Quantification of the nucleophilic reactivity of nicotine

Article abstract of DOI:10.1002/poc.3580

Rate and equilibrium constants of the reactions of nicotine and structurally related compounds with benzhydrylium ions have been determined UV-Vis spectroscopically using stopped-flow and laser-flash techniques. The pyridine nitrogen of nicotine was identified as the site of thermodynamically and kinetically controlled attack. Quantum chemical calculations showed that the introduction of a pyrid-3-yl moiety into the 2-position of N-methylpyrrolidine (to give nicotine) reduces the Lewis basicity of the pyrrolidine ring by 24 kJ mol^?1, whereas the analogous introduction of a phenyl ring decreases this quantity by only 11 kJ mol^?1. Copyright

Full text of DOI:10.1002/poc.3580

Special issue article
Received: 28 January 2016,
Revised: 5 April 2016,
Accepted: 8 April 2016,
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/poc.3580
Quantification of the nucleophilic reactivity of
nicotine
a
a
b
a
Peter A. Byrne , Shinjiro Kobayashi , Martin Breugst , Hans Laub and
a
Herbert Mayr *
Rate and equilibrium constants of the reactions of nicotine and structurally related compounds with benzhydrylium ions have
been determined UV-Vis spectroscopically using stopped-flow and laser-flash techniques. The pyridine nitrogen of nicotine
was identified as the site of thermodynamically and kinetically controlled attack. Quantum chemical calculations showed that
the introduction of a pyrid-3-yl moiety into the 2-position of N-methylpyrrolidine (to give nicotine) reduces the Lewis basicity
ꢀ
1
of the pyrrolidine ring by 24 kJ mol , whereas the analogous introduction of a phenyl ring decreases this quantity by only
1
ꢀ
1
1 kJ mol . Copyright © 2016 John Wiley & Sons, Ltd.
Keywords: equilibrium constants; nucleophilicity; Lewis basicity; kinetics; N-Heterocycles
INTRODUCTION
that reason, it is even more surprising that the pyrrolidine nitro-
gen reacts only 2.5 times faster with iodomethane than the
pyridine nitrogen of nicotine (1a) (Scheme 1) despite the 7
orders of magnitude higher basicity of pyrrolidine (pKaH in
acetonitrile = 19.56) [10]compared with pyridine (pKaH in
acetonitrile = 12.53).
In order to elucidate the origin of this behavior we first studied
the kinetics of the reactions of nicotine (1a) and the model com-
pounds 1(b–d) (Scheme 2) with the benzhydrylium ions 2(a–o)
(Table 1), which have been used as reference electrophiles in
many earlier studies, before determining the corresponding
equilibrium constants.
Nicotine (1a) is one of the most widespread drugs in our culture,
and there have been countless investigations of its reactivity and
[
1]
physiological activity. When Kekulé reported about the first al-
[
2]
kylations of nicotine in 1853, he assumed an empirical formula
of C10 N or C20 for nicotine, both incorrect, as later shown
H
7
H
N
14 2
[3]
by Pinner. Detailed studies on the alkylation of nicotine and re-
lated compounds were carried out in the Philip Morris Research
[4]
Center. Although the pyrrolidine nitrogen of nicotine (pKaH in
water = 7.84) is almost four orders of magnitude more basic than
its pyridine nitrogen (pKaH in water = 3.04),
[
4a]
the reaction with
methyl iodide gave a mixture of products arising from attack at
both nucleophilic positions (Scheme 1). The fact that alkylation
of 1a at the pyridine nitrogen is competitive with alkylation of
the pyrrolidine nitrogen could be a consequence of either of
the following effects, as delineated by Seeman: (i) a rate de-
crease in pyrrolidine alkylation caused by the pyridine ring or
RESULTS
Product studies
While compounds 1(a–c) were commercially available, N-methyl-
2-phenyl-pyrrolidine (1d) was synthesized according to Craig
(
ii) a pyridine nitrogen alkylation rate enhancement because of
[
11]
[
4a]
the presence of the pyrrolidine ring.
by reaction of N-methyl-α-pyrrolidone with phenylmagnesium
bromide, and subsequent reduction of the resulting crude prod-
uct with magnesium turnings and hydrochloric acid.
To confirm the identity of the products formed in the
reactions of these nucleophiles with benzhydrylium ions in
MeCN, selected representatives of these reactions were stud-
We now report on the investigation of the nucleophilic
[
5]
reactivity of nicotine by the benzhydrylium methodology. In
numerous articles we have shown that Eqn 1 allows one to calcu-
late the second-order rate constants of the reactions of electro-
philes with nucleophiles at 20°C using a solvent-independent
electrophilicity parameter
E and two solvent-dependent
3
ied by NMR in CD CN. The reactions of nicotine (1a) with
nucleophile-specific parameters N and sN.
+
-
-
(
2 4 4 2
mfa) CH BF (2h BF ) and (tol) CH-Br (2q-Br) at ambient
lg kð20°CÞ ¼ sNðE þ NÞ
(1)
*
Correspondence to: H. Mayr, Department Chemie, Ludwig-Maximilians-
Universität München, Butenandtstr. 5-13, 81377 München, Germany.
E-mail: herbert.mayr@cup.uni-muenchen.de
By employing p- and m-substituted benzhydrylium ions of
widely differing electrophilicity as reference electrophiles, we
succeeded in generating the most comprehensive nucleophilic-
[
6]
ity scale presently available. In previous work, we have charac-
terized the nucleophilic reactivities of differently substituted
a P. A. Byrne, S. Kobayashi, H. Laub, H. Mayr
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr.
5-13, 81377 München, Germany
[
7]
[8]
pyridines as well as of acyclic and cyclic tertiary amines. As
pyridines react with considerably higher intrinsic barriers than
alkylamines, they were found to be considerably weaker
b M. Breugst
Department für Chemie, Universität zu Köln, Greinstraße 4, 50939 Köln,
Germany
[
9]
nucleophiles than alkylamines of comparable pKaH values. For
J. Phys. Org. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

P. A. BYRNE ET AL.
Scheme 2. Structural analogues of nicotine
Scheme 1. Product ratio in the methylation of nicotine (1a) by
[4a]
iodomethane in MeCN solvent
+
temperature occur exclusively at the pyridine nitrogen to give
The reactions of (mfa)
2
CH (2h) with 3-methylpyridine (1b)
[
12]
complete (but reversible)
formation of N-(diarylmethyl)
3
and N-methylpyrrolidine (1c), respectively in CD CN, resulted in
pyridinium salts 3 (Scheme 3). No signals attributable to N-
methylpyrrolidinium salts 4 could be observed by NMR.
the quantitative formation of Lewis acid–base adducts 5b and
5c (Scheme 4).
Table 1. Abbreviations and electrophilicity parameters (E) of the reference electrophiles employed in this work
+
a
#
2
Ar
2
CH
X
Y
E
+
a
(ind)
2
CH
ꢀ8.76
+
2b
(thq) CH
2
ꢀ8.22
+
2
2
2
2
c
d
e
f
(pyr) CH
N(CH2)4
N(CH3)2
N(Ph)CH3
N(CH2)4
N(CH3)2
N(Ph)CH3
ꢀ7.69
ꢀ7.02
ꢀ5.89
ꢀ5.53
2
+
+
(dma) CH
2
(mpa) CH
2
+
(mor) CH
2
+
2
2
2
2
g
h
i
j
(dpa) CH
NPh2
NPh2
ꢀ4.72
ꢀ3.85
ꢀ3.14
ꢀ1.36
2
+
(mfa) CH
N(CH )CH CF
N(CH )CH CF
3
2
3
2
3
3
2
+
(pfa) CH
N(Ph)CH CF3
N(Ph)CH CF3
2
2
2
+
(fur) CH
2
+
2
k
fur(ani)CH
ꢀ0.81
+
2
2
2
2
2
2
2
2
l
m
n
o
p
q
r
(ani) CH
OCH3
OCH3
OCH3
H
OCH3
OPh
CH3
0.00
0.61
1.48
2.11
2.90
3.63
4.43
5.47
2
+
ani(pop)CH
+
ani(tol)CH+
ani(Ph)CH+
pop(Ph)CH
OCH3
H
CH
CH
CH
H
3
3
3
+
(tol)
tol(Ph)CH
2
CH
CH
H
3
+
+
s
Ph
2
CH
H
a
See reference 6.
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2016)

NUCLEOPHILIC REACTIVITY OF NICOTINE
Most rate constants were determined by laser-flash photolytic
techniques (Scheme 5). As tertiary phosphines are known to be
[
13]
good
photo-leaving
groups,
benzhydryltri-
phenylphosphonium tetrafluoroborates were prepared as pre-
+
ꢀ
cursors by heating Ar
2
CH-OH with Ph
3
PH BF
4
or by treatment
of Ar CH-Br with Ph P and subsequent anion exchange as de-
2
3
[
14]
scribed previously. The benzhydrylium ions 2 were then gen-
erated by laser-flash irradiation of the benzhydrylium precursors
+
ꢀ
Ar
a–d), and the decay of the benzhydrylium absorbances was
measured as a function of the nucleophile concentrations. As
the crystalline benzhydryltriphenylphosphonium salts (pfa) CHP
were in equilibrium with
P), they reacted with 1(a–d) within
2 3 4
CHP(Ph) BF in the presence of variable concentrations of 1
(
2
+
3
ꢀ
+
3
ꢀ
4
(
Ph)
BF
4
and (mfa)
2
CHP(Ph)
CH + Ph
3
BF
+
their precursors (Ar
2
seconds to give benzhydryl-ammonium or pyridinium ions,
which could not be cleaved photolytically. Therefore in each
measurement involving these compounds, phosphonium salt
solution and nucleophile (1(a–d)) solution were mixed in a
stopped-flow cell and irradiated immediately with a laser pulse.
Some reactions have been studied by stopped-flow as well as
by laser-flash techniques. The agreement was usually within
Scheme 3. Reactions of nicotine (1a) with benzhydrylium ions 2h and
2q to give N-diarylmethylpyridinium salts (3h and 3q)
1
1
0%, except for reactions with rate constants greater than
6
ꢀ1 ꢀ1
0 L mol
s . In these cases, the reaction time for these fast
reactions is comparable to or faster than the mixing time in the
stopped-flow instrument; thus, large quantity of the
a
benzhydrylium ions react before the reaction solution is properly
mixed. As a consequence, significantly smaller rate constants
were obtained by the stopped-flow method, because in effect
only the final portions of the decay curves can be recorded
and evaluated.
Linear plots of lg k vs. E of benzhydrylium ions have commonly
been used to determine the nucleophile-specific parameters N
and s of the reacting nucleophiles. However, Eqn 1 only applies
N
8
ꢀ1 ꢀ1
for rate constants below ca 2 × 10 L mol
s , because beyond
that point the correlation lines flatten out as the reaction rates
approach the diffusion limit (as can be seen in Fig. 1a). The cor-
relation line for 1d begins to flatten out at significantly lower
values of lg k than those for 1(a–c) (Fig. 1a). Similar behavior
has previously been observed for the reactions of benzhydrylium
[
8]
[8]
ions with Et
this occurrence to the greater steric bulk in the vicinity of the nu-
cleophilic nitrogen center in 1d and Et N compared with other
3 2 2
N in CH Cl and MeCN. As before, we attribute
+
ꢀ
2 4
Scheme 4. Reactions of (mfa) CH BF (2h) with (a) 3-methylpyridine
3
(1b) to give pyridinium 5b and (b) N-methylpyrrolidine (1c) to give N-
nitrogen nucleophiles (e.g. 1c or pyridines). Because reactions
of nitrogen nucleophiles with certain benzhydrylium ions (those
with E values below a certain point) are thermodynamically unfa-
vorable, an upper bound (related to diffusion control) and a
lower bound (related to thermodynamic stability of the product)
apply in selecting benzhydrylium ions of suitable reactivity to
employ in kinetic studies with these nucleophiles. Hence, rate
constants below the diffusion limit can be determined for the
reactions of only a few electrophiles (2) with the nucleophiles
1(a–d). As a consequence, it is not possible to derive meaningful
values of the reactivity parameters N and sN for these nucleo-
philes. Approximate values for 1(a–c) are given in Table 3, how-
ever. These were derived by least squares fitting of the linear
part of each plot to Eqn 1, as shown in Fig. 1b for the reactions
diarylmethyl-N-methylpyrrolidinium salt 5c
Kinetic investigations
+
As the benzhydrylium ions (Ar
2
CH , 2) are colored and their
reactions with 1(a–d) yield colorless adducts, the progress of
the reactions can be monitored by UV–vis spectroscopy. How-
ever, because of the low intrinsic barriers for the reactions of
benzhydrylium ions 2 with pyridines and tertiary amines, reac-
tions which lead to the formation of thermodynamically stable
pyridinium and quaternary ammonium ions are very fast and
cannot be followed by conventional UV–vis spectroscopy. In
some cases (underlined rate constants in Table 2) stopped-
flow-techniques could be applied to determine the rate of de-
cay of the UV–vis absorptions of the benzhydrylium ions 2 after
mixing the benzhydrylium tetrafluoroborates with an excess of
the nucleophiles 1(a–d) using pseudo-first order conditions
[
15]
carried out in CH Cl .
2
2
Table 2 as well as Fig. 1 shows that nicotine (1a) is generally
less reactive than N-methylpyrrolidine (1c), and within the reac-
tivity range studied is more reactive than N-methyl-2-phenyl-
pyrrolidine (1d). Its reactivity is almost identical to that of
3-methylpyridine (1b), which was not included in Fig. 1a for
(
0 0
[1] > > [2] ).
J. Phys. Org. Chem. (2016)
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P. A. BYRNE ET AL.
-1 -1
Table 2. Rate constants (Lmol s ) for the reactions of benzhydrylium ions 2 with nicotine (1a) and related compounds 1(b–d) at
2
0 °C determined by laser-flash and (underlined) stopped-flow experiments
+
Ar CH
2
#
CH CN
CH Cl2
CH CN
CH Cl2
CH CN
CH Cl2
CH CN
CH Cl2
2
3
2
3
2
3
2
3
+
6
(
(
(
(
(
thq) CH
2b
2c
2d
2e
2f
2.1 × 106
2
+
pyr) CH
7.2 × 10
2
+
+
7
dma) CH
mpa) CH
mor) CH
1.2 × 107
2
5
7
1.4 × 104
8.6 × 107
5.3 × 107
6.5 × 10
2
+
8.8 × 10
6.4 × 10
2
4
5
4
5
5
7.7 × 10
1.8 × 105
7.6 × 10
1.3 × 105
+
8
8
(
(
dpa) CH
2g
2h
6.2 × 106
4.1 × 106
3.0 × 108
1.9 × 108
2
+
6
6
6
6
mfa) CH
1.3 × 10
1
6.6 × 106
9.6 × 105
9.2 × 10
4.6 × 105
3.3 × 10
4.9 × 10
1.3 × 10
2
.1 × 106
3.1 × 10
7
6
1.7 × 10
6
8
8
6
+
(
(
pfa) CH
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
8.7 × 108
3.8 × 108
5.9 × 109
1.1 × 109
1.4 × 10
5.0 × 108
7.1 × 108
8.2 × 108
9.2 × 109
6.3 × 109
5.2 × 107
4.2 × 107
6.1 × 107
9.4 × 108
1.3 × 10
4.6 × 107
4.1 × 107
5.8 × 107
9.7 × 108
1.3 × 10
2
+
fur) CH
4.1 × 108
6.3 × 108
9.5 × 109
1.1 × 10
1.4 × 108
2.6 × 108
4.5 × 108
8.5 × 10
2.2 × 108
4.2 × 108
7.5 × 108
9.4 × 10
2.3 × 10
1.7 × 10
2
+
fur(ani)CH
+
9
(
ani)
2
CH
3.1 × 10
+
ani(pop)CH
ani(tol)CH
ani(Ph)CH
+
9
9
9
9
8
8
1.7 × 109
1.4 × 109
1.3 × 109
1.9 × 109
2.2 × 108
2.3 × 108
+
2.3 × 109
3.1 × 109
4.7 × 109
5.5 × 10
1.7 × 109
1.9 × 109
2.9 × 109
2.9 × 10
1.8 × 109
2.9 × 109
4.5 × 109
5.0 × 10
2.4 × 109
2.7 × 109
3.9 × 109
3.7 × 10
3.0 × 10
2.7 × 108
2.9 × 108
6.4 × 108
6.3 × 10
+
pop(Ph)CH
+
9
9
8
(
tol)
2
CH
4.1 × 10
3.6 × 109
8.0 × 109
+
tol(Ph)CH
3.7 × 10
1.0 × 10
+
9
9
9
9
9
8
(
Ph)
2
CH
2s
6.8 × 10
5.8 × 10
5.0 × 10
4.7 × 10
1.5 × 10
8.4 × 10
þ
½
Ar2CHNR3 ꢁ
A0 ꢀ At
K ¼
¼
À
-AtÁ
(2)
þ
A0
εl
½
Ar2CH ꢁ½NR3ꢁ A ½NR ꢁ ꢀ
t
3 0
where
Scheme
5. Laser-flash-induced
heterolytic
cleavage
of
+
+
•
[Ar CHNR ], [Ar CH ], and [NR ] are the equilibrium molar
2
3
2
3
benzhydrylphosphonium ions yields benzhydryl cations 2, which com-
bine with the amines 1 to yield adducts 3 or 5
concentrations of Lewis acid–base adduct, of benzhydrylium
ion and of Lewis base, respectively,
•
•
[NR
is the initial absorbance of the benzhydrylium ion solution
at the wavelength of measurement λ,
is the equilibrium absorbance of the reaction mixture at λ
proportional to current concentration of benzhydrylium ion),
ε is the molar absorption coefficient (L mol cm ) of the
benzhydrylium ion at λ,
l is the path length (cm) through which the incident UV–
visible light passes in the probe during measurement.
3 0
] is the initial molar concentration of Lewis base,
A
0
the sake of clarity because the correlation lines for nicotine (1a)
and 1b are almost coincident. It is thus indicated that the pyri-
dine nitrogen is also the site of kinetically controlled attack of
benzhydrylium ions at nicotine (1a). In order to rationalize this
behavior we have also studied equilibrium constants for these
reactions.
•
•
•
A
t
(
ꢀ1
ꢀ1
Several further aliquots of amine solution were added with the
Equilibrium studies
same result. Each reaction was repeated three or more times, and
for each repeat the concentration of the amine solution added to
the benzhydrylium ion solution was different. A value of K was
calculated for every addition of amine. All recorded values of K
for a given reaction were averaged to give the values reported in
Table 4 (see “Experimental” columns). In some cases, after the ad-
dition of several aliquots of Lewis base, the absorbance no longer
arrived at a constant value. Titration steps for which a constant
value of the absorbance was not reached were not used to calcu-
late the average values of K shown in Table 4.
Equilibrium constants for the reactions of amines 1a, 1c, and 1d
with selected benzhydrylium ions 2 were measured spectropho-
tometrically in dry MeCN at 20°C under an atmosphere of nitro-
gen (Table 4). Addition of an aliquot of amine solution to a
solution of 2 caused the absorbance to decrease from an initial
constant value to a new constant value. The change in the ab-
sorbance corresponds to the amount of Lewis acid–base adduct
formed, and so a value of the equilibrium constant K for each
[
16]
[
17]
individual titration could be calculated using Eqn 2
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NUCLEOPHILIC REACTIVITY OF NICOTINE
ꢀ
1
ꢀ1
Figure 1. (a) Plots of lg k (second-order rate constants; L mol
s
) for the reactions of nicotine (1a) and structurally related compounds 1(c,d) with
Cl , 20°C) of 2; (b) Close-up on the linear parts of Fig. 1a, which were used to deter-
benzhydrylium ions 2 versus the electrophilicity parameters E (CH
2
15]
2
[
mine approximate values of N and s
N
for 1a & 1d (see Table 2). The plot for 1b is almost coincident with that of 1a, and is omitted for clarity
magnitude lower than that of the structurally analogous phenyl
Table 3. Approximate nucleophile-specific reactivity param-
eters for 1(a–d) according to Eqn 1
substituted pyrrolidine 1d. The product characterization
Scheme 3) showed that nicotine (1a) is benzhydrylated at the
pyridine nitrogen. In line with this observation, the LB value of
[
15]
(
#
CH Cl2
CH CN
3
2
1a is similar to that of 3-methylpyridine (1b, LB = 12.27).
N
s
N
N
s
N
Although the equilibrium constants illustrated in Fig. 2 were
reproducible, the unexpected observation that the Lewis basicity
of nicotine is significantly lower than that of 1c and 1d,
prompted us to confirm this result by NMR competition experi-
ments, i.e. by using an independent method.
For that purpose, a solution of benzhydrylium tetrafluorobo-
rate 2h was mixed with approximately one equivalent each of
1
1
1
1
a
10.4
10.9
20.6
16.8
1.04
0.93
0.52
0.49
11.6
11.5
20.59
15.7
0.81
0.80
0.52
0.54
b
a
c
d
a
N
The quoted values of N and s for 1c were reported in ref. 8.
3
nicotine (1a) and N-methylpyrrolidine (1c) in CD CN. The blue
color of 2h disappeared, indicating quantitative consumption
of the benzhydrylium ion (indeed no signals attributable to 2h
appeared in the NMR spectra of the mixture). Because the
[
17]
It has been shown that the equilibrium constants K for the
reactions of benzhydrylium ions (Lewis acids) with DABCO and
quinuclidine, pyridines,
benzhydrylium ion is completely consumed, the equilibrium in
[
9]
[17]
[17]
phosphines,
thiocyanates (N-ter-
[22]
solution can be viewed as shown in Scheme 6.
The equilib-
[18]
[17]
[17]
[19]
minus),
imidazoles,
expressed by Eqn 3:
isoquinoline,
pyrimidine,
imidazoles,
benz-
rium constant at 25°C for this process (Kcomp = 14 ± 4), deter-
[
19]
[20]
and carboxylates
at 20°C in MeCN, can be
mined by NMR-spectroscopy, is in agreement with the low
[23]
Lewis basicity of nicotine shown in Fig. 2.
An analogous competition experiment with approximately
lg K ¼ LA þ LB
(3)
equal amounts of 2h, 1b, and 1c in CD CN gave K
= 15 ± 3
comp
3
[
23]
where LA is the Lewis acidity of the benzhydrylium ion, and LB is
the Lewis basicity of the base. Plots of lg K for the reactions listed
in Table 4 against the previously published LA parameters of the
benzhydrylium ions are linear with slopes of 1.0 (Fig. 2) indicat-
ing that Eqn 3 and the LA values of the benzhydrylium ions re-
ported in ref. 17 also apply for the corresponding reactions of
(a–d). From these plots, the values of the LB parameters for
a, 1c, and 1d have been extracted (Table 4). The observed equi-
librium constants agreed very well with those calculated from
the averaged LB parameters and the previously reported Lewis
acidity parameters LA of the benzhydrylium ions, as shown in
the last column of Table 4.
at 25°C,
Fig. 2.
again in agreement with the results in Table 4 and
DISCUSSION
[21]
1
1
In order to rationalize the nucleophilic reactivity of nicotine (1a),
we synthesized N-methyl-2-phenylpyrrolidine (1d), where the
pyridine ring of nicotine is replaced by a phenyl ring. According
to Table 2 and Fig. 1, the 2-phenyl group in 1d indeed reduces
the nucleophilic reactivity of the pyrrolidine ring by two orders
of magnitude (1c/1d), which may be explained by a steric effect.
However, the steric effect operates only in the transition state of
the reaction, and hardly affects the relative stabilities of the
products, as indicated by the similar Lewis basicities of 1c and
1d (Table 4, Fig. 2). The observation that nicotine (1a) is
The highest Lewis basicity is found for N-methylpyrrolidine
1c, 13.65), while N-methyl-2-phenylpyrrolidine (1d) shows a sim-
ilar but slightly lower value (LB = 13.39). Most strikingly, the LB
value exhibited by nicotine (1a, LB = 12.46) is one order of
(
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P. A. BYRNE ET AL.
a
Table 4. Equilibrium constants for the reactions of 1(a–d) with benzhydrylium ions (2) at 20°C in MeCN determined by UV–vis
spectrophotometry
+
b
c
#
1
Lewis base
LBMeCN
#
Ar CH
LAMeCN
Experimental
Correlation
2
Kcalc
ꢀ
1
ꢀ1
K
K (L mol
)
lg K
K
calc (L mol
)
+
+
+
a
12.46
2c
d
pyr
dma
mor
2
2
2
CH
CH
CH
ꢀ10.83
ꢀ9.82
ꢀ7.52
59
1.78
2.55
4.84
43
0.72
1.22
1.26
2
357
6.9 × 10
437
8.71 × 10
4
4
2
f
a
+
+
+
2 a
4 a
4 a
2 a
4 a
4 a
1
1
b
c
12.27
2d
dma CH
ꢀ9.82
ꢀ7.87
ꢀ7.52
2.52 × 10
2.71 × 10
6.00 × 10
2.40
4.43
4.78
2.86 × 10
2.54 × 10
5.66 × 10
1.13
0.94
0.94
2
2
e
mpa CH
2
2
f
mor CH
2
+
+
13.65
13.39
2a
ind CH
thq CH
ꢀ11.46
ꢀ11.27
150
253
2.18
2.40
155
240
1.03
0.95
2
2
b
2
+
+
+
1
d
2a
ind
thq
pyr
2
2
2
CH
CH
CH
ꢀ11.46
ꢀ11.27
ꢀ10.83
80
150
340
1.90
2.18
2.53
85
132
363
1.06
0.91
1.07
2
b
2
c
a
Values of equilibrium constant K and LB parameter for compound 1b are taken from ref. 17.
Values of LA parameters taken from ref. 17.
b
c
See Supporting Information for confidence intervals on the experimental values.
Scheme 6. Competition experiment for the determination of the rela-
[23]
tive Lewis basicities of 1a and 1c with respect to 2h
(Fig. 2) also indicate that the pyridine nitrogen is the reactive site
of nicotine.
There is a problem with this rationale, however. If one as-
sumes that the pyridyl and the phenyl groups have similar ef-
fects on the reactivity of the N-methylpyrrolidine fragment in
nicotine (1a) and in N-methyl-2-phenyl-pyrrolidine (1d), respec-
tively, one would expect that the pyrrolidine ring in nicotine
Figure 2. Plots of lg K for reactions of benzhydrylium ions (2) with
amines 1(a–d) vs. the Lewis acidity parameter LA in MeCN of the corre-
sponding benzhydrylium ions
[21]
(1a) would have a Lewis basicity similar to the pyrrolidine ring
approximately one order of magnitude more nucleophilic than
d (Fig. 1) can then be explained by the fact that nicotine is
in 1d. As the latter is significantly larger than the Lewis basic-
ity of 3-methylpyridine (1b, Fig. 2), one would expect that the
pyrrolidine nitrogen of nicotine (and not the pyridine nitrogen)
would be the most Lewis basic site (Lewis basicity with respect
to 2). Why is the opposite ranking observed, i.e. why is 3 and
not 4 formed in the reversible reactions in Scheme 3?
1
not attacked at the pyrrolidine moiety but at the pyridine ring,
in line with the observation that nicotine reacts with the same
rate as 3-picoline (1b). The rate constants for 1a and 1b are so
similar (Table 2) that the corresponding graphs overlap and are
not shown separately in Fig. 1. The NMR spectroscopic identifica-
tion of adduct 3 and the similar Lewis basicities of 1a and 1b
In order to resolve this paradox, we have performed quantum
chemical calculations (see below for details). As shown in
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NUCLEOPHILIC REACTIVITY OF NICOTINE
Scheme 7a, 3-methylpyridine (1b) was calculated to be
ꢀ
1
9
kJ mol more Lewis basic than N-methylpyrrolidine (1c) in
ꢀ
1
the gas phase, but 3 kJ mol less basic in acetonitrile solution,
in satisfactory agreement with the measured equilibrium con-
stants (ΔΔG = ꢀln10 × RT(LB1c ꢀ LB1b) = ꢀ7.9 kJ mol , Fig. 2).
The stabilizing solvation of quaternary ammonium ions appears
to be greater than that of pyridinium ions.
o
ꢀ1
It is fair to assume that solvation affects the Lewis basicity of
the pyrrolidine nitrogen in 1d and in 1a by the same amount.
ꢀ
1
From the 13.4 kJ mol difference of the Lewis basicities of the
pyrrolidine ring of 1a and 1d (Scheme 7b and 7c, left part) one
can calculate that the Lewis basicity of the pyrrolidine nitrogen
of nicotine should be 2.4 lg K units lower than that of 1d. When
the correlation line for 1d in Fig. 2 is shifted downwards by this
quantity (see Fig. 3), one obtains a good estimate for the exper-
imentally unobservable correlation line that would be generated
for the reaction at the pyrrolidinyl nitrogen of nicotine with
benzhydrylium ions (i.e. if attack of nicotine at its pyridyl nitro-
gen could be “switched off”). A comparison (Fig. 3) of this com-
putationally estimated correlation line for the reaction of the
pyrrolidinyl nitrogen of nicotine with the experimentally mea-
sured correlation line for reaction at the pyridyl nitrogen of nico-
tine (1a) makes it clear why 3 is more stable than the
regioisomer 4 (see Scheme 3).
Figure 3. Moving the correlation line for 1d down by 2.4 lg K units gives
a good estimate for the Lewis basicity of the pyrrolidinyl nitrogen of 1a in
acetonitrile. The estimated correlation line is indicated by the dashed red
line
6a and 6d with a trans arrangement of the benzhydryl and
ꢀ
1
Analogous phenomena appear to operate also for the
pyridyl/phenyl group, as depicted in Scheme 8, are 4 kJ mol
more stable than the corresponding cis isomers.
1
3
[25]
Brønsted basicities. C NMR spectra in D O at pD = 5.4 indicate
However,
2
that protonation of nicotine occurs at the pyrrolidine ring and
not at the pyridine ring as calculated for the gas phase (Scheme
whereas the pyrrolidinium ion derived from nicotine (1a) prefers
the conformation 6a-ee in which pyridyl and benzhydryl are
both in an equatorial position in the lowest energy structure,
the axial–axial conformation 6d-aa with phenyl and benzhydryl
trans to each other is the preferred conformation for the adduct
derived from 1d.
To rationalize these findings, we employed the model system
depicted in Scheme 8, where we replaced either the pyridine ni-
trogen of the 1a adduct by a CH group (6a-ee → 6d-ee) or the
CH group in the phenyl substituent of the 1d adduct by a
[24]
7
d).
Furthermore, the Brønsted basicities (in H O) of 1c
2
[
4a]
(pKaH = 10.18), 1a (pKaH = 7.84), and 1d (pKaH = 9.27), also indi-
cate that the pyridine ring in 1a lowers the basicity of the pyrrol-
idine ring by 1.43 pK units more than the phenyl ring does in 1d.
What is the reason for the different influence of the pyridyl and
the phenyl group on the basicity of the pyrrolidine?
Let us analyze the Lewis basicities of 1a and 1d toward 2.
Quantum chemical calculations show that the pyrrolidinium ions
ꢀ
1
Scheme 7. Calculated reaction free energies (ΔG/kJ mol ; M06-2X-D3/def2-QZVP//M06-2X-D3/6-31 + G(d,p)) for the reactions of N-nucleophiles with
+
2
the benzhydrylium ion Ph CH in the gas phase (values for MeCN (IEFPCM model) in parenthesis for selected examples)
J. Phys. Org. Chem. (2016)
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P. A. BYRNE ET AL.
3
sp -hybridized nitrogens proceed with lower intrinsic barriers
2
than those of sp -hybridized nitrogens, the pyrrolidine nitrogen
of nicotine reacted only 2½ times faster with methyl iodide than
[
4a]
the pyridine nitrogen of nicotine.
The question was raised
whether this small difference in reactivity was due (i) to a rate de-
crease in pyrrolidine alkylation caused by the pyridine ring or (ii)
to a pyridine nitrogen alkylation rate enhancement because of
[
4a]
the presence of the pyrrolidine ring. By studying rate and equi-
librium constants of the reactions of nicotine with benzhydrylium
ions, our reference electrophiles and reference Lewis acids, we
have provided clear evidence that hypothesis (i) applies.
Benzhydrylium ions attack the pyridine nitrogen of nicotine
(1a) with the same rate as that of 3-methylpyridine (1b). Further-
more, the equilibrium constants of the reactions of
benzhydrylium ions with nicotine (1a) and 1b are almost the
same, showing that neither nucleophilicity (k) nor Lewis basicity
(K) of the pyridine ring in nicotine are affected by the presence of
the pyrrolidine ring.
On the other hand, the Lewis basicity of nicotine (which refers
to the reactions of benzhydrylium ions with the pyridine nitrogen
of 1a) is approximately one order of magnitude smaller than the
Lewis basicity of N-methyl-2-phenyl-pyrrolidine (1d). From the
fact that under equilibrium conditions only the benzhydrylated
pyridine ring of nicotine is observable (compound 3), one can
conclude that the pyrrolidine ring of nicotine (1a) is more than
two orders of magnitude less Lewis basic than 1d. Quantum
chemical calculations showed that the pyrrolidine nitrogen in nic-
ꢀ
1
otine is 24 kJ mol less Lewis basic than N-methylpyrrolidine (1c)
Scheme 8. Structures of the lowest-energy N-benzhydrylpyrrolidinium
ions 6a-ee and 6d-aa and their isomers 6a-aa and 6d-ee generated by
CH/N exchange from 6a-ee and 6d-aa, respectively (For 6a-aa and 6d-
ee, only atoms marked in orange were allowed to relax during the opti-
mization) [M06-2X-D3/def2-QZVP//M06-2X-D3/6-31 + G(d,p)]
ꢀ
1
while 1d is only 11 kJ mol less Lewis basic than 1c.
The same factors which lower the Lewis basicity of the pyrrol-
idine ring of 1a toward benzhydrylium ions also account for the
difference of the Brønsted basicities (in H O) of 1a (pK = 7.84)
2
aH
and 1d (pKaH = 9.27). Thus, experimental and computational
studies agree that the low nucleophilicity and Lewis basicity of
nicotine are because of the deactivating effect of the pyridyl
group on the pyrrolidine ring, with the consequence that the
pyrrolidinyl nitrogen is surpassed by the pyridyl nitrogen in
terms of nucleophilicity and Lewis basicity.
nitrogen atom (6d-aa →6a-aa), and compared the electronic ener-
gies of both structures. Steric interactions between the equatorial
phenyl and benzhydryl groups in 6d-ee account for the higher sta-
bility of the bis-axial conformer 6d-aa. Although the conformational
preferences in substituted cyclopentanes are more complex than in
[26]
cyclohexanes,
ca 1.7 – 3.8 kJ mol ) were determined experimentally for 1,2-
small preferences of the axial–axial conformers
ꢀ
1
(
Acknowledgements
[27]
dihalocyclopentanes at 25°C in acetonitrile.
The calculated energy minimum structure for 6a is the bis-
equatorial conformer 6a-ee (in stark contrast to what is observed
for 6d). Conformer 6a-ee can be assumed to suffer from
destabilizing steric interactions comparable to those that exist
in 6d-ee. However, when comparing the energies of the fully op-
timized 6a-ee with the model 6a-aa (left in Scheme 8), a distor-
tion energy of 28 kJ mol is obtained. This indicates that some
destabilizing effect must exist in 6a-aa (one which does not af-
fect 6d-aa) whose magnitude exceeds that of the expected sta-
bilizing effect brought about by reduced steric interactions in
We thank the Deutsche Forschungsgemeinschaft (SFB 749, Pro-
ject B1) and the Fonds der Chemischen Industrie (Liebig-scholar-
ship to MB) for financial support, the Humboldt foundation for
the provision to PB of a Humboldt Research Fellowship for Post-
doctoral Researchers, Nathalie Hampel for the synthesis of the
reference electrophiles, and Hildegard Lipfert for help during
the preparation of this manuscript. Calculations were performed
on the DFG-funded Cologne High Efficiency Operating Platform
for Sciences (CHEOPS).
ꢀ
1
6
a-aa (vs. 6a-ee). The origin of this destabilizing effect is not
REFERENCES
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[
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CONCLUSION
Although pyrrolidine is a significantly stronger Brønsted base
than pyridine (7 pKaH units in acetonitrile)
[
10]
and alkylations of
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2016)

NUCLEOPHILIC REACTIVITY OF NICOTINE
[
[
[
[
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1
3, 336–345.
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2
+
ꢀ
9] M. Baidya, S. Kobayashi, F. Brotzel, U. Schmidhammer, E. Riedle, H.
constants for the reactions of (mfa)
2
CH BF
4
(2h) with 1c (K
1
)
½1c–E
þ
ꢁ
½1c–E
½1cꢁ½E
½1a–E
þ
ꢁ
ꢁ
ꢁ
Mayr, Angew. Chem. Int. Ed. 2007, 46, 6176–6179.
þ
þ
þ
and with 1a (K
2
), respectively: K ¼ ½
1c–E ꢁ½1aꢁ
þ
¼
½1a–Eþꢁ
½1cꢁ
¼
¼
K1
K2
[
10] I. Kaljurand, A. Kütt, L. Sooväli, T. Rodima, V. Mäemets, I. Leito, I. A.
½
1a–E ꢁ½1cꢁ
½1aꢁ
½1aꢁ½Eþꢁ
Koppel, J. Org. Chem. 2005, 70, 1019–1028.
+
+
[
[
11] L. C. Craig, J. Am. Chem. Soc. 1933, 55, 2543–2550.
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+
acid–base adducts of 2h with 1a & 1c, respectively, and [E ] is the
+
2
1537 See Supporting Information for a demonstration of the revers-
concentration of the Lewis acid (mfa) CH . The same argument
ibility of the reaction of 1c with 2h.
applies in the competition experiment with 3-methylpyridine in
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[
[
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[
23] See the Supporting Information for full details on how Kcomp was
1
34, 11481–11494;
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3902–13911.
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Table 3, and for details of the rate constants used for the calculation
of the N and s values from the lg k vs. E plots.
16] Note that if even slightly wet MeCN (ca. 50 ppm) was used, addition
of a single aliquot of amine solution would cause the absorbance to
decrease indefinitely, and never return to a constant value.
17] H. Mayr, J. Ammer, M. Baidya, B. Maji, T. A. Nigst, A. R. Ofial, T. Singer,
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1
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1
[
[
[
[
24] T. P. Pitner, J. I. Seeman, J. F. Whidby, J. Heterocyclic Chem. 1978, 15,
[
5
85–587.
N
25] For details of the calculations done on the cis-isomers, see
Supporting Information.
N
26] B. Fuchs, in: Topics in Stereochemistry, Vol. 10 (Eds: E. L. Eliel , N. L.
Allinger), John Wiley & Sons, Inc, Hoboken, 1978, 1–94.
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[
9
83–997.
[
[
[
[
[
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1
4126–14132.
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30, 3012–3022.
SUPPORTING INFORMATION
1
Additional supporting information can be found in the online
version of this article at the publisher’s website.
1
21] A slope of 1 has been enforced for each line in Fig. 2. The generally
small deviation of the slopes of the calculated best fit lines from the
J. Phys. Org. Chem. (2016)
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