Organocatalytic activity of cinchona alkaloids: Which nitrogen is more nucleophilic?

Article abstract of DOI:10.1021/jo901670w

(Chemical Equation Presented) The cinchona alkaloids 1a-d react selectively at the quinuclidine ring with benzyl bromide and at the quinoline ring with benzhydrylium ions (diarylcarbenium ions). The kinetics of these reactions have been determined photometrically or conductimetrically and are compared with analogous reactions of quinuclidine and quinoline derivatives. Quantum chemical calculations [MP2/6-31+G(2d,p)//B3LYP/6-31G(d)] show that the products obtained by attack at the quinuclidine ring (N_sp3) of quinine are thermodynamically more stable when small alkylating agents (primary alkyl) are used, while the products arising from attack at the quinoline ring (N _sp2) are more stable for bulkier electrophiles (Ar₂CH). In some cases, rate and equilibrium constants for their reactions with benzhydrylium ions could be determined. These data gave access to the Marcus intrinsic barriers, which are approximately 20 kJ mol^-1 lower for attack at the N_sp3-center than at the N_sp2-center.

Full text of DOI:10.1021/jo901670w

pubs.acs.org/joc
Organocatalytic Activity of Cinchona Alkaloids: Which Nitrogen Is More
Nucleophilic?
Mahiuddin Baidya, Markus Horn, Hendrik Zipse, and Herbert Mayr*
€
Department Chemie und Biochemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13
€
(Haus F), 81377 Mu€nchen, Germany
herbert.mayr@cup.uni-muenchen.de
Received August 3, 2009
The cinchona alkaloids 1a-d react selectively at the quinuclidine ring with benzyl bromide and at the
quinoline ring with benzhydrylium ions (diarylcarbenium ions). The kinetics of these reactions have
been determined photometrically or conductimetrically and are compared with analogous reactions
of quinuclidine and quinoline derivatives. Quantum chemical calculations [MP2/6-31+G(2d,p)//
B3LYP/6-31G(d)] show that the products obtained by attack at the quinuclidine ring (Nsp3) of
quinine are thermodynamically more stable when small alkylating agents (primary alkyl) are used,
while the products arising from attack at the quinoline ring (Nsp2) are more stable for bulkier
electrophiles (Ar2CH). In some cases, rate and equilibrium constants for their reactions with
benzhydrylium ions could be determined. These data gave access to the Marcus intrinsic barriers,
which are approximately 20 kJ mol-1 lower for attack at the Nsp3-center than at the Nsp2-center.
Introduction
syntheses.1a,b A breakthrough were Pracejus’ alcoholyses
of disubstituted ketenes in the presence of cinchona alka-
loids.1c Though numerous other classes of tertiary amines
have since been investigated with respect to their catalytic
efficiencies,1 the naturally occurring cinchona alkaloids 1a,b
Since the beginning of the 20th century, alkaloids, such as
quinine or quinidine, have been used as catalysts for asymmetric
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DOI: 10.1021/jo901670w
r
Published on Web 08/21/2009
J. Org. Chem. 2009, 74, 7157–7164 7157
2009 American Chemical Society

Baidya et al.
CHART 1. Cinchona Alkaloids and Related Compounds
JOCArticle
and derivatives thereof (Chart 1) have remained in the focus
of interest.2-15
Nucleophilic attack of quinine at the carbonyl groups of
the intermediate ketenes has been suggested to rationalize
the asymmetric halogenations of carboxylic acid derivatives2
and of the enantioselective syntheses of β-lactams3 and
β-lactones4 via [2 þ 2] cycloadditions of ketenes.5 Asym-
metric syntheses of 1,4-benzoxazinones have been achieved
via [4 þ 2] cycloaddition of benzoquinone imides with chiral
ketene enolates derived from acid chlorides and catalytic
amounts of cinchona alkaloids.6 Cinchona alkaloids were
reported to catalyze asymmetric cyanations and cyanosilyla-
tions of ketones and aldehydes7 as well as desymmetrizations
of meso-anhydrides.8 Chiral ammonium enolates, obtained
by nucleophilic attack of cinchona alkaloids and their deri-
vatives at Michael acceptors, were involved in enantioselec-
tive Baylis-Hillman reactions.9 Conjugate additions of
cinchona alkaloids to Baylis-Hillman carbonates10 and
allylic trichloroacetimidates11 were suggested to account
for the enantioselective synthesis of R-substituted methyl
acrylates and trichloroacetylated allyl amides, respectively.
Nucleophilic attack of cinchona alkaloids at R-haloketones
or esters in the presence of carbonates generates chiral
ammonium ylides, which were used for asymmetric cyclo-
propanation reactions.12 Sharpless et al. employed cinchona
alkaloids for osmium-catalyzed asymmetric dihydroxyla-
tions of alkenes and reported that the binding strengths to
OsO4 are very sensitive to steric effects.13
the quinoline ring,14,15 it is generally assumed that the
catalytic activity of the cinchona alkaloids is due to the
nucleophilicity of the Nsp3 center of the quinuclidine ring.
During our efforts to characterize the nucleophilic reactivity
of cinchona alkaloids in comparison with other organocata-
lysts, we had noticed that in contrast to most other electro-
philes, benzhydrylium ions (diarylcarbenium ions) attack
selectively at the Nsp2 center of the quinoline ring. This
observation prompted us to systematically investigate the
nucleophilic reactivity of the two basic positions in cinchona
alkaloids.
Though Adamczyk and Rege reported that 1,3-propane
sultone reacts with quinine selectively at the Nsp2 center of
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Results
Product Identification. In agreement with earlier reports,16,17
compounds 1a-d react with benzyl bromide at the quinucli-
dine ring (Scheme 1). The quaternary ammonium salts
resulting from benzylation of 1a and 1d are commercially
available and are used as phase-transfer catalysts.
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65, 6984–6991. (f) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195–196.
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In contrast, benzhydrylium ions attack cinchona alkaloids
1
at the quinoline nitrogen. Comparison of the H and 13C
NMR chemical shifts of the adducts of quinuclidine (1e),
6-methoxyquinoline (1h), and O-acetylquinine (1c) with
(mfa)2CHþ and (ani)2CHþ (Chart 2) reveals exclusive attack
of benzhydrylium ions at the Nsp2 center of cinchona alkaloids.
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J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897–4905.
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Yamane, Y.; Mukaiyama, T. Chem. Asian J. 2007, 2, 123–134. (b) Matsushita,
M.; Yoshida, K.; Yamamoto, N.; Wirsching, P.; Lerner, R. A.; Janda, K. D.
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7158 J. Org. Chem. Vol. 74, No. 18, 2009

Baidya et al.
JOCArticle
SCHEME 1. Reactions of Quinine (1a) with Benzyl Bromide
and Benzhydrylium Salts
SCHEME 2. Comparison of 1H and 13C NMR Chemical Shifts
(in ppm, solvent=CD3CN) of the Benzhydryl Center in Different
Adducts with Amines
CHART 2. Abbreviations and Electrophilicity Parameters (E)
of Benzhydrylium Ions (Ar2CHþ)
higher field (Δδ = 2-2.6 ppm), the benzhydryl carbon is
more deshielded (Δδ=7-10 ppm).
Kinetics. To rationalize the contrarian selectivities of
different electrophiles, we have studied the kinetics of the
reactions of benzhydrylium ions and of benzyl bromide with
quinine (1a) and compared them with the corresponding
reactions of related compounds (Chart 1).
In a first set of experiments we determined the kinetics of
the reactions of the amines 1 (Chart 1) with benzhydrylium
ions (Chart 2), which have been used as reference electro-
philes for characterizing the reactivities of σ-, n-, and
π-nucleophiles.19,20
While the reactions of quinuclidine (1e) (δH(NCH2)=2.78 ppm)
with (mfa)2CHþ and (ani)2CHþ are accompanied by a 0.6-
0.8 ppm deshielding of the NCH2-protons, the chemical shifts of
the quinuclidine protons remained unaffected when O-acetyl-
quinine (1c) was combined with these benzhydrylium ions. On
the other hand, benzhydrylation of 1c led to distinct changes in
the chemical shifts of the quinoline moiety similar to those
observed upon treatment of 6-methoxyquinoline (1h) with
benzhydrylium salts (see Supporting Information).
A further argument for the attack of benzhydrylium ions
at the quinoline ring of 1c comes from the comparison of the
chemical shifts of 9-H and C-9 of the adducts in Scheme 2,
which have been assigned by COSY and HSQC. The NMR
chemical shifts of the benzhydryl proton 9-H and the benz-
hydryl carbon C-9 in the adducts obtained from benzhydry-
lium ions and O-acetylquinine (1c) are very similar to those
of the corresponding adducts with 6-methoxyquinoline (1h),
indicating the same environment of the benzhydryl center in
both pairs of adducts. In contrast, the corresponding che-
mical shifts of the adducts with quinuclidine (1e) differ
significantly. While the benzhydryl proton resonates at much
FIGURE 1. Exponential decay of the absorbance A at 590 nm and
linear correlation of the pseudo-first-order rate constants kobs with
[1a] for the reaction of (mfa)2CHþBF4- (c0 = 1.8 ꢀ 10-5 M) with
amine 1a in CH2Cl2 at 20 °C (as the reaction is reversible, the final
absorbance is not zero).
(19) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. 1994, 33, 938–957.
(b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.;
Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am.
Chem. Soc. 2001, 123, 9500–9512. (c) Mayr, H.; Ofial, A. R. Carbocation
Chemistry; Olah, G. A., Prakash, G. K. S., Eds.; Wiley: Hoboken, 2004, Chapter
13, pp 331-358.
J. Org. Chem. Vol. 74, No. 18, 2009 7159

Baidya et al.
JOCArticle
TABLE 1. Second-Order Rate Constants for Reactions of Amines
1a-h with Benzhydrylium Tetrafluoroborates at 20 °C
k/M-1 s-1
amine
N/s
Ar2CHþ
CH2Cl2
CH3CN
1a
10.46/0.75 (CH2Cl2)
(mfa)2CHþ 8.88 ꢀ 104
(dpa)2CHþ 1.76 ꢀ 104
(mor)2CHþ 4.98 ꢀ 103
(dma)2CHþ no rxn
1b
10.54/0.74 (CH2Cl2)
(mfa)2CHþ 9.36 ꢀ 104
(dpa)2CHþ 1.74 ꢀ 104
(mor)2CHþ 5.38 ꢀ 103
(dma)2CHþ no rxn
1c
1e
(mfa)2CHþ 8.23 ꢀ 104 2.68 ꢀ 104
20.54/0.60a (CH3CN) (mfa)2CHþ
(mor)2CHþ
9.97 ꢀ 108a
3.34 ꢀ 108a
1.18 ꢀ 108a
5.22 ꢀ 107a
1.08 ꢀ 107a
1.84 ꢀ 105
1.13 ꢀ 105
4.12 ꢀ 104
1.63 ꢀ 104
no rxn
(dma)2CHþ
(pyr)2CHþ
(ind)2CHþ
1f
15.66/0.62 (CH3CN) (dma)2CHþ
(pyr)2CHþ
(thq)2CHþ
FIGURE 2. Plots of log k versus E for the reactions of amines with
(ind)2CHþ
benzhydrylium ions Ar2CHþ.
(jul)2CHþ
(lil)2CHþ
no rxn
1.78 ꢀ 105
TABLE 2. Second-Order Rate Constants for the Reactions of Amines
1g
1h
11.60/0.62 (CH3CN) (pfa)2CHþ
with Benzyl Bromide at 20 °C
(mfa)2CHþ 1.23 ꢀ 105 4.22 ꢀ 104
k/M-1 s-1
(dpa)2CHþ
(mor)2CHþ
3.46 ꢀ 104
3.34 ꢀ 103
4.04 ꢀ 103
no rxn
amine
DMSO
CH3CN
(mpa)2CHþ
(pyr)2CHþ
1a
1d
1e
1f
2.88 ꢀ 10-2
3.68 ꢀ 10-2
17.3
10.86/0.66 (CH3CN) (pfa)2CHþ
1.37 ꢀ 105
(mfa)2CHþ 7.96 ꢀ 104 2.16 ꢀ 104
6.32
6.16 ꢀ 10-2
(dpa)2CHþ
(mor)2CHþ
(dma)2CHþ
2.10 ꢀ 104
2.33 ꢀ 103
no rxn
1g
1.7 ꢀ 10-4
aFrom ref 18.
As a consequence of the previously reported proportionality
between salt concentration and conductance in acetonitrile,
the formation of the ammonium salts gave rise to an ex-
ponential increase of the conductances G (eq 2).21 The
second-order rate constants (Table 2) were obtained from
plots of kobs versus [1].
The decay of the benzhydrylium absorbances has been
followed photometrically after combining benzhydrylium
tetrafluoroborates with variable excesses of the amines.
Pseudo-first-order rate constants kobs were obtained by
fitting the decay of the absorbances to the monoexponential
obst
function A=A0 e-k þ C. Plots of kobs versus the concen-
dG=dt ¼ Gmaxð1 - e-k Þ þ C
obst
ð2Þ
trations of the amines were linear (Figure 1), with the second-
order rate constants (Table 1) being the slopes of the
correlation lines. Because of solubility problems, different
solvents had to be used for the different reaction series.
Comparison of rate constants in CH3CN and CH2Cl2 reveals
a 3- to 4-times higher reactivity in CH2Cl2.
Plots of log k versus the electrophilicity parameter E of the
benzhydrylium ions (Figure 2) are linear as required by eq 1,
where k20 °C (L mol-1 s-1) is the second-order rate constant,
E is the electrophilicity parameter, N is the nucleophilicity
parameter, and s is a nucleophile-specific slope parameter.19,20
Discussion
The similarity of the slope parameters s in Table 1 implies
that the relative reactivities of the different amines depend
only slightly on the nature of the benzhydrylium ions. For
that reason, the relative reactivities toward (mfa)2CHþ given
in Scheme 3 can be considered to be representative also for
reactions with other benzhydrylium ions.
Asshownin Scheme3, the quinoline ringinquinine(1a) has
a similar reactivity toward benzhydrylium ions as the
4-methyl- and 6-methoxy-substituted quinolines 1g and 1h.
Quinuclidine (1e) reacts >4 orders of magnitude faster with
benzhydrylium ions, and the 50-fold reduced reactivity of 1f
can be assigned to the steric shielding by the neighboring
naphthylmethyl group. The additional hydroxy group in
the naphthylmethyl group of 1a must be responsible for a
further >103-fold reduction of reactivity which is derived
from the exclusive attack of benzhydrylium ions at the quino-
line ring of 1a (with krel=0.70). Though unlikely, one cannot
log k20 °C ¼ sðN þ EÞ
ð1Þ
From the slopes and the intercepts on the abscissa, we can
derive the nucleophile-specific parameters s and N, respec-
tively, which are listed in the second column of Table 1.
The kinetics of the reactions of benzyl bromide with
quinine (1a) and several of its substructures have been
followed conductimetrically. In all cases, pseudo-first-order
conditions were employed with the amines 1 in high excess.
(21) (a) Yoh, S.-D.; Cheong, D.-Y.; Lee, C.-H.; Kim, S.-H.; Park, J.-H.;
Fujio, M.; Tsuno, Y. J. Phys. Org. Chem. 2001, 14, 123–130. (b) Kim, S. H.;
You, S.-D.; Lim, C.; Mishima, M.; Fujio, M.; Tsuno, Y. J. Phys. Org. Chem.
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7160 J. Org. Chem. Vol. 74, No. 18, 2009

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JOCArticle
SCHEME 3. Relative Reactivities of Different Amines toward the Benzhydrylium Ion (mfa)2CHþ and Benzyl Bromide in CH3CN
at 20 °C
aValue in CH2Cl2 divided by 3, as for 1c (from Table 1). bCalculated by eq 1 from E, N, and s. cValue in DMSO divided by 2.7, as for 1e (from Table 2).
rigorously exclude a faster, highly reversible electrophilic
attack of benzhydrylium ions at the Nsp3 center of 1a and
1b. The observed monoexponential decays of the benzhydry-
retarded by the naphthylmethyl group in 1f. The additional
hydroxy group in the cinchona alkaloids 1a,b reduces the
reactivities toward the sterically less demanding benzyl
group much less (by a factor of 6) than toward the diaryl-
methylium ions (>103).
-
lium absorbances in the reactions of Ar2CHþBF4 with
an excess of 1a or 1b (pseudo-first-order conditions) allow
us, however, to exclude the appearance of noticeable concen-
trations of intermediate ammonium ions, where the diaryl-
methyl group is located at the Nsp3 center. The observed rate
constants for the reactions of 1a,b with Ar2CHþ can, there-
fore, unequivocally be assigned to the reactions at the Nsp2
center.
Comparison of the nucleophilic reactivities of 1e-g toward
benzhydrylium ions and benzyl bromide shows common
features (Scheme 3). Quinuclidine (1e) is 4 orders of magni-
tude more reactive than 1g toward both types of electro-
philes, and the attack of both electrophiles is 102-fold
Computational Analysis
To rationalize why benzyl bromide reacts selectively at the
sp3 center of cinchona alkaloids while benzhydrylium ions
N
react selectively at the Nsp2 center, we have calculated the
benzhydryl cation and benzyl cation affinities of quinine and
its building blocks at the MP2(FC)/6-31þG(2d,p)//B3LYP/
6-31G(d) level.
As illustrated by the reaction enthalpies ΔH298 in Figure 3,
the substituent effects on the quinoline ring affect its
FIGURE 3. Comparison of gas-phase benzyl and benzhydryl cation affinities ΔH298 (kJ mol-1) of quinine 1a and several substructures
[MP2(FC)/6-31þG(2d,p)//B3LYP/6-31G(d)].
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FIGURE 4. Benzhydryl, benzyl, and methyl cation affinities of the different nitrogen atoms of quinine (1a) [MP2(FC)/6-31þG(2d,p)//
B3LYP/6-31G(d)].
benzhydryl cation and benzyl cation affinities almost
equally. Replacement of CH3 in lepidine (1g) by CH2OH
(f 1i) reduces the carbocation affinities by 2.5 ( 0.1 kJ
mol-1, whereas replacement of the 4-CH3 group in 1g by 6-
OCH3 (f 1h) raises the cation affinities by 2.8 ( 0.6 kJ
mol-1. Introduction of the 6-methoxy group into lepidine
(1g f 1j) increases the cation affinities by 11.4 ( 0.3 kJ
mol-1, and benzhydrylation or benzylation of the Nsp2
center of quinine (1a) is 19.6 ( 0.5 kJ mol-1 more exothermic
than that of lepidine (1g).
Eventually, Figure 4 (left) shows that ΔH298(g) is almost
identical for the benzhydrylation of both nitrogens of
quinine (1a), while ΔH298(g) for benzylation and methyla-
tion are considerably more negative for attack at the Nsp3
-
than at the Nsp2-center. When ΔG298(g) values are compared,
a shift in favor of Nsp2 alkylation is observed (Figure 4,
middle), which is enhanced when solvation is included
(Figure 4, right). As a result, the preferred attack of benz-
yl bromide at Nsp3 and of benzhydryl cations at Nsp2 are
in line with the relative thermodynamic stabilities of the
reaction products. From these results, one can extrapo-
late that thermodynamic effects will direct sterically de-
manding electrophiles to the Nsp2 center of the cinchona
alkaloids, while small electrophiles are directed to the Nsp3
center.
In contrast to the similar trends of the Ph2CHþ and
þ
PhCH2 affinities of the differently substituted quino-
lines, large differences were calculated for the relative benz-
hydrylation and benzylation enthalpies of the quinucli-
dines. While the benzylation of quinuclidine (1e) is 37 kJ mol-1
more exothermic than the benzylation of lepidine (1g),
this difference shrinks to 10 kJ mol-1 for benzhydrylation,
which can be explained by two additional gauche interac-
tions.
Intrinsic Barriers
Relative reactivities are, however, not exclusively con-
trolled by the relative stabilities of the products. The Marcus
equation (eq 3) expresses the activation free enthalpy of a
reaction (ΔGq) by a combination of the reaction free enthal-
q
py (ΔG0) and the intrinsic barrier (ΔG0 ). The latter term
q
(ΔG0 ) corresponds to the activation free enthalpy (ΔGq) of a
reaction without thermodynamic driving force (i.e., for
ΔG0=0).22
2
q
q
ΔGq ¼ ΔG0 þ 0:5ΔG0 þ ½ðΔG0Þ =16ΔG0 ꢁ
ð3Þ
In previous work, we have shown that quinuclidine is a
much stronger nucleophile than DMAP, although the Lewis
basicities, i.e., the equilibrium constants for the generation of
the ammonium ions, are the other way around (Scheme 4).18
The lower carbocation affinity of 2-hydroxymethylquinu-
clidine 1k (compared with quinuclidine 1e) can be assigned to
the loss of an intramolecular hydrogen bridge by the qua-
ternization. Surprisingly, the introduction of side chains into
1e to give 1a or 1f increases the affinity toward benzhydryl
cations more than toward benzyl cations.
(22) (a) Marcus, R. A. J. Phys. Chem. 1968, 72, 891–899. (b) Albery, W. J.
Annu. Rev. Phys. Chem. 1980, 31, 227–263.
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SCHEME 4. Comparison of Second-Order Rate Constants k
(M-1 s-1) and Equilibrium Constants K (M-1) for Reactions of
Quinuclidine and DMAP with (ind)2CHþBF4- in CH3CN at
20 °C (from ref 18)
TABLE 3. Equilibrium Constants (K), Reaction Free Energies (ΔG0),
Activation Free Energies (ΔGq), and Intrinsic Barriers (ΔG0q) for the
Reactions of the Benzhydrylium Ion (mfa)2CHþ with Amines 1a-c in
CH2Cl2 at 20°C
amine
K/M-1
ΔG0/kJ mol-1a ΔGq/kJ mol-1b ΔG0q/kJ mol-1
1a
1b
1c
1.55 ꢀ 104
1.79 ꢀ 104
4.98 ꢀ 103
-23.5
-23.9
-20.7
44.0
43.8
44.2
55.1
55.1
54.1
aΔG0 = -RT ln K. bFrom k in Table 1, using the Eyring equation.
respectively, and inserted into the Marcus equation (eq 3) to
q
give the intrinsic barriers (ΔG0 ) listed in Table 3.
q
With ΔG0 ≈ 55 kJ mol-1, the intrinsic barriers for the
reactions of (mfa)2CHþ with 1a, 1b, and 1c in CH2Cl2 are of
similar magnitude as the intrinsic barriers for the reactions of
pyridine and of para-substituted pyridines with benzhydrylium
ions in the same solvent.24 Because the intrinsic barriers for the
reactions of benzhydrylium ions with quinuclidine have pre-
viously been reported to be approximately 20 kJ mol-1 smaller
than those for the corresponding reactions with pyridines,18 we
can conclude that a similar difference holds for the electrophilic
attack at the two different nucleophilic sites of the cinchona
alkaloids. As a consequence, electrophilic attack at the Nsp3
center can be expected if the thermodynamic stabilities of the
two different products are similar.
The fact that quinuclidine (1e) reacts 103 times faster with
benzhydrylium ions than DMAP and also departs 50,000
times faster from the benzhydrylium fragment than DMAP
has been assigned to the lower intrinsic barrier ΔG0q for the
q
reaction of quinuclidine (ΔG0 =43 kJ mol-1) compared to the
Conclusion
corresponding reaction of DMAP (ΔG0q = 65 kJ mol-1).23
Presumably, a large portion of the higher reorganization
In previous work we have demonstrated that the N and s
parameters of amines, which have been derived from reac-
tions with benzhydrylium ions, can be used to calculate rate
constants for their reactions with ordinary Michael accep-
tors25 and to predict their relative reactivities toward methyl
iodide.26 For that reason, it can be assumed that the kinetic
data derived in this work and the resulting conclusions are
also relevant for the reactions of cinchona alkaloids with
other types of C-electrophiles.
q
energy (λ=4ΔG0 ) in the reaction with DMAP comes from
the reorganization of solvent molecules during the formation
of the pyridinium ions.
To examine whether differences in intrinsic barriers also
affect the different nucleophilicities of the two nitrogen centers
in 1a, we have now determined the intrinsic barriers for the
reactions of benzhydrylium ions with some cinchona alkaloids.
The combinations of (mfa)2CHþ with 1a-c in CH2Cl2
(eq 4) do not proceed quantitatively, and the corresponding
equilibrium constants have been determined by UV-vis spec-
troscopy. Assuming a proportionality between the absor-
bances and the concentrations of the benzhydrylium ions
(Lambert-Beer law), the equilibrium constants for reaction 4
can be expressed by the absorbances of the benzhydrylium ions
before (A0) andafter(A) the addition of the amines 1a-c (eq5).
Quinuclidinium ions arising from Nsp3 attack of primary
alkylating agents at cinchona alkaloids are more stable than
the isomeric quinolinium ions arising from the correspond-
ing Nsp2 attack. In contrast, quinolinium ions are more stable
than the isomeric quinuclidinium ions when sterically more
demanding alkylating agents are used. Because more reor-
ganization energy is needed for the electrophilic attack at the
Nsp2- than at the Nsp3-center, kinetically controlled quinu-
clidine alkylation cannot only be expected when the Nsp3
attack is the thermodynamically favored but also when
the Nsp2 attack is slightly favored by thermodynamics, i.e.,
when the less negative ΔG0 term for Nsp3 attack of eq 3 is
q
overcompensated by the smaller intrinsic barrier ΔG0 .
Experimental Section
½ðmfaÞ2CH-NR3þꢁ A0 -A
K ¼
¼
ð5Þ
Materials. Commercially available acetonitrile (HPLC gra-
dient grade) and DMSO (H2O content <50 ppm) were used
½ðmfaÞ2CHþꢁ½1ꢁ
A½1ꢁ
The equilibrium constants K (Table 3) and rate con-
stants k (Table 1) were then converted into ΔG0 and ΔGq,
(24) (a) Brotzel, F.; Kempf, B.; Singer, T.; Zipse, H.; Mayr, H. Chem.;
Eur. J. 2007, 13, 336–345.
(23) In line with these observations, pyridines have generally been found
to be weaker nucleofuges in aminolysis reactions of esters compared with
isobasic trialkylamines: (a) Castro, E. A.; Andujar, M.; Toro, A.; Santos,
J. G. J. Org. Chem. 2003, 68, 3608–3613. (b) Castro, E. A.; Aliaga, M.;
Campodonico, P.; Santos, J. G. J. Org. Chem. 2002, 67, 8911–8916.
(c) Castro, E. A.; Cubillos, M.; Santos, J. G. J. Org. Chem. 1999, 64, 8298–
8301.
(25) (a) Seeliger, F.; Berger, S. T. A.; Remennikov, G. Y.; Polborn, K.;
Mayr, H. J. Org. Chem. 2007, 72, 9170–9180. (b) Kaumanns, O.; Mayr, H.
J. Org. Chem. 2008, 73, 2738–2745. (c) Berger, S. T. A.; Seeliger, F. H.;
Hofbauer, F.; Mayr, H. Org. Biomol. Chem. 2007, 5, 3020–3026. (d) Baidya,
M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
(26) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006, 45,
3869–3874.
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Baidya et al.
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without further purification. CH2Cl2 was freshly distilled over
CaH2. Compounds 1c, 1f, and benzhydryl chloride were synthe-
sized according to literature procedures.27 The benzhydrylium
tetrafluoroborates were prepared as described before.19b All
other chemicals were purchased from commercial sources and
(if necessary) purified by recrystallization or distillation prior to use.
Kinetics. The reactions of amines with the colored benzhydry-
lium ions (Ar2CHþ) were followed photometrically at the ab-
sorption maxima of Ar2CHþ by UV-vis spectroscopy using
stopped flow techniques as described previously.19,20 The pseu-
do-first-order rate constants kobs were obtained by least-squares
fitting of the absorbances to the monoexponential function
At =A0 exp(-kobst) þ C. The reactions of amines with benzyl
bromide were followed by conductimetry. The first-order rate
constants kobs were obtained by least-squares fitting of the
conductance data to the single exponential equation as men-
tioned in the text before. The temperature of the solutions during
all kinetic studies was kept constant at 20 °C using a circulating
bath thermostat.
studies of carbocation affinities of neutral N- and P-based
nucleophiles.28 This protocol involves a combination of geome-
try optimizations using the MM3 force field as implemented in
the Tinker program package29 with geometry optimizations and
frequency calculations at the B3LYP/6-31G(d) level of theory
and finally single point calculations at the MP2(FC)/6-31þ
G(2d,p) level. To account for the effects of solvation in apolar
organic solvents, solvation free energies in dichloromethane
have been calculated for all conformers located in the gas phase
through single point calculations at the PCM/UAHF/RHF/
6-31G(d) level of theory.30 All quantum mechanical calculations
have been performed using the Gaussian 03 program package.31
Acknowledgment. We thank the Deutsche Forschungsge-
meinschaft (Ma673/21-2) and the Fonds der Chemischen
Industrie for financial support. Valuable suggestions by
Dr. Armin R. Ofial are gratefully acknowledged.
Supporting Information Available: NMR spectroscopic
characterization of the products, details of the equilibrium
and rate measurements, and computational details. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
Determination of Equilibrium Constants. Equilibrium con-
stants were determined by UV-vis spectroscopy as follows:
To solutions of the benzhydrylium tetrafluoroborate (mfa)2-
-
CHþBF4 in CH2Cl2 were added small amounts of stock
solutions of the amines 1a-c, and the absorbances of (mfa)2-
-
CHþBF4 were monitored at λmax (593 nm) before (A0) and
(28) (a) Wei, Y.; Sastry, G. N.; Zipse, H. Org. Lett. 2008, 10, 5413–5417.
(b) Wei, Y.; Sastry, G. N.; Zipse, H. J. Am. Chem. Soc. 2008, 130, 3473–3477.
(c) Wei, Y.; Singer, T.; Mayr, H.; Sastry, G. N.; Zipse, H. J. Comput. Chem.
2008, 29, 291–297.
(29) Ponder, J. W. TINKER, 4.2 ed.; 2004; http://dasher.wustl.edu/
tinker/.
immediately after (A) the addition of amines. This procedure
was carried out with five to six different concentrations of the
amines 1a-c. The temperature was kept constant at 20 °C using
a circulating bath thermostat.
(30) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032–3041. (b) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151–
5158. (c) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett.
1998, 286, 253–260. (d) Amovilli, C.; Barone, V.; Cammi, R.; Cances, E.;
Cossi, M.; Mennucci, B.; Pomelli, C. S.; Tomasi, J. Adv. Quantum Chem.
1998, 32, 227–261. (e) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem.
Phys. 2002, 117, 43–54.
Computational Details. The protocol for searching the con-
formational space of the, in part, very flexible systems and for
calculating reaction enthalpies follows closely that used in recent
(27) (a) For the synthesis of 1c: Pettit, G. R.; Gupta, S. K. J. Chem. Soc. C
1968, 1208–1213. (b) For the synthesis of 1f: see ref 13a. (c) For the synthesis
of benzhydryl chloride: Denegri, B.; Streiter, A.; Juric, S.; Ofial, A. R.;
Kronja, O.; Mayr, H. Chem.;Eur. J. 2006, 12, 1648–1656.
(31) Frisch, M. J. et al.; Gaussian 03, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2004.
7164 J. Org. Chem. Vol. 74, No. 18, 2009