Hydride-donor abilities of 1,4-dihydropyridines: A comparison with π nucleophiles and borohydride anions

Article abstract of DOI:10.1002/anie.200804263

(Chemical Equation Presented) How are dihydropyridines like indoles? Both groups of compounds have similar nucleophilicity parameters N and are therefore suitable substrates for iminium-catalyzed reactions of α,β- unsaturated aldehydes. The N parameters of 1,4-dihydropyridines were derived from the rates of hydride transfer reactions to benzhydrylium ions (see scheme).

Full text of DOI:10.1002/anie.200804263

Communications
DOI: 10.1002/anie.200804263
Organocatalysis
Hydride-Donor Abilities of 1,4-Dihydropyridines: A Comparison with
p Nucleophiles and Borohydride Anions**
Dorothea Richter and Herbert Mayr*
Dedicated to Professor Ingo-Peter Lorenz on the occasion of his 65th birthday
Table 1: Benzhydrylium ions Ar2CH+ (1) and their electrophilicity
parameters E.
Because of its analogy to biological reduction with NADH,
hydride abstraction from various types of dihydropyridines
has been studied intensively for several decades.[1] In recent
years, dihydropyridines, in particular Hantzsch esters, have
found numerous applications in organic synthesis, as they
were found to be optimal reducing agents for organocatalytic
hydrogenation.[2,3] It was our goal in this study to quantify the
hydride-donating ability of 1,4-dihydropyridines and to
compare the reactivity of these compounds with the reac-
tivities of other hydride donors and of p nucleophiles that
might be suitable for iminium-catalyzed reactions.
Ar2CH+ (1)
E[a]
1a
1b
1c
1d
1e
1f
X=N(Ph)CH2CF3
X=N(CH3)CH2CF3
X=NPh2
X=N(CH2CH2)2O
X=N(Ph)CH3
X=N(CH3)2
ꢁ3.14
ꢁ3.85
ꢁ4.72
ꢁ5.53
ꢁ5.89
ꢁ7.02
ꢁ7.69
1g
X=N(CH2)4
We have shown previously that benzhydrylium ions
(Ar2CH+) and structurally related quinone methides can be
employed as reference electrophiles for comparing the
p nucleophilicity of alkenes, allylsilanes, and enol ethers
with the s nucleophilicity of hydride donors, such as organo-
silanes and organostannanes.[4] Although the same method
has been employed to quantify the reactivities of strong
p nucleophiles, such as pyrroles,[5] indoles,[6] and enamines,[7]
we have not yet included stronger hydride donors in our
comprehensive nucleophilicity scales.
1h (n=2)
1i (n=1)
ꢁ8.22
ꢁ8.76
1j (n=2)
1k (n=1)
ꢁ9.45
ꢁ10.04
[a] Electrophilicity parameter E as defined in Equation (1) (from Ref. [4]).
We have now studied the kinetics of the reactions of
dihydropyridines and borohydride anions with benzhydry-
lium ions 1 of known electrophilicity E to determine the
nucleophilicity parameters N and s of the hydride donors 2
according to the definition in Equation (1).
log kð20 ꢀCÞ ¼ sðNþEÞ
ð1Þ
With this information, it should be possible to predict the
rates of hydride transfer from these hydride donors to any
hydride acceptor of known electrophilicity E.
Product studies showed that the benzhydrylium tetra-
fluoroborates (1a–k)–BF4 (Table 1) reacted quantitatively
with the borohydrides 2a–e and the dihydropyridines 2 f–j to
give the corresponding diarylmethanes 3a–k [Eq. (2)].
The conversion of the blue carbocations 1a–k into the
colorless diarylmethanes 3a–k was monitored photometri-
cally by using the methods described previously.[4a] All kinetic
investigations were performed under first-order conditions by
using the hydride donors 2a–j in large excess (10–100 equiv-
alents). In accordance with Equations (3) and (4), plots of the
resulting first-order rate constants kobs versus the concentra-
tions of 2a–j were linear with negligible intercepts; their
slopes gave the second-order rate constants k2 (see the
Supporting Information).
[*] Dipl.-Chem. D. Richter, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77717
E-mail: herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.uni-muenchen.de/oc/mayr
[**] We thank the Deutsche Forschungsgemeinschaft (Ma673/21-2) and
the Fonds der Chemischen Industrie for financial support, Dr.
Gabriele Lang and Dr. Ludwig Schappele for preliminary experi-
ments, and Dr. Armin Ofial for helpful discussions.
ꢁd½1ꢂ=dt ¼ k2 ½1ꢂ ½2ꢂ ¼ kobs ½1ꢂ
for ½2ꢂ ꢃ const:; k2 ¼ kobs=½2ꢂ
ð3Þ
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804263.
ð4Þ
1958
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Chemie
Most electrophile–nucleophile combinations have been
studied previously in dichloromethane, acetonitrile, or
dimethyl sulfoxide (DMSO) as the solvent.[4–10] As several
of the borohydrides studied are only slightly soluble in CH2Cl2
and CH3CN, we investigated their reactivity in DMSO.
The almost identical reactivities of NaBH4, KBH4, and
Bu4NBH4ꢁindicate that we are observing the reactions of the
free BH4 anions (Table 2). B(OAc)3Hꢁ is approximately
three times less reactive than BH4ꢁ, and BH3CNꢁ is 103 times
less reactive than BH4ꢁ. Smaller differences in the reactivity
of these anions were observed previously for their reaction
by a factor of three to four. Zhu, Cheng, et al. observed the
same trend in reactions of 2h–j with p-trifluoromethylbenzy-
lidenemalononitrile.[12]
Solvent effects were studied for the reaction of the
dihydropyridine 2g with 1 f. This reaction was four times
faster in acetonitrile (k2 = 88.8mꢁ1 sꢁ1) than in dichlorome-
thane (Table 3). An increase in the water content of the
solution in acetonitrile accelerated the hydride transfer
significantly: In 90% water/10% acetonitrile the reaction
proceeded eight times faster than in 100% acetonitrile.
Plots of logk2 versus the electrophilicity parameters E of
the benzhydrylium ions are linear (Figure 1), which indicates
the applicability of Equation (1). The slopes of these corre-
ꢁ
with tritylium ions in aqueous solution (k(BH4ꢁ)/
k(BH3CNꢁ) = 12 for malachite green, and k(BH4 )/
k(BH3CNꢁ) = 144 for (4-MeO-C6H4)3C+).[11]
Table 2: Second-order rate constants k2 (mꢁ1 sꢁ1) for the reactions of the
borohydrides 2a–e with the benzhydrylium ions 1 in DMSO at 208C.
Ar2CH+ NaBH4
KBH4
Bu4NBH4 NaB(OAc)3H NaBH3CN
(2a)
(2b)
(2c)
(2d)
(2e)
1 f
4.32ꢂ105
9.98ꢂ102
4.37ꢂ102
1.53ꢂ102
1g
1h
1j
5.24ꢂ105 4.87ꢂ105 5.11ꢂ105 1.61ꢂ105
2.01ꢂ105 2.27ꢂ105 2.03ꢂ105 5.50ꢂ104
1.66ꢂ104 1.87ꢂ104 1.85ꢂ104 5.55ꢂ103
7.17ꢂ103 9.10ꢂ103 7.88ꢂ103 2.52ꢂ103
1k
In an analogous manner, hydride abstraction from the
dihydropyridines 2 f–j was measured in dichloromethane. In
general, the Hantzsch ester 2 f is two to five times more
reactive than N-benzyl-1,4-dihydronicotinamide (2g;
Table 3). The replacement of the N-benzyl group in 2g with
an N-phenyl group (to give 2h) decreases the reactivity by a
factor of four to six. The introduction of a methyl substituent
at the para position of the N-phenyl group (to give 2i) leads to
an acceleration of the hydride transfer by a factor of two,
whereas a para methoxy group (in 2j) activates the reaction
Figure 1. Correlation of logk2 with the electrophilicity parameter E(1)
for reactions of the hydride donors 2 with the benzhydrylium ions 1 at
208C (borohydrides in DMSO, dihydropyridines in CH2Cl2).
Table 3: Second-order rate constants k2 (mꢁ1 sꢁ1) for the reactions of the dihydropyridines 2 f–j with the
benzhydrylium ions 1 at 208C.
lations gave the parameters s,
and the nucleophilicity parame-
ters N (listed in Table 4) were
found by changing the sign of the
x coordinate at the position at
which the lines intercepted the
x axis.
To examine the relevance of
the N and s parameters of the
hydride donors 2a–j listed in
Table 4 for reactions with other
types of electrophiles, we inves-
tigated the kinetics of hydride
transfer from some borohydrides
and dihydropyridines to Michael
acceptors and tritylium ions.
The reactions of tetrabuty-
lammonium borohydride (2c)
with five different Michael
acceptors [for example with 4a,
Eq. (5)] were found to be 4 to 19
times faster (see the Supporting
Ar2CH+
CH2Cl2
CH2Cl2
90W10AN[a]
CH2Cl2
CH2Cl2
CH2Cl2
1a
1b
1c
1d
1e
1 f
1g
1h
1i
5.48ꢂ103
1.82ꢂ103
3.74ꢂ102
3.56ꢂ104
8.43ꢂ103
4.85ꢂ103
6.72ꢂ102
5.60ꢂ103
2.04ꢂ103
2.75ꢂ102
9.87ꢂ101
1.69ꢂ103
3.66ꢂ102
1.68ꢂ102
7.92ꢂ102
4.68ꢂ101
2.22ꢂ101
3.83ꢂ101
5.07
2.28ꢂ101 6.93ꢂ102[b]
2.30ꢂ102
(1.1)[c]
2.16
1.44ꢂ102
1.70
4.97ꢂ101
1j
1.54ꢂ101
1k
7.73
[a] 90W10AN=mixture of 90% water and 10% acetonitrile (v/v). [b] Rate constants in further acetonitrile–
water mixtures: 360mꢁ1 sꢁ1 in 80W20AN, 165mꢁ1 sꢁ1 in 67W33AN, 87.4mꢁ1 sꢁ1 in 50W50AN, and
88.8mꢁ1 sꢁ1 in pure acetonitrile. [c] Less-reliable k2 value, not used for the determination of the N and s
parameters of 2i.
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Communications
and co-workers at 258C,[11] the reported rate constant for the
reaction of the parent tritylium ion 5d with 2g is 382 times
lower than that calculated with Equation (1) (Table 5,
entry 5).[13] As this rate constant was the basis for the
mechanistic analysis of hydride abstraction from NADH
analogues,[14] we reexamined the hydride transfer from 2g to
5d and found it to be much faster than reported, in agreement
with the prediction based on Equation (1). Although our
equipment does not enable us to follow the kinetics of this fast
reaction, our measurements showed clearly that the previ-
ously published rate constant is much too small.
Table 4: N and s parameters for the hydride donors 2a–j.
Hydride donor
Solvent
N
s
2a
2b
2c
2d
2e
2 f
2g
DMSO
DMSO
DMSO
DMSO
DMSO
CH2Cl2
CH2Cl2
14.74
15.14
14.94
14.45
11.52
9.00
0.81
0.77
0.79
0.76
0.67
0.90
0.82
0.66
0.87
0.95
0.92
With E = ꢁ3.72 for the tropylium ion[4c] and the N and s
parameters for the N-phenyl substituted dihydropyridines
2h–j in Table 4, hydride-transfer rate constants can be
calculated which deviate by less than a factor of two to four
from those reported by Zhu, Cheng, et al.[15]
8.67
H2O/MeCN (9:1, v/v)
CH2Cl2
CH2Cl2
11.35
7.53
7.68
Let us now compare the reactivities of the borohydrides
and dihydropyridines with those of previously investigated
2h
2i
ꢁ
2j
CH2Cl2
8.11
hydride donors (Figure 2). The borohydrides BH4 and
B(OAc)3Hꢁ are approximately five orders of magnitude
more reactive than the Hantzsch ester 2 f, which is slightly
more reactive than the dihydronicotinamides 2g and 2h.
Whereas trialkylstannanes and the borane–triethylamine
complex have similar reactivities to those of the dihydropyr-
Information) than calculated with Equation (1) from the N
and s parameters in Table 4 and the electrophilicity param-
eters E of the Michael acceptors.[8,9] These deviations are
acceptable in view of the reactivity range of 1040 covered by
the three-parameter Equation (1) and the fact that the
E parameters of the Michael acceptors were derived from
reactions with carbanions.[8,9]
However, significant differences between expected and
reported rate constants were found for the reactions of
tritylium ions 5 with the dihydronicotinamide 2g (Table 5).
Whereas the calculated second-order rate constants, k2,calcd
,
for the reactions of 2g with 5a–c agree within a factor of three
with the experimental rate constants determined in this study
and are in line with the rate constants determined by Bunton
Table 5: Experimental (k2,exp) and calculated (k2,calcd) second-order rate
constants (mꢁ1 sꢁ1) for the reactions of 2g with tritylium ions 5 in CH2Cl2
and water at 208C.
Entry
E[a]
Solvent k2,calcd
k2,exp
k2,exp (258C)
(this study) (literature)
1
2
3
4
5
5a ꢁ10.29 H2O[b]
5.0
1.5ꢂ101
2.7ꢂ101[c]
2.1ꢂ105[c]
8.9ꢂ104[d]
5b
ꢁ4.35 CH2Cl2 3.5ꢂ103 2.4ꢂ103
H2O[b]
4.2ꢂ104 1.2ꢂ105
5c
5d
ꢁ1.21 CH2Cl2 1.3ꢂ106 6.1ꢂ105
0.51 CH2Cl2 3.4ꢂ107 @106
[a] Electrophilicity parameter from Ref. [10]. [b] Rate constants k2,calcd and
k2,exp (this study) refer to the reaction in H2O/MeCN (9:1, v/v). [c] Data
was taken from Ref. [11]; because of the low solubility in pure water, we
assume that these rate constants were also determined in the presence
of a small amount of a cosolvent. [d] Data from Ref. [13].
Figure 2. Comparison of the nucleophilic reactivities N of hydride
donors and p nucleophiles; the solvent is CH2Cl2 unless otherwise
noted (N parameters are from Table 4 and Refs. [4–7,19]).
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In detailed mechanistic studies, in which carbocations with
different counterions were used, we demonstrated previously
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trialkyl- and triarylsilanes,[17] and analogous stannanes and
germanes[18] do not proceed by single-electron transfer but by
polar mechanisms.
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What are the consequences of these data for iminium
catalysis? Figure 2 shows that dihydropyridines have similar
nucleophilic reactivities to those of indoles and pyrroles,
which have been employed previously as nucleophiles in
iminium-activated Friedel–Crafts reactions.[3a,i] The nucleo-
philicity parameters N can thus be used as a clue for the
suitability of certain nucleophiles in iminium-catalyzed reac-
tions. However, N is not the only criterion to be considered.
Although amine–boranes and dihydropyridines have similar
nucleophilicities,[4a,16] our efforts to use the former for
iminium-catalyzed conjugate reductions have not been suc-
cessful so far because of competing 1,2-addition reactions. On
the other hand, the similar N values of N-methylpyrrole and
some trialkylsilanes suggest that the latter compounds may
also be suitable for iminium-catalyzed reductions if those
amines are used as organocatalysts, which were previously
found to catalyze Friedel–Crafts reactions with N-methylpyr-
role.
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Received: August 28, 2008
Revised: November 11, 2008
Published online: February 2, 2009
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Keywords: iminium catalysis · kinetics ·
linear free-energy relationships · nucleophilicity · reduction
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