Elemental steps of the thermodynamics of dihydropyrimidine: a new class of organic hydride donors

Article abstract of DOI:10.1039/C6OB02195F

25 Dihydropyrimidine derivatives, a new class of organo-hydrides, were designed and synthesized by the Biginelli reaction. For the first time, the thermodynamic driving forces of the six elemental steps to obtain a hydride in acetonitrile were determined by isothermal titration and electrochemical methods, respectively. The effects of molecular structures and substituents on these thermodynamic parameters were examined, uncovering some interesting structure-reactivity relationships. Both the thermodynamic and kinetic studies show that the hydride transfer from dihydropyrimidines to 9-phenylxanthylium (PhXn⁺ClO₄^-) prefers a concerted mechanism.

Full text of DOI:10.1039/C6OB02195F

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Takeharu Haino et al.
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DOI: 10.1039/C6OB02195F
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ARTICLE
Elemental Step Thermodynamics of Dihydropyrimidine: a New
Class of Organic Hydride Donors†
Received 00th January 20xx,
Accepted 00th January 20xx
Fan-kun Meng* and Xiao-qing Zhu*
25 dihydropyrimidine derivatives, a new class of organo-hydrides, were designed and synthesized by the Biginelli reaction.
For the first time, thermodynamic driving forces of their six elemental steps to obtain a hydride in acetonitrile were
determined by an isothermal titration and electrochemical methods, respectively. The effects of molecular structures and
substituents on those thermodynamic parameters were examined, uncovering some interesting structure-reactivity
relationships. Both the thermodynamic and kinetic studies show that the hydride transfer from dihydropyrimidines to 9-
DOI: 10.1039/x0xx00000x
www.rsc.org/
-
phenylxanthylium (PhXn+ClO4 ) prefers a concerted mechanism.
Introduction
Inspired by the functions of organic hydride cofactors in vivo
such as coenzyme NAD(P)H1-6 and F4207-11, organo-hydrides
have received significant attentions from the fields of
chemistry, biology, pharmaceuticals and energy science, etc. In
recent years, biomimetic organo-hydrides, represented by N-
benzyl-1,4-dihydronicotinamide (BNAH)12-16, Hantzsch esters
(HEH)17-23 and dihydrobenzoimidazole (ImH2)24-28 (Scheme 1)
have been widespreadly applied in the hydrogenation of C=C,
C=O, C=N double bonds to afford versatile building blocks,
owing to their advantages of excellent reactivity, mild
experimental conditions, good functional group tolerance,
readily available and environmental-friendly. The redox
potentials of organic-hydrides and bond dissociation energies
to release a hydride or a hydrogen atom are vital to measure
their hydrogenation abilities and judge the hydrogenation
mechanisms in both organic synthesis and the living
metabolism. Consequently, those basic parameters and
reaction mechanisms related with organo-hydrides were
extensively studied through thermodynamic and kinetic
methods during the past half century. T. C. Bruice29-33, L. L.
Miller34-37, S. Fukuzumi38-42, J. M. Mayer43-46, H. Mayr47, 48, Y,
Lu49-51 and other groups52-58 have figured out the detailed
hydride transfer mechanisms from NADH models to various
substrates using integrated approaches, including the
intermediate capture, spectrum detection and kinetic analysis.
J.-M. Savéant and others59-63 devoted a lot to the mechanistic
Scheme 1 Conventional organic hydride donors widely employed in synthesis.
studies of multi-step oxidation of NADH models in acetonitrile
through electrochemical kinetics. The structure-reactivity
relationships of NADH and ImH2 models were extensively
investigated by M. M. Kreevoy and I. S. H. Lee64-69 via
investigating the location of the substitution and the tightness
of the transition state as well as the resemblence of the
transition state to reactants and products. Combined with the
thermodynamic cycles from Hess’s law, our group have
systematically determined the thermodynamic parameters in
each elemental step for various organic hydride donors and
corresponding intermediates by experimental techniques, and
further established the thermodynamic driving-force database
for hundreds of biomimetic organic hydrides in acetonitrile
solution.70-74 Through our thermodynamic analytic platform,
the most possible pathway of the hydride transfer from NADH
analogues to olefin, imine, carbonyl compounds and some
carbocations can be well diagnosed.75-78 Besides, a classical but
new kinetic equation was established to estimate the rate
constants of hydride transfer reactions in acetonitrile by two
available parameters related to bond energies.79
Although great advance has been achieved in the
mechanistic studies and their synthetic application, almost all
the existed organo-hydrides have been limited to the skeleton
of the dihydropyridine, complementary by few benzimidazole
derivatives (Scheme 1). The paucity of the species diversity has
seriously restricted the further development of organic
hydride chemistry. Therefore, design and synthesis of a new
class of organo-hydrides, and determination of their reducing
capacity are challenging and urgently needed to respond the
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booming development of organic hydride chemistry. Similar to A(PhXn+) is the hydride affinity of PhXn+ in acetoniVtrieiwleA,rtwiclheiOcnhlinise
105
DOI: 10.1039/C6OB02195F
the structure of pyridine, pyrimidine is another ubiquitous available from our previous work (-96.8 kcal/mol).
The
heterocyclic moiety as a privileged structure in various drugs molar enthalpy changes (ΔHr) of the hydride transfer from
–
and natural products.80-84 Naturally, we wonder whether dihydropyrimidine derivatives XH to PhXn+ClO4 (Eq. 3) were
dihydropyrimidine can act as a good hydride donor. Is the measured using titration calorimetry in acetonitrile (Fig. 3 and
hydride-donating ability influenced by incorporation of two N ESI†). The detailed enthalpy changes and thermodynamic
atoms into benzene ring? What’s the difference between the driving force of 25 XH to release hydride anion in acetonitrile
reduction ability of 1,2- and 1,4-dihydropyrimidine? are summarized in Table 1.
Fortunately, we found that the Biginelli reaction85-89, a
CV
OSWV
(a)
(b)
0.0
generally accepted method to synthesize various
dihydropyrimidines, supplied us a good opportunity to design
and synthesize some dihydropyrimidine-type organo-hydrides
with a novel skeleton. In present work, we have synthesized 25
dihydropyrimidine derivatives (Scheme 2) and determined
their thermodynamic parameters for hydride-donating abilities
(defined as the enthalpy changes to release a hydride).
Considering that the electron-donating ability is also one of the
basic parameters to measure the reducing capacity, and the
hydride transfer is often initiated by the electron transfer, the
redox potential was also determined. Through thermodynamic
cycles, the thermodynamic driving forces of their six elemental
steps to release a hydride in acetonitrile were obtained. The
mechanism of hydride transfer from dihydropyrimidine to 9-
CV
OSWV
1.5x10-5
-5.0x10-6
-1.0x10-5
-1.5x10-5
-2.0x10-5
1.0x10-5
5.0x10-6
0.0
1500
1000
500
-1000
-1200
-1400
-1600
E (mV) vs Fc0/+
E (mV) vs Fc+/0
(c)
2.1x10-5
(d)
2.0x10-5
1.5x10-5
1.0x10-5
CV
OSWV
CV
OSWV
1.4x10-5
7.0x10-6
0.0
5.0x10-6
0.0
-7.0x10-6
-800
-900
-1000
-1100
-1200
-1300
-1400
-700
-800
-900
-1000
-1100
-1200
(mV vs Fc+/0
)
E
(mV vs Fc+/0
)
E
Figure 1 CV and OSWV for the oxidation of 1H(R = H) (a), the reduction of 1+(R =
H) (b), 2+(R = Cl) (c) and 2+(R = NO2) (d) (about 1 mol/L) in deaerated acetonitrile
containing 0.1 M n-Bu4NPF6 as supporting electrolyte (sweep rate = 0.1 V s−1),
respectively.
–
phenylxanthylium (PhXn+ClO4 ) was diagnosed through both
thermodynamic and kinetic experiments.
3.0
0.5
(a)
(b)
0.8
0.6
0.4
0.2
0.0
2.5
2.0
1.5
1.0
0.4
0.3
0.2
0.1
0.0
0
500 1000 1500 2000 2500
t (s)
Scheme 2 Structures of dihydropyrimidine derivatives (XH) examined in this work.
400
450
500
550
0
1000
2000
3000
4000
5000
6000
 (nm)
t (s)
Results
-
Figure 2 (a) Profiles of the hydride transfer from 1H(R = OCH3) to PhXn+ClO4 in
The target dihydropyrimidine derivatives were synthesized
acetonitrile at 298 K. (b) Decrease of the absorbance at 450 nm during the
through the Biginelli reaction90-96 and identified by H NMR.79,
reaction of PhXn+ClO4 (cal. 2 x 10-4 mol/L) with 1H(R = OCH3) (4.8 x 10-3 mol/L);
-
97-104
Oxidation potentials of the 25 dihydropyrimidines (XH
)
)
insert: fit to a single exponential decay function.
and reduction potentials of their corresponding cations (X+
were
determined
using
BAS-100B
electrochemical
60
50
40
30
20
10
0
workstations by cyclic voltammetry (CV) and Osteryoung
square wave voltammetry (OSWV) methods in acetonitrile at
298 K. All the potential values are calibrated to Fc+/0 (Fig. 1).
The results are summarized in Table 1. The kinetic of the
hydride transfer from 1H(R = OCH3) (4.8 x 10-3 mol/L) to
PhXn+ClO4 (cal. 2 x 10-4 mol/L) in acetonitrile at 298 K was
-
determined by UV spectrum under a pseudo-first-order
condition (details seeing Experimental Section) (Fig. 2).
The thermodynamic driving forces in this work was defined
as the enthalpy changes (ΔHH-D(XH)) of XH to release a hydride
anion in acetonitrile (Eqs. 1 and 2), which can be obtained
from the reaction enthalpy changes (ΔHr) of hydride transfers
0
1000
2000
3000
4000
5000
Time (s)
Figure 3 Isothermal titration calorimetry (ITC) for the reaction heat of 1H(R =
OCH3) with 9-phenylxanthylium perclorate (PhXn+ClO4–) in acetonitrile at 298 K.
Titration was conducted by adding 10 μL of 1H(R = OCH3) (3.03 mM) every 300 s
into the acetonitrile containing PhXn+ClO4– (ca. 30 mM).
from XH to 9-phenylxanthylium perclorate (PhXn+ClO4 ) in
–
acetonitrile (Eqs. 3 and 4). In Eq. 4, ΔHr is the enthalpy change
of the reaction of Eq. 3 in acetonitrile, which can be
determined using isothermal titration calorimetry (ITC); ΔHH-
2 | J. Name., 2012, 00, 1-3
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and

HHD
(
XH•+) are easy to obtain if ΔHH-D(XH), E(XVi+e/w0)A,rtEic(leXOHn+li/n0e),
+/0
E(H0/–) and E(H+/0) are available. In fact, ΔHH-D(XH), E(
DOI: 10.1039/C6XOB0)21a9n5dF
(1)
(2)
E(XH+/0) are available from above work (Table 1). E(H0/–) and
E(H+/0) can also be obtained from literature.106 The detailed
ΔHH-D(XH) = ΔHf(X+) +ΔHf(H-) -ΔHf(XH
ΔHH-D(XH) = ΔHr - ΔHH-A(PhXn+)
)
values of ΔHHD
(
XH), ΔHPD(XH•+
)
and ΔHHD
( ) of 25
XH•+
(3)
(4)
dihydropyrimidine derivatives
summarized in Table 2.
(
XH in acetonitrile are
)
Table 1 Reaction enthalpy changes of XH with PhXn+ as well as the redox
potentials of relative species in acetonitrile at 298 K.
b
b
E(XH+/0
)
E(X+/0
)
XH
1H
R
ΔHra
CV
OSWV
0.719
0.730
0.745
0.766
0.818
0.756
0.768
0.788
0.800
0.844
0.606
0.612
0.630
0.648
0.692
0.608
0.620
0.632
0.652
0.700
0.585
0.596
0.612
0.636
0.694
CV
OSWV
OCH3
CH3
H
-21.8
-21.7
-21.4
-21.1
-20.3
-21.0
-20.8
-20.6
-20.2
-19.4
-20.1
-20.0
-19.9
-19.8
-19.4
-18.8
-18.7
-18.5
-18.4
-17.8
-19.9
-19.9
-19.7
-19.5
-19.1
0.736
0.743
0.763
0.792
0.843
0.772
0.786
0.805
0.820
0.872
0.626
0.634
0.656
0.670
0.713
0.627
0.642
0.650
0.674
0.725
0.604
0.619
0.632
0.652
0.727
-1.373
-1.342
-1.267
-1.204
-0.973
-1.298
-1.254
-1.213
-1.138
-0.933
-1.453
-1.424
-1.386
-1.307
-1.098
-1.270
-1.248
-1.217
-1.172
-1.046
-1.440
-1.409
-1.341
1.253
-1.358
-1.318
-1.249
-1.170
-0.950
-1.278
-1.240
-1.190
-1.115
-0.908
-1.438
-1.408
-1.360
-1.285
-1.080
-1.248
-1.228
-1.199
-1.150
-1.028
-1.422
-1.388
-1.324
-1.236
-1.052
Cl
Scheme 3 Thermodynamic cycles of XH constructed on the basis of Hess’s law.
NO2
OCH3
CH3
H



HHD
HPD(XH•+) =
HHD
XH•+) =
(
XH) =

HH-D(XH) – F[E(X+/0) – E(H0/-)]
HHD
XH) – F[E(XH+/0) – E(H+/0)]
HH-D(XH) – F[E(XH+/0) – E(H0/-)]
(5)
(6)
(7)

(
2H
3H
4H
5H
Cl
(

NO2
OCH3
CH3
H
Discussion
Cl
Thermodynamic driving forces of dihydropyrimidine
derivatives (XH) and related intermediates (XH•+) in
acetonitrile. The enthalpy change (ΔHH-D(XH)) is a very
important thermodynamic parameter of XH to scale the ability
of XH to donate hydride anion. Overall, the enthalpy changes
of 25 XH range from 75.0 kcal/mol for 1H (R = OCH3) to 79.0
kcal/mol for 4H (R = NO2). The relative small span (about 4
kcal/mol) indicates an insensitivity of the hydride-donating
ability to remote substituent effects and structural variants.
That is, the substituent at para position of benzene ring plays a
small part of roles in the hydride-donating ability of the
dihydropyrimidine derivatives. Electron-donating groups at
para position of benzene ring, such as methyl and methoxyl
groups, can slightly increase the hydride-donating ability; while
electron-withdrawing groups, such as chlorine atom and -NO2,
decrease it.
NO2
OCH3
CH3
H
Cl
NO2
OCH3
CH3
H
Cl
NO2
-1.074
a ΔHr was obtained from the reaction heats of Eq. 3 by ITC in acetonitrile at 298 K.
The data, given in kcal/mol, were average values of at least three independent
runs, each of which was an average value of more than ten consecutive titrations.
The reproducible is ± 0.05 kcal/mol. b Measured by CV and OSWV methods in
acetonitrile at 298 K, the unit is V vs Fc+/0 and reproducible to 5 mV or better.
The elaborate variants of core structures allowed a close
investigation of the structure-reactivity relationship for the
process of dihydropyrimidine derivatives to release hydrides. A
relative energy scale was established in Fig. 4, with 1H(R = H)
as a reference. Intriguingly, the hydride donor abilities of 1,2-
isomers are undoubtedly 1.5 kcal/mol weaker than those of
1,4-ones, which completely depart from previous observations
in all dihydropyridine-type hydrides, such as BNAH, HEH, AcrH2.
The contradiction is probably attributed to the electron-
withdrawing abilities of two incorporated nitrogen atoms
compared with carbon atoms, as well as the resonance of the
methoxyl group ortho to two nitrogen atoms. The resonance
should be more significant to the conjugated dienes in the 1,2-
isomers than the separated dienes in the 1,4-isomers and
naturally, stabilized the former better. Replacement of methyl

HHD

(
XH) is the enthalpy change of XH to release hydrogen
atoms.
HDP(XH•+) and XH•+) are the enthalpy changes of

HHD
(
the intermediate XH•+ to release protons and hydrogen atoms,
respectively. Evidently, it is difficult to directly determine the
enthalpy changes of XH to release a hydrogen and that of XH•+
to release protons or hydrogen atoms in acetonitrile,
experimentally. In order to obtain their enthalpy changes in
acetonitrile, three thermodynamic cycles were constructed
according to the chemical process of XH to release hydride
anion (Scheme 3). 24
From three thermodynamic cycles, Eqs. 5-7 were derived
according to Hess's law. In Eqs. 5-7, E(X+/0), E(XH+/0), E(H0/-),
and E(H+/0) are the standard redox potentials of X+
,
XH, H+ and

H- in acetonitrile, respectively. Obviously,

HHD
(
XH), )
HPD(XH•+
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by phenyl group resulted in a 0.8 kcal/mol decrease of
hydride-donating abilities. It’s not unexpected since the
electron density on the dihydropyrimidine skeleton could
delocalize to the benzene ring better. Additionally, change the
-CO2Et group on the 1,2-isomer into -COCH3 increase the
enthalpy changes slightly (about 0.2 kcal/mol), because of the
slightly stronger electron-withdrawing ability of -COCH3 than -
CO2Et. The quantitative analysis of the dependence of the
hydride-donating abilities on the structural variants could
supply us a theoretical guidance and a practical tool to
rationally modify and design new hydride donors.
View Article Online
DOI: 10.1039/C6OB02195F
Figure
4
Effects of structural variants on hydride-donating abilities of
In order to intuitively compare the hydride-donating
abilities of dihydropyrimidine derivatives (XH) with some other
conventional hydride donors, a thermodynamic scale was
established according to their enthalpy changes to release
hydride anion in acetonitrile (Fig. 5). From Fig. 5, it is clear that
the enthalpy changes of the 25 XH lie in the middle of the scale,
indicating their moderate hydride-donating abilities. In other
words, their corresponding cations generated by release
dihydropyrimidine derivatives in acetonitrile (1H(R = H) as a reference).
hydride anion, can also be moderate hydride acceptors. The
enthalpy changes are larger than some typically strong
hydrides which are widely employed as hydride reductants,
such as LiAlH4 (48 kcal/mol)107, 108, NaBH4 (55 kcal/mol)107, 108
,
BNAH (64.2 kcal/mol), Hantzsch (69.3 kcal/mol) and so on; but
smaller than 9-phenyl-9H-xanthene (96.8 kcal/mol), TEMPOH
(105.6 kcal/mol), toluene (118.0 kcal/mol), whose
corresponding cations are always used as the hydride
acceptors in organic synthesis. Actually, their values are close
to 9,10-dihydro-10-methylacridine (AcrH2 81.1 kcal/mol).
Therefore, the moderate hydride-donating abilities of
dihydropyrimidine derivatives perform a well balance of their
stabilities and reactivities as hydride donors, and make them
be potentially used as ideal reductants and in some case, their
corresponding cations as good oxidants.
Table 2 Enthalpy changes of XH to release hydride anion and hydrogen atoms as well
as those of XH•+ to release protons and hydrogen atoms in acetonitrile at 298 K (in
kcal/mol).
a
b
ΔHPD
(
XH•+
)
ΔHHD( )
XH•+
XH
R
OCH
CH3
H
ΔHH-D(XH
75.0
75.1
75.4
75.7
76.5
75.8
76.0
76.2
76.6
77.4
76.7
76.8
76.9
77.0
77.4
78.0
78.1
78.3
78.4
79.0
76.9
76.9
77.1
77.3
77.8
)
ΔHHD(XH)
80.1
79.3
77.9
76.4
72.2
79.0
78.4
77.5
76.1
72.1
83.6
83.0
82.0
80.4
76.1
80.6
80.2
79.7
78.8
76.5
83.9
82.7
81.4
79.6
75.8
10.3
9.3
7.6
5.6
0.1
32.2
32.1
31.9
31.8
31.4
32.1
32.1
31.8
31.9
31.7
36.5
36.4
36.1
35.9
35.2
37.8
37.6
37.5
37.2
36.6
37.2
37.0
36.8
36.4
35.5
1H
Cl
NO2
OCH
CH3
H
The hydrogen-donating ability of dihydropyrimidine
8.41
7.46
6.15
4.41
-0.55
16.5
15.7
14.3
12.3
7.0
13.4
12.7
11.9
10.5
7.1
derivatives (XH) is defined by the enthalpy changes (ΔHHD
of XH to release a hydrogen atom. From Table 2, it shows that
ΔHHD XH) spans a range of about 12 kcal/mol, from the most
(XH))
2H
3H
4H
5H
(
Cl
stronger hydrogen donor 2H(R = NO2) 72.1 kcal/mol to the
weakest one 5H(R = OCH3) 83.9 kcal/mol. Those values are
comparable to the common antioxidants109 (CH3)3SnH 68.8
kcal/mol, PhSH 78.6 kcal/mol, i-C3H7OOH 80.3 kcal/mol, PhOH,
81.7 kcal/mol, HOOH 83.4 kcal/mol, indicating it’s a good
alternative to be used in the antioxidant process. The higher
hydrogen-donating abilities of XH with electron-withdrawing
groups than those with electron-donating groups implies that
the electron-donating group can improve the stability of the
resulted carbon radical (X•) better, which further hints that
those radicals have some positive charge densities on the
radical carbon atom and tend to be electron-deficient. Similar
to the tendency observed in the hydride-donating ability, the
enthalpy changes of 1,2-isomers to release hydrogen atoms
are averagely 2 kcal/mol larger than those of 1,4-isomers.
That’s to say, the separated dienes in the 1,4-isomers can
delocalize the single electron in resulted carbon radicals more
effectively than the conjugated dienes in the 1,2-isomers and
therefore, lead to a better stability for the radicals of 1,4-
isomers.
NO2
OCH
CH3
H
Cl
NO2
OCH
CH3
H
Cl
NO2
OCH
CH3
H
Cl
NO2
17.2
15.8
14.1
11.7
6.6
aΔHH-D(XH) were derived from Eq. 4, taking ΔHH-A(PhXn+) = -96.8 kcal/mol in
acetonitrile, the uncertainties are all smaller than
kcal/mol. bΔHHD(XH),
1
ΔHPD(XH•+) and ∆HHD(XH•+) were estimated from Eqs. 5-7, respectively, taking
E(H+/0) = -2.307 V, E(H0/–) = -1.137 V, which were derived from Parker’s work
adjusted to versus Fc+/0 by adding -0.357 V.106 Relative uncertainties were
estimated to be smaller than or close to 1 kcal/mol in each case. The standard
oxidation potential values of XH and X• in acetonitrile were all derived from the
experimental results using OSWV method, because OSWV has been verified to be
a more exact electrochemical method for evaluating the standard one-electron
redox potentials of analyte with irreversible electrochemical processes than CV.
The radical cation is one of the most important reactive
intermediates in both the academic research and the industrial
production. Due to their high reactivities, their thermodynamic
parameters are generally unavailable and thus, invaluable.
Through our thermodynamic cycles, the enthalpy changes of
4 | J. Name., 2012, 00, 1-3
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Figure 5 Comparison of hydride dissociation energies of some typical organic hydrides (XH) in acetonitrile.
XH•+ to release protons ΔHPD(XH•+) and hydrogen atoms solution or another substrates, to generate neutral radicals
∆HHD
(
XH•+) could be derived, which are two vital parameters
(
X•), as described above112. The effect of bases or acids on the
to measure the stabilities of corresponding radical cations. deprotonation process of the radical cations (XH•+), produced
Those parameters range from -0.6 kcal/ mol 2H(R = NO2) to in situ by electrochemical oxidation, have detailedly been
97
17.2 kcal/mol 5H(R = OCH3) for ΔHPD(XH•+), and from 31.4 analyzed in some previous work.59-62,
Those oxidation
kcal/mol 1H(R = NO2) to 37.8 kcal/mol 4H(R = OCH3) for potentials are remarkably larger than conventional
∆HHD
XH•+), respectively. The relative small ΔHPD(XH•+) values dihydropyridine hydride donors70, 0.219 V for BNAH, 0.460 V
show that the resulted radical cations should be extremely for AcrH2 and 0.479 V for HEH, corresponding to their very
(
110
strong organic acids, compared with PhCO2H 32.5 kcal/mol
weaker single-electron reductants. It is noteworthy that the
and CF3CO2H 22.4 kcal/mol111 in acetonitrile. If there are basic radicals (X•), generated through the deprotonation of XH•+
,
substrates in reaction system or even in neutral system, the should be very strong single-electron reducing agents, which
degradation of radical cations (XH•+) through the acid-base were immediately oxidized at the oxidation potential of parent
neutralization could proceed, preferentially and smoothly. XH. Hence, the CV peaks of the parent XH likely correspond to
Considering the larger values of ΔHHD
mechanisms through the hydrogen transfer pathway seem
(
XH•+), their degradation a two-electron transfer process.
Because of the inaccessibility of the high reactive radicals
inhibited, unless there is a strong hydrogen acceptor in X• in our experimental conditions, their oxidation potentials
reaction system or under an acidic reaction condition. are determined by the reduction process of X+, instead. The
Therefore, the high instabilities of XH•+ are mainly originated reduction potentials of related cations X+ distribute between -
from their strong proton-donating abilities, in other 1.440 for 5H(R = OCH3) and -0.933 for 2H(R = NO2), implying
terminology “their stronger acidities”, which can be further them very weak oxidants. Conversely, their corresponding
verified by the irreversibility of the electrochemical neutral radicals X• are extremely strong single-electron
measurements in following sections.
reduction reagents. Additionally, cyclic voltammetry (CV)
technology can be employed to test the relative stabilities of
Electrochemical behaviors for the redox of dihydropyrimidine resulted radicals according to the reversibility of the CV peaks.
(XH) and related X+ in acetonitrile. The redox potential is a For serials 1H
, 3H and 5H, which have a methyl group at 6
basic thermodynamic parameter to measure the single- position of the pyrimidine, the reduction of X+ is an irreversible
electron redox capacity of organic compounds. In present process, indicating the resulted X• is too reactive to be
work, the oxidation potentials of dihydropyrimidine derivatives captured under present electrochemical conditions. However,
and the reduction potentials of their corresponding cations (X+
) when the methyl at 6 position of the benzene was replaced by
were determined by cyclic voltammetry (CV) and Osteryoung the phenyl, the CV behave nearly reversible for serials 2H and
square wave voltammetry (OSWV) methods in acetonitrile at 4H, except those with a strong withdrawing group NO2 (Fig. 1c
298 K. All the hydride donors exhibit an irreversible oxidation and 1d). It is directly indicated that the produced radicals 2•
peak with a range of 0.604 V vs Fc+/0 for 5H(R = OCH3) to 0.872 and 4• are more stable than 1• 3• and 5•. The different
,
V for 2H(R = NO2) as shown in Fig. 1 and ESI†. The reversibility between the reduction of serial 1+ and 2+ shows
irreversibility of the electrochemical oxidation process is that the phenyl at 6 position of the pyrimidine stabilizes the X•
ascribed to the rapid degradation of the resulted radical better than the methyl group, through its delocalization.
cations (XH•+), mainly through a deprotonation process to the Additionally, for 2H and 4H, the radicals X• with R = OCH3, CH3,
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H, and Cl are more stable than R = NO2, from which we can position of the phenyl, it is easy to estimate the enthalpy
View Article Online
safely speculate that the radicals X• are somewhat electron changes and redox potentials, as long as the corresponding σ
DOI: 10.1039/C6OB02195F
deficiency and an electron-donating substituent can value is available. Hence, these formulae might quantitatively
significantly stabilize the reactive X•
.
guide us to modify dihydropyrimidine analogues with suitable
Interestingly, as a hydride reductant, the 1,4-isomer (75.35 substituents for a special use.
kcal/mol for 1H(R = H)) is stronger than the 1,2-isomer (76.88
kcal/mol for 3H(R = H)). While used as an electron reductant, it Diagnoses mechanistic possibilities for the hydride transfer
is just the opposite, 0.656 V for 3H(R = H) vs 0.763 V for 1H(R = from dihydropyrimidines XH to PhXn+. Possible reactions
H). Such a rare discrepancy offered an alternative mechanistic between XH and hydride acceptors should include the hydride
probe to diagnose whether dihydropyrimidine derivatives are transfer, hydrogen transfer, and electron transfer, which could
oxidized through a concerted hydride transfer or electron be assigned to the possible elemental steps of hydride transfer
transfer initiated multi-step pathway, if the suitable reaction reactions (Scheme 4). Since thermodynamics could offer
system could be well-designed.
intrinsic criteria in diagnosing the possibilities of reactions, it
From Tables 1 and 2, it is clear that all the enthalpy might be efficient and comprehensive to elucidate the
changes of XH and their intermediates XH•+ depend on the possibilities of all the elemental steps of hydride transfer. With
nature of substituents at the para position of the phenyl ring, all the six thermodynamic parameters, the thermodynamic
as well as the redox potentials of XH and X+. To elucidate the analytic platform for the hydride donor XH can be constructed.
relationship of substituents with those parameters, the effects The same does for the hydride acceptor PhXn+, whose
of remote substituents are examined, respectively.113, 114 The parameters were available from our previous work76 (Scheme
results in Fig. s40-s41 (ESI†) show that all these values are 4). According to Hess’s law, it is easy to access the
linearly dependent on Hammett substituent parameters σp thermodynamic driving forces of all possible elemental steps
with good correlation coefficients, implying that the linear free of the hydride transfer from XH to PhXn+, as shown in Scheme
energy relationship holds well in these chemical and 4. Herein, the reaction of 1H(R = OCH3) with PhXn+ was taken
electrochemical processes. With the slopes and the intercepts as an example to diagnose the detailed mechanisms of hydride
of these linear correlations, mathematical formulae are transfers according to the thermodynamic analytic platform.
derived [Fig. s40-s41 in ESI†]. Evidently, for any para or meta
Scheme 4 Thermodynamic diagnosis of possible hydride transfer mechanisms between 1H(R = OCH3) and PhXn+ in acetonitrile.
6 | J. Name., 2012, 00, 1-3
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From Scheme 4, it is obvious that among three initial steps constants are exactly held. The mechanism of hydride transfer
(steps a, b and c) of the four possible pathways, hydride from the dihydropyrimidine XH to PhXn+ is most probably
transfer (step c) from XH to PhXn+ should be spontaneous, through
a concerted pathway according to both the
since it’s thermodynamically favorable by 21.8 kcal/mol. While thermodynamic and kinetic analysis. Those thermodynamic
the electron transfer (step a) and hydrogen atom transfer (step and mechanistic studies are critical to understanding the
b) are thermodynamically forbidden by more than 25.7 reducing properties of dihydropyrimidine derivatives, offering
kcal/mol). Even if the electron transfer or hydrogen transfer is a practical guide for the rational design of new organic-
triggered, the generated transient ion pairs of XH•+ and PhXn•, hydrides and opening an avenue for the wide application of
or X• and PhXnH•+ would immediately react with each other dihydropyrimidine derivatives in various hydrogenation
through the possible stepwise routes (steps b-f, a-e, or a-d-f), processes.
until they give the same pair of stable products of X+ and
PhXnH as produced by the concerted hydride transfer (step c).
Therefore, it might be concluded that the hydride transfer
Experimental Section
reaction tends to proceed through a concerted manner, rather
than the stepwise hydrogen or electron transfer patterns.
In order to further verify the reaction mechanism of 1H(R =
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 (n-Bu4NPF6, Aldrich) was recrystallized
from CH2Cl2 and dried at 110 °C overnight before preparation
of supporting electrolyte solution. 9-Phenylxanthium
–
OCH3) with PhXn+ClO4 , the kinetics of the reaction was
examined (Fig. 2) in acetonitrile at 298 K under a pseudo-first-
order condition. The reaction rates k2 were 0.16 L/(mol s) (for
details seeing Experimental Section). Activation parameter was
obtained from Eyring equation (18.5 kcal/mol), which is much
smaller than the enthalpy changes of the initial electron
transfer (step a, 25.7 kcal/mol) and hydrogen transfer (step b,
36.89 kcal/mol). On the basis of a general reaction law115 that
the activation energy change is always larger than or at least
equal to the corresponding standard state energy change for
any elemental reaction, it is evident that both the initial steps a
and b could be ruled out. Therefore, from the kinetic analysis,
the hydride transfer from XH to PhXn+ClO4– is also concerted.
– 70
90-96
perclorate (PhXn+ClO4 ) and dihydropyrimidines (XH
)
were obtained according to literature methods, and the final
products were identified by 1H NMR.
Isothermal Titration Calorimetry (ITC). The titration
experiments were performed on
a CSC4200 isothermal
titration calorimeter in acetonitrile at 298 K as described
previously. The performance of the calorimeter was checked
by measuring the standard heat of neutralization of aqueous
solution of sodium hydroxide with standard aqueous HCl
solution. The heat of reaction was determined following 10
automatic injections from a 250 µL injection syringe containing
Conclusions
In present work, we have developed a serial of readily standard solution (3mM) into the reaction cell (1.30 mL)
available dihydropyrimidine organo-hydrides. Thermodynamic containing 1mL concentrated 9-Phenylxanthium perclorate
–
driving forces of each elemental step for hydride donors in ((PhXn+ClO4 ). Injection volume (10 µL) were delivered 0.5 s
acetonitrile were obtained for the first time through time interval with 300-350 s between every two injections. The
thermodynamic cycles, as well as those for corresponding reaction heat was obtained by integration of each peak except
reactive intermediates, which allow us to evaluate their the first.
reducing capacity quantitatively and elucidate the most Measurment of Redox Potentials. The electrochemical
accessible hydride transfer mechanism. Thermodynamic experiments were carried out by cyclic voltammetry (CV) and
parameters indicated that they are moderate reducing Osteryoung square wave voltammetry (OSWV) using
a
reagents in both the hydride and electron redox process, lying BAS100B electrochemical apparatus in deaerated acetonitrile
between conventional biomimetic hydride donors BNAH and under argon atmosphere at 298 K as described previously.70, 71,
76, 77, 105
AcrH2. The 1,4-isomers are stronger hydride donors than 1,2-
n-Bu4NPF6 (0.1 M) in acetonitrile was employed as the
isomers, different from any reported dihydropyridine supporting electrolyte. A standard three-electrode cell consists
derivative. The opposite tendency between the electron and of a glassy carbon disk as work electrode, a platinum wire as
hydride reducing ability supplies
a potential probe in counter electrode, and 0.1 M AgNO3/Ag (in 0.1 M n-Bu4NPF6-
mechanistic researches. The linear free energy relationships acetonitrile) as reference electrode. The ferrocenium/
between those thermodynamic parameters and substituent ferrocene redox couple (Fc+/0) was taken as internal standard.
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25. E. Hasegawa, T. Ohta, S. Tsuji, K. Mori, K. Uchida, T. Miura, T. Ikoma, E.
The reproducibilities of the potentials were usually
≤ 5 mV for
View Article Online
Tayama, H. Iwamoto, S. Takizawa and S. Murata, Tetrahedron, 2015, 71,
DOI: 10.1039/C6OB02195F
ionic species and
≤ 10 mV for neutral species.
5494-5505.
Kinetic Measurements. Kinetic measurements were carried
out in acetonitrile by UV/vis spectrophotometer connected to
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a
super thermostat circulating bath to regulate the
temperature of cell compartments. The oxidation rate of XH by
PhXn+ClO4 was measured at 298 K by monitoring the changes
–
of absorption of PhXn+ClO4 (cal. 2 x 10-4 mol/L) at 450 nm
-
under pseudo-first-order conditions (1H(R = OCH3) 4.8 x 10-3
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Acknowledgements
Financial support from the National Natural Science
Foundation of China (Grant No. 21472099, 21390400 and
21102074) and the 111 Project (B06005) is gratefully
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