Conversion and origin of normal and abnormal temperature dependences of kinetic isotope effect in hydride transfer reactions

Article abstract of DOI:10.1021/jo3005952

The effects of substituents on the temperature dependences of kinetic isotope effect (KIE) for the reactions of the hydride transfer from the substituted 5-methyl-6-phenyl-5,6-dihydrophenanthridine (G-PDH) to thioxanthylium (TX⁺) in acetonitrile were examined, and the results show that the temperature dependences of KIE for the hydride transfer reactions can be converted by adjusting the nature of the substituents in the molecule of the hydride donor. In general, electron-withdrawing groups can make the KIE to have normal temperature dependence, but electron-donating groups can make the KIE to have abnormal temperature dependence. Thermodynamic analysis on the possible pathways of the hydride transfer from G-PDH to TX⁺ in acetonitrile suggests that the transfers of the hydride anion in the reactions are all carried out by the concerted one-step mechanism whether the substituent is an electron-withdrawing group or an electron-donating group. But the examination of Hammett-type free energy analysis on the hydride transfer reactions supports that the concerted one-step hydride transfer is not due to an elementary chemical reaction. The experimental values of KIE at different temperatures for the hydride transfer reactions were modeled by using a kinetic equation formed according to a multistage mechanism of the hydride transfer including a returnable charge-transfer complex as the reaction intermediate; the real mechanism of the hydride transfer and the root that why the temperature dependences of KIE can be converted as the nature of the substituents are changed were discovered.

Full text of DOI:10.1021/jo3005952

Article
pubs.acs.org/joc
Conversion and Origin of Normal and Abnormal Temperature
Dependences of Kinetic Isotope Effect in Hydride Transfer Reactions
Xiao-Qing Zhu,* Xiu-Tao Li, Su-Hui Han, and Lian-Rui Mei
State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The effects of substituents on the temperature dependences of kinetic isotope effect (KIE) for the reactions of the
hydride transfer from the substituted 5-methyl-6-phenyl-5,6-dihydrophenanthridine (G-PDH) to thioxanthylium (TX+) in
acetonitrile were examined, and the results show that the temperature dependences of KIE for the hydride transfer reactions can
be converted by adjusting the nature of the substituents in the molecule of the hydride donor. In general, electron-withdrawing
groups can make the KIE to have normal temperature dependence, but electron-donating groups can make the KIE to have
abnormal temperature dependence. Thermodynamic analysis on the possible pathways of the hydride transfer from G-PDH to
TX+ in acetonitrile suggests that the transfers of the hydride anion in the reactions are all carried out by the concerted one-step
mechanism whether the substituent is an electron-withdrawing group or an electron-donating group. But the examination of
Hammett-type free energy analysis on the hydride transfer reactions supports that the concerted one-step hydride transfer is not
due to an elementary chemical reaction. The experimental values of KIE at different temperatures for the hydride transfer
reactions were modeled by using a kinetic equation formed according to a multistage mechanism of the hydride transfer
including a returnable charge-transfer complex as the reaction intermediate; the real mechanism of the hydride transfer and the
root that why the temperature dependences of KIE can be converted as the nature of the substituents are changed were
discovered.
temperature can be well rationalized by semiclassical models
based on transition state theory and was supported by lots of
experiment results,4−6 it has been widely accepted as a well-
known conception and called as a normal temperature
dependence of KIE (“normal KIE” for short in this work).4,5
However, there are also a quite lot of examples in which the
dependence of KIE on the temperature has a character of the
direct proportion; that is, KIE increases with a temperature
increase, or KIE decreases with a temperature decrease.7−13
Since this relationship between KIE and the temperature with
the direct proportion cannot be explained by the orthodox
kinetic theory, chemists generally call this kinetic phenomenon
as an abnormal temperature dependence of KIE (“abnormal
KIE” for short in this work). By examining the past publications
on the relationship between KIE and the temperature, it is
found that although the “normal KIE” phenomenon and the
“abnormal KIE” phenomenon have received a lot of
examination, most of the chemists' attention focused on the
isolated cases, no or very little attention has been focused on
INTRODUCTION
■
Kinetic isotope effect (KIE) is a change of reaction rates when
an isotopic atom is substituted by another isotopic atom in
reaction molecules and is conventionally expressed by the ratio
of reaction rates of two different isotopically labeled molecules
in a chemical reaction.1 KIE is a very common chemical kinetic
phenomenon, and the magnitude of KIE not only depends on
the nature of isotopic atom, but also depends on the reaction
mechanism as well as many other factors, such as temperature,
solvent, pressure, and so on. So, KIE is very useful in chemical
research, especially in mechanistic studies of reactions, which
can provide insight into the transition state of the reactions
examined.2 In recent years, the relationship between KIE and
the temperature has drawn more and more attention from
biochemists, and the reason is that the dependence of KIE on
the temperature can be used as an indicator for the physical
nature of enzyme-catalyzed H-transfer reactions.3 In fact, for
the most chemical reactions, the investigations show that the
relationship between KIE and the temperature is more or less
in an inverse proportion; i.e., KIE decreases with a temperature
increase, or KIE increases with a temperature decrease. Since
the inverse proportion relationship between KIE and the
Received: March 23, 2012
Published: April 23, 2012
© 2012 American Chemical Society
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the intrinsic relationship between the different kinetic KIE
phenomena. In fact, it is quite difficult until now to safely
answer the following questions: (1) Why do some reactions
have “normal KIE”, but some other reactions have “abnormal
KIE”? (2) Can or cannot the conversion between the “normal
KIE” and the “abnormal KIE” take place in a chemical reaction?
(3) What is the real reason that results in the “abnormal KIE”?
It is clear that these scientific questions on the temperature
dependence of KIE should be not only fundamental but also
very interesting and important, which, of course, has attracted
our high attention for a long time. In order to answer the
questions mentioned above and dig up the root resulting in the
abnormal temperature dependence of KIE in a chemical
reaction, it is conceived that the key work is to thoroughly
elucidate the intrinsic relationship between the “normal KIE”
phenomenon and the “abnormal KIE” phenomenon. Since the
nature of the substituent groups in molecules generally have
significant effects on the temperature dependence of KIE, the
hydride transfer reaction is one type of very important
fundamental chemical processes, and the mechanistic detail
for many hydride transfer reactions is still a conflicting issue
and has been the focus of interest for many chemists and
biochemists,14−19 in this work, a series of substituted 5-methyl-
6-phenyl-5,6-dihydrophenanthridine (G-PDH) were synthe-
sized as the hydride donors, and thioxanthylium (TX+) was
chosen as the hydride acceptor. The mechanistic details of the
hydride transfer from G-PDH to TX+ and the effects of the
substituent groups on the temperature dependences of KIE for
the hydride transfer process from G-PDH to TX+ in acetonitrile
were all examined in detail. The experiment results show that
the temperature dependence of KIE for the hydride transfer
reaction in eq 1 can be altered from the “normal KIE” to the
“abnormal KIE”, as the substituents changed from electron-
withdrawing groups to electron-donating groups.
RESULTS
■
The substituted 5-methyl-6-phenyl-5,6-dihydrophenanthridine
(G-PDH) and the corresponding deuterated compounds (G-
PDD) as well as thioxanthylium perchlorate (TX+ClO4 ) were
−
synthesized in this work according to conventional synthetic
strategies, and the target products were identified by H NMR
1
and MS; the detailed synthetic routes were provided in the
Supporting Information. The standard one-electron oxidation
potentials of G-PDH and TXH and the standard one-electron
reduction potentials of their corresponding salts (G-PD+ and
TX+) in acetonitrile were determined by using two electro-
chemical methods CV and OSWV (Figures 1 and 2); the
detailed experimental results are summarized in Table 1. When
G-PDH were treated by TX+ in acetonitrile at room
temperature, the final products are identified to be G-PD+
and TXH, and the reaction stoichiometric relationship between
the hydride donors and the hydride acceptor is 1 mol per 1
mol, which means that these reactions were completed by one
hydride anion transfer. The molar enthalpy change (ΔHrxn) of
the hydride transfer from G-PDH to TX+ in acetonitrile at 298
K was determined by titration calorimeter on a CSC 4200
isothermal titration calorimeter (Figure 3). The detailed results
are also listed in Table 1.
The pseudofirst-order rate constants of the hydride transfer
from the substituted 5-methyl-6-phenyl-5,6-dihydrophenanthri-
dine (G-PDH) to thioxanthylium (TX+) (eq 1) in acetonitrile
were determined using an Applied Photophysics SX.18MV-R
stopped-flow spectrometer by monitoring the spectra change of
thioxanthylium (TX+) at λ = 500 nm with the concentration of
G-PDH at more than 20-fold excess of TX+ (Figure 4). The
second order observed rate constants (kobs) for the reactions at
different temperatures between 298 and 318 K were derived
from the corresponding pseudofirst-order rate constants by the
linear correlation against the concentration of the hydride
donors and listed in Table 2. The Arrhenius parameters, Ea and
A, were calculated from the slope and the intercept of the
Arrhenius plots of ln(kobs) versus the reciprocal of the absolute
temperature (1/T), which were also listed in Table 2. The
kinetic isotope effects (kobsH/kobsD) of the reactions at different
temperatures between 298 and 319 K were listed in Table 3.
Figure 1. Cyclic voltammogram (CV), Osteryong square wave voltammogram (OSWV) of H-PDH (a) and H-PD+ (b) in anhydrous deaerated
acetonitrile solution containing 0.1 M (n-Bu)4NPF6 as supporting electrolyte: CV graph (black line), OSWV graph (red line). The sweep rate is 100
mV/s.
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Figure 2. Cyclic voltammogram (CV), Osteryong square wave voltammogram (OSWV) of TXH (a) and TX+ (b) in anhydrous deaerated
acetonitrile solution containing 0.1 M (n-Bu)4NPF6 as supporting electrolyte: CV graph (black line), OSWV graph (red line). The sweep rate is 100
mV/s.
Table 1. Enthalpy Changes of the Hydride Transfer from G-
PDH with TX+ClO4− in Acetonitrile at 298 K Together with
Redox Potentials of the Related Species in Acetonitrile at
Room Temperature
b
b
Eox(XH)
Ered(X+)
a
species (XH)
ΔHrxn
CV
OSWV
CV
OSWV
G-PDH
p-CF3
p-Cl
−24.7
−26.4
−26.6
−27.5
−28.1
−29.2
0.459
0.436
0.415
0.420
0.410
0.398
0.983
0.435
0.411
0.398
0.394
0.383
0.372
0.962
−1.241
−1.271
−1.307
−1.313
−1.322
−1.329
−0.258
−1.256
−1.294
−1.312
−1.325
−1.346
−1.356
−0.227
m-CH3O
p-H
Figure 4. UV−vis spectra change obtained from the reaction of H-
p-CH3
p-CH3O
TXH
−
PDH (5.5 × 10−3 mol/L) with TX+ClO4 (ca. 2.0 × 10−4 mol/L) in
dry acetonitrile at 298 K at 1 s intervals. Inset: the time-resolved
spectrum at 500 nm.
a
ΔHrxn was obtained from the reaction heats of G-PDH with
−
TX+ClO4 in acetonitrile by switching the sign; the latter were
measured by titration calorimetry in acetonitrile at 298 K. The data,
given in kcal/mol, were average values of at least three independent
DISCUSSION
■
From Table 3 it is clear that when the substituent group (G) in
the molecule of the hydride donor G-PDH is p-CF3, the KIE
value of the hydride transfer from G-PDH to TX+ decreases
from 3.29 to 2.77 as the temperature increases from 298 to 318
K. But when the substituent group in G-PDH is p-CH3O, the
relationship between KIE and the temperature is as reverse as
in the case that G is p-CF3; i.e., when the temperature increases
from 298 to 318 K, the KIE value does not decrease, but
increases from 2.86 to 3.90. This result indicates that for the
reaction of the hydride transfer from G-PDH to TXH+ in
acetonitrile, the KIE has two different temperature depend-
ences: a normal temperature dependence (“normal KIE”) for G
= p-CF3 and an abnormal temperature dependence (“abnormal
KIE”) for G = p-CH3O. As we know, this should be the first
example of the hydride transfer reactions that the KIE has two
different temperature dependences in the same reaction. If the
effect of each substituent among the six substituents on the
temperature dependence of KIE all was examined, respectively
(Figure 5), it is found that the KIE values for the six substituted
groups all have good linear dependences on the temperature
when the temperature increases from 298 to 318 K. In general,
when the substituent is an electron-withdrawing group, the
temperature dependence of KIE is “normal”, but when the
substituent is an electron-donating group, the temperature
dependence of KIE is “abnormal”. In addition, from the line
slopes in Figure 5, it is clear that the stronger the electron-
b
runs. The reproducibility is ≤0.5 kcal/mol. Measured by CV and
OSWV methods in acetonitrile at room temperature, the unit in volts
vs Fc+/Fc0 and reproducible to 5 mV or better.
Figure 3. Isothermal titration calorimetry (ITC) for the reaction heat
of p-CH3−PDH with TX+ClO4− in acetonitrile at 298 K. Titration was
conducted by adding 10 μL of p-CH3−PDH (2.34 mM) every 300s
−
into the acetonitrile containing TX+ClO4 (ca. 10 mM).
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Table 2. Rate Constants of the Hydride Transfer from G-PDH and G-PDD to TX+ClO4 in Acetonitrile at Different
−
Temperatures between 298 and 318 K Together with the Corresponding Arrhenious Parameters
a
kobs × 10−2 (M−1 s−1
)
b
c
hydrides
298 K
303 K
308 K
313 K
318 K
A
Ea
G-PDH
p-CF3
2.86
9.11
3.28
10.61
14.99
19.90
27.74
30.50
3.77
11.77
17.98
22.87
32.88
36.61
4.36
13.90
20.99
27.28
38.55
43.62
4.86
14.91
23.68
32.28
45.80
51.56
1.46 × 106
2.71 × 106
1.78 × 107
3.57 × 107
1.14 × 108
1.86 × 108
5.06
4.73
5.63
5.89
6.40
6.63
p-Cl
m-CH3O
p-H
13.27
17.26
23.09
25.57
p-CH3
p-CH3O
G-PDD
p-CF3
0.87
2.90
4.16
5.35
7.13
8.93
1.04
3.52
4.67
6.13
8.21
9.94
1.25
4.00
5.75
6.87
9.39
11.22
1.50
4.82
1.76
5.38
6.78 × 106
5.64 × 106
4.75 × 106
4.10 × 106
3.70 × 106
4.83 × 105
6.67
5.84
5.54
5.30
5.07
3.72
p-Cl
m-CH3O
p-H
6.48
7.36
8.09
9.42
p-CH3
p-CH3O
10.70
12.14
12.23
13.23
a
Second-order observed rate constants kobs for the hydride transfer reactions were obtained from the corresponding pseudofirst-order rate constants
b
by the linear correlation against the concentration of the hydride donors; the experimental error is within 5%. From the intercepts of the Arrhenius
plots. From the slopes of the Arrhenius plots, the unit is kcal/mol, and the uncertainty is smaller than 0.05 kcal/mol.
c
D
Table 3. Dependence of Kinetic Isotope Effect (kobsH/kobs
)
temperatures of 298, 303, 308, 313, and 318 K against the
Hammett substituent parameters σ were made (Figure 6).
for the Reactions of G-PDH(D) with TX+ in Acetonitrile on
the Reaction Temperature
D
kobsH/kobs
groups
σ
298 K
303 K
308 K
313 K
318 K
p-CF3
p-Cl
0.54
0.23
3.29
3.14
3.19
3.23
3.24
2.86
3.15
3.02
3.21
3.25
3.38
3.07
3.03
2.94
3.13
3.33
3.50
3.26
2.91
2.88
3.24
3.37
3.60
3.59
2.77
2.77
3.22
3.42
3.75
3.90
m-CH3O
p-H
0.12
0.00
p-CH3
p-CH3O
−0.17
−0.27
D
Figure 6. Plots of kinetic isotope effect kobsH/kobs against the
Hammett substituent parameters σ for the hydride transfer reactions
−
from G-PDH(D) to TX+ClO4 in acetonitrile at the various
temperatures.
From Figure 6, it is clear that the substituent group that the
Hammett parameter σ value is about 0.12, such as m-MeO,
which could make the temperature dependences of KIE to
convert.
Figure 5. Plot of kinetic isotope effect kobsH/kobsD against temperature
From the statements described above, it is evident that the
reaction of the hydride transfer from G-PDH to TX+ in
acetonitrile has two reversed temperature dependences of KIE;
i.e., when the σ-value of the substituent is larger than 0.12, the
reaction has “normal” KIE, but when the σ-value of the
substituent is smaller than 0.12, the reaction has “abnormal”
KIE. Why can the nature of the substituents cause the
conversion of the relationship between KIE and the temper-
ature? What is the reason that the substituents with the σ-values
smaller than 0.12 can result in “abnormal” KIE for the hydride
transfer reaction?
for the hydride transfer from G-PDH(D) to TX+ClO4− in acetonitrile.
withdrawing ability or electron-donating ability of the
substituent group is, the greater the effect of the substituent
on the temperature dependence of KIE is, which indicates that
whether “normal” or “abnormal” temperature dependence of
KIE in the hydride transfer reactions directly depends on the
nature of the substituent groups.
In order to determine the substituent group that can make
the temperature dependences of KIE to convert from “normal”
to “abnormal”, plots of the KIEs for the reactions of the hydride
In order to dig out the origin that results in the questions
mentioned above, KIEs of the six hydride transfer reactions
−
transfer from G-PDH(D) to TX+ClO4 in acetonitrile at the
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with different substituents were examined. Table 3 shows that
the KIE values of the six hydride transfer reactions with
different substituents range from 3.29 for G = p-CF3 to 2.86 for
p-CH3O at 298 K. Since the KIE values of the six hydride
transfer reactions with different substituents are all quite large,
generally greater than 3.0, the six hydride transfer reactions
with different substituents all have primary KIE, which means
that the dissociation of C−H(D) bond in G-PDH(D) should
take place in the rate-determining step for each of the six
hydride transfer reactions. When the logarithmic values of kobs
against Hammett substituent parameters σ were plotted in
Figure 7, it is found that the linearity of the six points is not
a, c, e, and d all have primary KIE), evidently, it is necessary to
elucidate the mechanistic details of the six hydride transfer
reactions with different substituents in acetonitrile.
To elucidate the most likely mechanisms of the hydride
transfer from G-PDH to TX+ in acetonitrile, the thermodynamic
analysis platform20 on the possible mechanism of the hydride
transfer from G-PDH to TX+ in acetonitrile was constructed
(Scheme 1), and the change of the standard state energy of
each reaction step for the hydride transfer can be estimated
according to eqs 2−7, of which eqs 4−6 were derived from
three suitable thermodynamic cycles according to Hess’ law (in
the Supporting Information).21 The detailed results for the
change of the standard state energy of each reaction step are
summarized in Table 4.
ΔH(step a) = ΔHrxn
(2)
ΔG(step b) = −F[Ered(TX+) − Eox(G‐PDH)]
(3)
ΔH(step c) = ΔHrxn − F[Ered(G‐PD+) − Eox(TXH)]
(4)
ΔH(step d) = ΔHrxn − F[Ered(G‐PD+) − Eox(TXH)]
+ F[Ered(TX+) − Eox(G‐PDH)]
(5)
ΔH(step e) = ΔHrxn + F[Ered(TX+) − Eox(G‐PDH)]
(6)
Figure 7. Plot of ln(kobs) against the Hammett substituent parameters
σ for the reactions of G-PDH and G-PDD with TX+ in acetonitrile at
298 K.
ΔG(step f ) = F[Ered(G‐PD+) − Eox(TXH)]
(7)
From Table 4, it is clear that for the six hydride transfer
reactions with different substituents, the state energy changes of
the three initial steps range from −24.7 to −29.2 kcal/mol for
step a (hydride transfer in one step), from 15.3 to 13.8 kcal/
mol for step b (electron transfer), and from 26.4 to 24.3 kcal/
mol for step c (hydrogen atom transfer). Since the state energy
changes of step b and step c are all quite large positive values
(greater than 13.8 and 24.3 kcal/mol, respectively), it is
reasonable to suggest that the processes of electron transfer
(step b) and hydrogen atom transfer (step c) can be all ruled
out as the initial step of the hydride transfer from G-PDH to
TX+ in acetonitrile whether the substituent is an electron-
donating group or an electron-withdrawing group. As a result,
the remaining step a (the concerted hydride transfer in one
step) should be the merely viable process for the hydride
transfer from G-PDH to TX+ in acetonitrile because the state
good. But when the effects of the electron-donating groups and
of the electron-withdrawing groups on the logarithmic values of
kobs were examined, respectively, two quite straight lines (black
lines in Figure 7) were obtained with the line slopes of −1.69
and −3.67 for electron-donating groups and for electron-
withdrawing groups, respectively, which means that it is
impossible that the reactions of the hydride transfer from G-
PDH to TX+ in acetonitrile take place by one step mechanism
as an elementary chemical reaction. Since the hydride transfer
may proceed by multistep sequence (e−−H+−e−, e−−H•, and
H•−e−) in addition to by one-step (Scheme 1), and the
chemical processes of the hydrogen atom transfer (steps c and
e) and proton transfer (step d) like hydride transfer (step a) all
involve the C−H(D) bond dissociations (i.e., the reaction steps
Scheme 1. Possible Reaction Pathways of the Hydride Transfer from G-PDH to TX+ in Acetonitrile
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Table 4. Energetics of Each Mechanistic Step of the Hydride
Transfer from G-PDH to TX+ Shown in Scheme 1 (kcal/
ab
,
mol)
ΔH (or ΔG) (kcal/mol)
groups
step a
step b
step c
step d
step e
step f
p-CF3
p-Cl
−24.7
−26.4
−26.6
−27.5
−28.1
−29.2
15.3
14.7
14.4
14.3
14.1
13.8
26.4
25.6
25.8
25.2
25.1
24.3
11.2
10.8
11.4
10.9
11.1
10.5
−40.0
−41.1
−41.0
−41.8
−42.2
−43.0
−51.1
−52.0
−52.4
−52.7
−53.2
−53.5
m-CH3O
p-H
p-CH3
p-CH3O
a
The state energy changes are scaled by using enthalpy changes for
b
steps c−e and by using free energy changes for steps b and f. The
standard redox potentials in acetonitrile were derived from the
experimental results by using CV method, but if the electrochemical
redox is irreversible, the standard redox potentials in acetonitrile were
derived from the OSWV results, because OSWV has been verified to
be a more exact electrochemical method for evaluating the standard
one-electron redox potentials of analyte with irreversible electro-
chemical processes than CV.22
Figure 8. Comparison of state energy changes for the three possible
initial steps of the hydride transfer from H-PDH to TX+ and the
activation energy of the hydride transfer in acetonitrile.
From the discussion given above, it is sure that the hydride
transfers all took place via one-step mechanism from G-PDH to
TX+ in acetonitrile whether the substituent (G) is an electron-
withdrawing group or an electron-donating group. However,
according to Arrhenious equation, it is impossible that an
elementary reaction has an abnormal temperature dependence
of KIE, and the reason is that ED − EH is always larger than zero
in the equation of kH/kD = AH/AD exp[(ED − EH)/RT], which
indicates that the transfer of the hydride anion from G-PDH to
TX+ in acetonitrile by one step mechanism is not an elementary
chemical reaction. In fact, from Figure 7, we clearly find that
when the substituent groups are electron-donating, the line
slope is −1.67, but when the substituent groups are electron-
withdrawing, the line slope is −3.67; the marked difference
between the two line slopes evidently indicates that the one-
step of the hydride transfer from G-PDH to TX+ in acetonitrile
is not a single, discrete reaction step (i.e., an elementary
chemical reaction step). Since the hydride anion can be divided
into two electrons and one hydrogen atomic nucleus (or
proton), and the mass of electron is much smaller than that of
hydrogen atomic nucleus, it is conceived that during the
hydride transfer, the electron transfer should be more favorable
than the hydrogen atomic nucleus transfer; i.e., the transfer of
electron and the transfer of the hydrogen atomic nucleus could
not be at same time during the hydride transfer, which, of
course, also can receive the strong support from Franck−
Condon principle.24 So, it is reasonable to suggest that the
charge-transfer complex (CT-complex) could be formed as an
reaction intermediate during the hydride transfer in one-step.
The most likely reaction mode for the hydride transfer from G-
PDH to TX+ in acetonitrile may be proposed as shown in
Scheme 2. In this mode, the process of the hydride transfer
energy changes of step a are all quite negative (more negative
than −24.7 kcal/mol). That is to say, whether the substituent is
an electron-donating group or an electron-withdrawing group,
the mechanism of the hydride transfer from G-PDH to TX+
should be the same; i.e., the hydride transfers all take place in
one-step. In fact, the one-step mechanism of the hydride
transfer can be further verified from the comparison of the state
energy changes of the three possible initial steps of the hydride
transfer and the Arrhenious activation energy of the hydride
transfer reaction. Table 2 shows that the value scale of the
Arrhenious activation energies (Ea) of the reactions range from
4.73 to 6.63 kcal/mol when H atom was used as the isotopic
atom. Since the Arrhenious activation energies of the reactions
(4.73−6.63 kcal/mol) are much smaller than the corresponding
standard state energy changes of the initial electron transfer
(step b) (15.3−13.8 kcal/mol) and the corresponding standard
state energy changes of the initial hydrogen transfer (step c)
(26.4−24.3 kcal/mol), but larger than the corresponding
standard state energy changes of the concerted hydride transfer
(step a) (−29.2 ∼ −24.7 kcal/mol), the initial electron transfer
and the initial hydrogen atom transfer as the isolated reaction
step in the hydride transfer from G-PDH to TX+ both are
impossible to take place according to the collision theory as one
of the most fundamental reaction laws that the Arrhenious
activation energy is always larger than or at least equal to the
corresponding standard state energy change for any elemental
reaction.23 It is evident that both of the two reaction steps b
and c must be ruled out as the initial reaction steps in the
reactions of G-PDH with TX+ in acetonitrile; the only
remaining step a is suitable for the reaction law (Figure 8).
As such, a convincing conclusion can be made that the
mechanisms of the hydride transfer from G-PDH to TX+ in
acetonitrile should be the same to each other whether the
substituent group is electron-withdrawing or electron-donating.
On the basis of the statement above, it is clear that the
discovery that the reactions of G-PDH with TX+ in acetonitrile
have two different temperature dependences of KIE seems to
have nothing to do with the mechanism of the hydride transfer.
As such, the real reason that makes the hydride transfer
reaction to have two different temperature dependences of KIE
is still a conundrum.
Scheme 2. Two-Stage Mechanism of the Hydride Transfer
from G-PDH to TX+
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Table 5. Suitable Values of β and γ Together with Theoretic Values of Observed KIE at Different Temperatures; The Latter
Were All Derived from the Fitting Curves at α = 1.08 kcal/mol
d
D
kobsH/kobs
a
b
c
groups
α
β
γ
298 K
303 K
308 K
313 K
318 K
p-CF3
p-Cl
1.08
1.08
1.08
1.08
1.08
1.08
1.84
0.67
3.58 × 10−2
2.27 × 10−1
6.39 × 10
7.11 × 102
5.09 × 104
4.22 × 107
3.30
3.14
3.17
3.21
3.23
3.16
3.04
3.18
3.27
3.38
3.09
3.02
2.95
3.19
3.32
3.51
3.37
2.90
2.87
3.20
3.37
3.63
3.62
2.79
2.79
3.20
3.41
3.72
3.83
m-CH3O
p-H
−2.66
−4.07
−6.59
p-CH3
p-CH3O
−10.78
2.80
c
a
b
d
D
H
H
α = E2 − E2H, the unit is kcal/mol. β = E2 − E−1H, the unit is kcal/mol. γ = A−1H/A2
. The theory data of the observed KIE at different
temperatures.
Table 6. Suitable Values of β and γ Together with Theoretic Values of Observed KIE at Different Temperatures; The Latter
Were All Derived from the Fitting Curves at α = 1.36 kcal/mol
d
D
kobsH/kobs
a
b
c
groups
α
β
γ
298 K
303 K
308 K
313 K
318 K
p-CF3
p-Cl
1.36
1.36
1.36
1.36
1.36
1.36
1.12
0.23
5.26 × 10−2
2.13 × 10−1
1.53 × 10
3.30
3.13
3.16
3.21
3.23
3.16
3.03
3.17
3.27
3.37
3.02
2.94
3.18
3.32
3.49
3.33
2.90
2.86
3.18
3.37
3.62
3.59
2.79
2.78
3.19
3.41
3.73
3.85
m-CH3O
p-H
−2.28
−3.26
−4.90
−8.12
8.08 × 10
p-CH3
1.30 × 103
p-CH3O
2.26 × 105
2.81
c
3.06
d
a
b
D
H
α = E2 − E2H, the unit is kcal/mol. β = E2 − E−1H, the unit is kcal/mol. γ = A−1H/A2H. The theoretic data of the observed KIE at different
temperatures.
from G-PDH to TX+ in acetonitrile may be divided into two
isolated different stages: the first stage is that the two reactants
approach to each other to form a CT-complex by charge
transfer (i.e., partial electron transfer); in this stage, there are no
bonds formed or broken. The second stage is that the transfer
of hydrogen atom with partial negative charge takes place from
GPDH-moiety to TX-moiety to form the products. In fact, this
reaction pattern has been widely verified and accepted.25−30
From Scheme 2, it is clear that the observed rate constant
(kobs) of the hydride transfer from G-PDH to TX+ in the
observed one-step actually consists of three rate constants: k1,
k−1 and k2, where k1 is the rate constant of the charge transfer
from G-PDH to TX+ to form CT-complex, k−1 is the rate
constant of the reverse process, and k2 is the rate constant of
the hydride transfer in the second stage, i.e., the transfer of
hydrogen atom with partial negative charge.
the abnormal temperature dependence of KIE for the reactions
of the hydride transfer from G-PDH to TX+ in acetonitrile is
that k−1 and k2 are comparable in magnitudes.
H
D
D
kobs
kobs
k2H(k−1Dk2
k2D(k−1Hk2
)
=
≈
H
)
(9)
(10)
(11)
H
D
H
kobs
kobs
k2
D
k2
H
D
kobs
kobs
≈ 1
According to Arrhenious equation, eq 9 can be rewritten as:
H
kobs
kobs
k−1D/k2D + 1
If the amount of the CT-complex as a reaction intermediate
during the hydride transfer is constant, the observed rate
constant kobs can be expressed by eq 8 with k1, k−1, and k2
according to the steady state assumption.
=
=
k−1H/k2 + 1
D
H
A−1D/A2Dexp[(E2 − E−1D)/RT] + 1
D
A−1H/A2Hexp[(E2 − E−1H)/RT] + 1
H
(12)
k1k2
k−1 + k2
kobs
=
where A and E are Arrhenious parameters and R and T are
molar gas constant and temperature, respectively. Equation 12
describes the special relationship between the KIE and the
temperature for the reaction of the hydride transfer from G-
PDH to TX+ in acetonitrile.
(8)
Since the first stage (charge transfer) of the hydride transfer
was not involved with the break or formation of C−H(D)
bonds, the corresponding rate constants k1 and k−1 should be
insensitive to the change of isotopic atoms. Only the second
stage, represented by k2, has a primary hydrogen kinetic isotope
effect. And the observed isotope effect, kobsH/kobsD, can be
expressed by eq 9, which was directly derived from eq 8. In eq
9, k−1H is equal to k−1D. If k−1 ≫ k2, eq 9 can be reduced into eq
10; if k−1 ≪ k2, eq 11 can be obtained from eq 9. Obviously,
neither of the two cases have the abnormal temperature
dependence of KIE. The only possible case that can produce
D
Since A−1H ≈ A−1D and A2H ≈ A2 , eq 12 can be replaced by
eq 13:
H
D
D
kobs
kobs
A−1H/A2Hexp[(E2 − E−1D)/RT] + 1
=
H
A−1H/A2Hexp[(E2 − E−1H)/RT] + 1
(13)
If E2D − E2H = α, E2H − E−1H = β, and A−1H/A2H = γ, eq 13
can be rewritten into eq 14:
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H
temperature dependences of KIE. Meanwhile, the result of this
work should be also a safe response to the skepticism of some
chemists about the multistage mechanism of the hydride
transfer reactions.31
Herein, it is worthwhile to point out that although the
hydride transfer reaction from G-PDH to TX+ in acetonitrile
has abnormal temperature dependence of KIE in the
temperature region between 298 and 318 K, this does not
mean that in all temperature regions the reaction has abnormal
temperature dependence of KIE. From Figure 9, it is clear that
kobs
kobs
γ exp[(β + α)/RT] + 1
γ exp(β/RT) + 1
=
D
(14)
From eq 14, it is clear that the specific relationship between
the KIE and the temperature is not only dependent on β and γ,
but also dependent on α. Since the second process of the
hydride transfer in Scheme 2 is an elementary reaction process,
the α value should be a constant. If the difference of zero-point
energies of the two bonds (C−H and C−D) for stretching
vibrations was considered, the α value should be 1.08 kcal/
mol.4a But if the difference of zero-point energies between the
two bonds for the bending vibrations together with stretching
vibrations were considered, the α value should be 1.36 kcal/
mol.4a
In order to explore and derive the possible and suitable
values of β and γ that make the observed hydride transfer
reaction to have two different temperature dependences of KIE,
the experimental data of KIE against the temperature for the
hydride transfer from G-PDH to TX+ in acetonitrile (Table 3)
were modeled using eq 14 by adjusting β and γ at α = 1.08 and
1.36 kcal/mol, respectively; the related fitting results were
summarized in Tables 5 and 6, respectively.
From Tables 5 and 6, it is clear that whether α is equal to
1.08 kcal/mol or equal to 1.36 kcal/mol, when β is positive
value and γ is smaller than 1, the reactions of the hydride
transfer from G-PDH to TX+ in acetonitrile have normal
temperature dependences of KIE, but when β is negative value
and γ is larger than 1, the reactions of the hydride transfer from
G-PDH to TX+ in acetonitrile have abnormal temperature
dependences of KIE; i.e., if the activation energy of the hydride
transfer in the second stage is larger than that of the hydride
transfer in the first revered stage and the A-value of the hydride
transfer in the second stage is larger than that of the hydride
transfer in the first revered stage, the reactions of the hydride
transfer from G-PDH to TX+ have normal temperature
dependences of KIE. On the contrary, if the activation energy
of the hydride transfer in the second stage is smaller than that
of the hydride transfer in the first revered stage and the A-value
of the hydride transfer in the second stage is smaller than that
of the hydride transfer in the first revered stage, the reactions of
the hydride transfer from G-PDH to TX+ have abnormal
temperature dependences of KIE. Since the model data of KIE
in Tables 5 and 6 are quite in agreement with the
corresponding experimental results in Table 3, it is believable
that the proposed reaction pattern of the hydride transfer
reaction shown in Scheme 2 should be reasonable and true; i.e.,
the one-step process of the hydride transfer from G-PDH to
TX+ in acetonitrile actually consists of two different elementary
stages: “transfer of charge (partial electron)” and “transfer of
hydrogen atom with partial negative charge”. When the
substituent is p-CF3, p-Cl, and m-CH3O, the electron-
withdrawing potential of the substituents is favorable to the
return of charge (partial electron) in the CT-complex, but
unfavorable to the hydride transfer in the second stage; the
result is to make the KIE of the hydride transfer to show
normal temperature dependence. But when the substituent is p-
CH3O, p-CH3, and p-H, the electron-donating potential of the
substituents is favorable to the hydride transfer in the second
stage, but unfavorable to the return of charge (or partial
electron) in the CT-complex; the result is to make the KIE of
the hydride transfer to exhibit abnormal temperature depend-
ence. Clearly it is the multistage mechanism of the hydride
transfer as the real root that results in the two different
Figure 9. Fitting curves of eq 14 according to the experimental data
and using α = 1.36 kcal/mol. The points represent the experimental
data. Inset: Enlarging figure of the curves in temperature regions
between 298 and 318 K.
for the reaction of the hydride transfer from G-PDH to TX+
with p-CH3O as the substituent, the reaction has no abnormal
temperature dependence of KIE when the temperature is larger
than 372.5 K. The temperature at 372.5 K is a temperature
turning point, and the values of the turning point of
temperature are varied as the substituents changed.
CONCLUSIONS
■
In this work, the values of the kinetic isotope effect for the
reactions of the hydride transfer from the substituted 5-methyl-
6-phenyl-5,6-dihydrophenanthridine (G-PDH) to thioxanthy-
lium (TX+) in acetonitrile were determined at various
temperatures. Results show that the KIE of the reactions has
two different temperature dependences, which are controlled
by the nature of the substituents. By detailed examination of the
thermodynamics, kinetics, and mechanism of the hydride
transfer reactions as well as the effects of the substituents on the
temperature dependence of KIE, the following conclusions can
be made: (1) Reactions of the hydride transfer from G-PDH to
TX+ in acetonitrile take place by a concerted one-step hydride
transfer mechanism, but the concerted one-step hydride
transfer reaction is not an elementary chemical reaction in
kinetics, which includes two different elementary stages:
“transfer of partial electron” and “transfer of hydrogen atom with
partial negative charge”. It may be a common phenomenon that
the hydride transfer in one-step actually is carried out by
formation of CT-complex as an intermediate. (2) The KIE of
the hydride transfer from G-PDH with TX+ in acetonitrile is an
apparent kinetic behavior of the reaction. The abnormal
dependence of KIE on the temperature for the hydride transfer
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from G-PDH with electron-donating groups to TX+ in
acetonitrile is due to the kinetic competition between the
return of charge and forward transfer of hydrogen atom with
partial negative charge in the CT-complex during the hydride
transfer. (3) The root that the temperature dependence of KIE
for hydride transfer can be transformed by changing the nature
of the substituents is that, in the CT-complex, the effects of the
substituents on the kinetics of the hydride transfer in the
second stage are different from that on the kinetics of the
hydride transfer in the first reversed stage. Generally, electron-
withdrawing groups can make the KIE of the reaction to have
normal temperature dependence, but the electron-donating
groups can make the KIE of the reaction to have abnormal
temperature dependence. (4) The abnormal temperature
dependence of KIE for hydride transfer is not only dependent
on the nature of the substituent mechanism of the reaction but
also dependent on the temperature regions. If the practice
temperature is beyond the temperature regions, the KIE of the
reaction has no abnormal temperature dependence.
Measurement of Redox Potentials. The electrochemical
experiments were carried out by CV and OSWV using a BAS-100B
electrochemical apparatus in deaerated acetonitrile under argon
atmosphere at 298 K as described previously.35 n-Bu4NPF6 (0.1 M)
in acetonitrile was employed as the supporting electrolyte. A standard
three-electrode cell consists of a glassy carbon disk as work electrode, a
platinum wire as a counter electrode, and 0.1 M AgNO3/Ag (in 0.1 M
n-Bu4NPF6/acetonitrile) as reference electrode. The ferrocenium/
ferrocene redox couple (Fc+/Fc0) was taken as the internal standard.
The reproducibilities of the potentials were usually ≤5 mV for ionic
species and ≤10 mV for neutral species.
Isothermal Titration Calorimetry (ITC). The titration experi-
ments were performed on a CSC4200 isothermal titration calorimeter
in acetonitrile at 298 K as described previously.36 The performance of
the calorimeter was checked by measuring the standard heat of
neutralization of an aqueous solution of sodium hydroxide with a
standard aqueous HCl solution. Data points were collected every 2 s.
The heat of reaction was determined following 10 automatic injections
from a 250 μL injection syringe containing a standard solution (2
mM) into the reaction cell (1.30 mL) containing 1 mL of other
concentrated reactant (∼10 mM). Injection volumes (10 μL) were
delivered in 0.5 s time intervals with 300−450 s between every two
injections. The reaction heat was obtained by integration of each peak
except the first. Note: typically the first injection shows less heat than
expected. This is often due to diffusion across the tip of the needle or
to difficulties in positioning the buret drive.
Kinetic Measurements. The kinetics of the hydride transfer
reactions were conveniently monitored with an Applied Photophysics
SX.18MV-R stopped-flow, which was thermostatted at 298−318 K
under strict anaerobic conditions in dry CH3CN. The rates were
determined from disappearance of the absorbance due to the hydride
acceptor (TX+) at λ = 500 nm. The method of the kinetic
measurement was pseudofirst-order method. The concentration of a
hydride donor was maintained at more than 20-fold excess of the
hydride acceptor to attain pseudofirst-order conditions. The kinetic
traces were recorded on an Acorn computer and analyzed by Pro-K
Global analysis/simulation software or translated to PC for further
analysis. The well data fitting used the equation of Abs =
P1*EXP(−P2*x) + P3, which integrated in the Pro-K Global
analysis/simulation software or Origin Software, and P2 was the
pseudofirst-order rate constants k1. Thus the second-order observed
rate constants (kobs) were derived from plots of the pseudofirst-order
rate constants versus the concentrations of the excessive reactants. In
each case, it was confirmed that the rate constants derived from 5−7
independent measurements agreed within an experimental error of
5%.
In one word, the most significant contribution of this work is
not only to dig out the root that makes the KIE of the hydride
transfer reaction to have the abnormal temperature dependence
for the first time, but also further verify the complex process of
the hydride transfer by the concerted one-step mechanism.
EXPERIMENTAL SECTION
■
Materials. All reagents were of commercial quality from freshly
opened containers or were purified before use. Reagent-grade
acetonitrile was refluxed over KMnO4 and K2CO3 for several hours
and was doubly distilled over P2O5 under argon before use. The
commercial tetrabutylammonium hexafluorophosphate (Bu4NPF6,
Aldrich) was recrystallized from CH2Cl2 and was dried in vacuo at
110 °C overnight before preparation of supporting electrolyte solution.
The substituted 5-methyl-6-phenylphenanthridinium perchlorate (G-
−
PD+ClO4 ) was prepared by the reaction of the corresponding
substituted 6-phenylphenanthridine with methyl iodide in acetone,
followed by metathesis with NaClO4.32 The substituted 6-phenyl-
phenanthridine were synthesized according to conventional synthetic
strategies.33 The substituted 5-methyl-6-phenyl-5,6-dihydrophenan-
thridine (G-PDH) and the substituted [6-2H]-5-methyl-6-phenyl-5,6-
dihydrophenanthridine (G-PDD) were prepared by reduction of the
corresponding iodide salts with NaBH4 and NaBD4, respectively. The
−
thioxanthylium perchlorate (TX+ClO4 ) was synthesized according to
literature method.34 All the final products were identified by 1H NMR
ASSOCIATED CONTENT
1
■
and MS. G-PDH (G = p-CF3): H NMR (δ, ppm, CD3CN, 400 M)
S
* Supporting Information
2.94 (s, 3H); 5.62 (s, 1H); 6.70 (d, 1H); 6.88 (t, 1H); 7.23−7.41 (m,
6H); 7.52 (d, 2H); 7.84 (d, 1H); 7.91 (d, 1H); ESI-MS/[M + 1] =
340.87. G-PDH (G = p-Cl): 1H NMR (δ, ppm, CD3CN, 400 M) 2.88
(s, 3H); 5.48 (s, 1H); 6.65 (d, 1H); 6.83 (t, 1H); 7.09 (d, 2H); 7.08−
7.26 (m, 5H); 7.34 (t, 1H); 7.80 (d, 1H); 7.86 (d, 1H); ESI-MS/[M +
1] = 306.14. G-PDH (G = m-OCH3): 1H NMR (δ, ppm, CD3CN, 400
M) 2.93 (s, 3H); 3.65 (s, 3H); 5.46 (s, 1H); 6.71 (s, 2H); 6.75 (t,
2H); 6.86 (t, 1H); 7.13 (t, 1H); 7.24 (m, 3H); 7.36 (t, 1H); 7.83 (d,
1H); 7.88 (d, 1H); ESI-MS/[M + 1] = 302.42. G-PDH (G = p-H): 1H
NMR (δ, ppm, CD3CN, 400M) 2.92 (s, 3H); 5.50 (s, 1H); 6.67 (d,
1H); 6.85 (t, 1H); 7.15−7.26 (m, 8H); 7.36 (t, 1H); 7.83 (d, 1H);
Three thermodynamic cycles, which were used to construct eqs
1
4−6, and copies of H MNR spectra of the hydride donors G-
PDH(D) and TXClO4. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xqzhu@nankai.edu.cn.
1
Notes
7.89 (d, 1H); ESI-MS/[M + 1] = 272.48. G-PDH (G = p-CH3): H
The authors declare no competing financial interest.
NMR (δ, ppm, CD3CN, 300 M) 2.23 (s, 3H); 2.90 (s, 3H); 5.45 (s,
1H); 6.65 (d, 1H); 6.84 (t, 1H); 7.01 (s, 4H); 7.17 (d, 1H); 7.24 (q,
2H); 7.34 (t, 1H); 7.82 (d, 1H); 7.88 (d, 1H); ESI-MS/[M + 1] =
ACKNOWLEDGMENTS
■
1
286.15. G-PDH (G = p-OCH3): H NMR (δ, ppm, CD3CN, 400 M)
Financial support from the National Natural Science
Foundation of China (Grants No. 21072104, 20921120403,
20832004, and 21102074), the Ministry of Science and
Technology of China (Grant No. 2004CB719905), and the
111 Project (B06005) is gratefully acknowledged.
2.87 (s, 3H); 3.67 (s, 3H); 5.41 (s, 1H); 6.62 (d, 1H); 6.71 (d, 2H);
6.82 (t, 1H); 7.01 (d, 2H); 7.13 (d, 1H); 7.21 (q, 2H); 7.32 (t, 1H);
−
7.79 (d, 1H); 7.85 (d, 1H); ESI-MS/[M + 1] = 302.13. TX+ClO4 : 1H
NMR (δ, ppm, CD3CN, 300 M) 8.25 (t, 2H); 8.47 (t, 2H); 8.80 (d,
2H); 8.89 (d, 2H); 10.31 (s, 1H); ESI-MS/[M+] = 197.34.
4782
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Article
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B 2010, 114, 2058−2075. (c) Zhu, X.-Q.; Mu, Y.-Y.; Li, X.-T. J. Phys.
Chem. B 2011, 115, 14794−14811.
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