gest that the material used to construct the reactor might
affect the rate, as it does for formic acid [54].
study when extrapolation is made between the temper-
ature ranges used. The decarboxylation rates of these
three amino acids are almost the same despite the dif-
ference in the side chains. The order of rates of the six
ꢀ-amino acids is as follows: Gly > Leu ≈ Ile ≈ Val >
Ala > ꢀ-Aib.
The variation of the decarboxylation rate with tem-
perature followed the Arrhenius equation as shown in
Fig. 8. The resulting Arrhenius parameters are listed in
Table II. Also listed in Table II are the regressed acti-
vation energy and frequency factor for alanine based
on all reported data except those of Qian et al. ꢁ-
Aminobutyric acid has smaller Arrhenius parameters
compared to the other aliphatic ꢀ-amino acids.
Effect of the Amino Acid Concentration
on the Decarboxylation Rate
Comparisons of decarboxylation rate of valine,
leucine, and isoleucine are made in Fig. 7. The mea-
sured rate constants by Vallentyne [10] for valine,
leucine, and isoleucine are consistent with the present
Kawamura and Yukioka [23] observed the formation
of amino acid anhydrides in their real time study of
racemization of amino acids, when the concentration
was high and residence time was long. To eliminate
Table III The Effect of Concentration on the Decarboxylation Rate of Alanine at Its Natural pH and 275 bar
Temperature (◦C)
0.5 m
0.25 m
0.1 m
0.05 m
310
320
330
5.30 0.26
12.41 0.60
23.39 0.62
5.87 0.17
12.19 0.30
21.42 0.50
4.99 0.16
10.18 0.35
18.44 0.50
3.92 0.09
8.46 0.20
16.30 0.44

608
LI AND BRILL
stability is achieved when the NH2 substitution occurs
at the terminus of the side chain. It is understandable
that the decarboxylation rate of ꢁ-aminobutyric acid
is about two times slower than that of ꢀ-aminobutyric
acid. Repositioning the NH2 group from the ꢀ-carbon
to the ꢁ-carbon reduces the inductive and electrostatic
effectsfavoringdecarboxylation. Ontheotherhand, the
ꢁ-NH2 group can engage in intramolecular hydrogen
bonding with the carboxylate group, which would re-
duce the activation energy of decarboxylation [30–34].
These factors compete. There is no possibility for ꢂ-
aminobutyric acid to form such an intramolecular hy-
drogen bond and the inductive and electrostatic effects
are further reduced, which leads to higher hydrother-
mal stability of ꢂ-aminobutyric acid.
Decarboxylation Versus Racemization
Figure 9 shows that decarboxylation and racemiza-
tion have approximately inverse behavior as a function
of pH. This comparison gives insight into the mech-
anisms. Shou [21] used four absolute rate constants
and Smith et al. [19] used six rate constants to repre-
sent the variation of the observed racemization rates of
amino acids with the solution pH. Each pair of racem-
ization rate constants corresponded to acid- and base-
catalyzed reactions for the cationic, the anionic, and the
zwitterionic forms of the amino acid. A similar proce-
dure to obtain multiple absolute rate constants for the
pH dependence of decarboxylation was not followed
here because of the relatively narrow pH range and the
difficulty in determining the true solution pH at high
temperatures.
Figure 9 Comparison of the pH dependence of the decar-
boxylation rate at 320◦C and for the racemization rate at
142◦C of aliphatic amino acids.
this possibility here, the initial concentration and resi-
dence time were reduced. At the same time, the influ-
ence of concentration on the decarboxylation rate was
evaluated, and the results are shown in Table III. It can
be seen that only a small change in the rate constant
occurs when the concentration of alanine is varied be-
tween 0.5 and 0.05 m. This observation supports the
first-order rate model for decarboxylation (Fig. 3).
Mechanistically, it is well accepted that the rate-
determining step of racemization results when pro-
ton abstraction occurs at the ꢀ-carbon atom to give
a three-coordinate carbanion intermediate as shown in
Scheme 1 [16]. On the other hand, the zwitterion form
of the amino acid decarboxylates by catalysis involv-
ing a hydrogen-bonded water molecule [56]. Scheme 2
summarizes the reactant ground state, the transition
state, and the final products. Notice that an H atom
of the water molecule moves toward the ꢀ-carbon
atom creating, in effect, a five-coordinate carbon
atom. Hence, since racemization involves formation of
Effect of the Position of the NH2 Group
The decarboxylation rate of aminobutyric acid with
three different positions of the amino group (ꢀ, ꢁ, and
ꢂ) was studied with the FT-IR spectroscopy flow re-
actor operating at 330◦C with a residence time of 35
s. The NH2 position had a profound effect on the de-
carboxylation rate: ꢀ > ꢁ ꢀ ꢂ. In fact, no release of
CO2 was observed from ꢂ-aminobutyric acid in the
present study. Combined with Schroede and Bada’s ob-
servation [55], it seems that the highest hydrothermal
Scheme 1

SPECTROSCOPY OF HYDROTHERMAL REACTIONS
609
Scheme 2
three-coordinate carbon and decarboxylation involves
formation of five-coordinate carbon, the driving force
can be expected to be the reverse of the other. Hence
the inverse trend in the pH profile of decarboxylation
vs. racemization is observed in Fig. 9.
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