Gas phase versus solution chemistry: On the reversal of regiochemistry of methylation of sp2- and sp3-nitrogens

Article abstract of DOI:10.1016/S0040-4039(01)01419-8

The nicotine analogue 3-(N,N-dimethylaminomethyl)pyridine 2, which reacts with methyl iodide in acetonitrile exclusively on the sp³-nitrogen, methylates exclusively on the pyridine nitrogen with trimethyloxonium in the gas phase. Calculations a

Full text of DOI:10.1016/S0040-4039(01)01419-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6949–6952
Gas phase versus solution chemistry: on the reversal of
regiochemistry of methylation of sp2- and sp3-nitrogens
Jennifer S. Brodbelt,a John Isbell,a,† Jonathan M Goodman,b Henry V. Secorc and
Jeffrey I. Seemanc,‡
aDepartment of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712-1167, USA
bDepartment of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK
cPhilip Morris, PO Box 26583, Richmond, VA 23261-658, USA
Received 22 May 2001; revised 24 July 2001; accepted 2 August 2001
Abstract—The nicotine analogue 3-(N,N-dimethylaminomethyl)pyridine 2, which reacts with methyl iodide in acetonitrile
exclusively on the sp3-nitrogen, methylates exclusively on the pyridine nitrogen with trimethyloxonium in the gas phase.
Calculations at the RHF/6-31G**//6-31G** level suggest that there is an interaction between the side chain nitrogen and
hydrogens on the aromatic ring. This interaction affects both the conformation of 2 as well as the relative basicity of its two
nitrogens. Calculations also indicate that, in the gas phase, the pyridine methylated product (no counterion) is more stable than
the pyrrolidine methylated product. © 2001 Elsevier Science Ltd. All rights reserved.
hydrogens [C(2)–H and C(4)–H], thereby decreasing its
The nicotine 1 analogue 3-(N,N-dimethylaminomethyl)-
sp3-nitrogen nucleophilicity. Calculations demonstrate
that, in the isodesmic reaction between 3 and 4, 4 is the
thermodynamically more stable isomer. These two theo-
retical results suggest an explanation for the shift to
pyridine methylation in the gas phase.
pyridine 2 reacts exclusively at the sp3-nitrogen with
methyl iodide in acetonitrile solution to give exclusively
the quaternary salt 3 (Scheme 1; counterion, not shown,
is I−).1 This regiochemistry is due to two well known
factors: (1) that the rate of the Menschutkin reaction is
strongly correlated to the basicity of the nitrogen atom;
and (2) that sp3-amines are significantly more basic
than sp2-pyridine nitrogens.2,3 We herein report that the
gas phase methylation of 2 with trimethyloxonium 5
results exclusively in the formation of 4, a reversal of
methylation regiochemistry. We also report the results
of calculations at the RHF/6-31G**//6-31G** level
which demonstrate weak hydrogen bonding between
the sp3-nitrogen of 2 and two of its pyridine ring
All experiments were performed in a Finnigan MAT
quadrupole ion trap mass spectrometer (ITMS). Sam-
ples were introduced into the vacuum chamber through
a heated leak valve at a static nominal pressure of
Scheme 1.
† Current Address: CombiChem, Inc., 9050 Camino Santa Fe, San Diego, CA 92121, USA.
‡ Current Address: SaddlePoint Frontiers, 12001 Bollingbrook Place, Richmond, VA 23236-3218, USA.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01419-8

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1–2×10−6 torr. Dimethyl ether was added to nominally
1–2×10−5 torr. Helium buffer gas was added to increase
the pressure to one millitorr. Solids were introduced to
the chamber via a heated direct insertion probe.
Trimethyloxonium and trimethyloxonium-d6, generated
from dimethyl ether and dimethyl ether-d6 ions, respec-
tively, was isolated and permitted to react with the neu-
tral analyte for ca. 100 ms. The (M+CH3)+ and
(M+CD3)+ product ions were isolated using the apex iso-
lation method4 and subjected to resonance collisionally
activated dissociation (CAD), typically at a qz of 0.3.
To evaluate the dichotomy between the gas phase and
solution methylation reactions of 2, we consider in turn
gas phase and solution methylation reactions.
The isodesmic reactions shown in Scheme 3 were exam-
ined at the RHF/6-31G**//6-31G** level using Cad-
pac.5 The reaction between methylpyridinium and
trimethylamine is found to favor tetramethylammonium
and pyridine by 12.2 kJ mol−1, corresponding to a ratio
of more than 100:1 at room temperature in the gas
phase. In contrast, ion 4 is calculated to be more stable
than 3 by 21.4 kJ mol−1, corresponding to a room tem-
perature/gas phase ratio of over 5000:1 in favor of 4.
When 2 is methylated with trimethyloxonium, the only
fragment observed from (M+CH3)+ is m/z 108, due to
loss of 43 u. The loss of 43 u is best rationalized as the
loss of CH3–NꢀCH2, which can readily occur from the
dimethylamino portion of the molecule (see Scheme 2).
The (M+CD3)+ ion also dissociated exclusively by loss of
43 u to form m/z 111, which means the same loss of
CH3–NꢀCH2 occurs.
This contrast may in part be explained by the decrease in
the basicity of the sp3-amine in 2 and 4, because of the
presence of the electron withdrawing properties of the
pyridine ring. In addition, calculations reveal a weak
hydrogen bond between the sp3-amine’s lone pair of
electrons and the C(2)–H and C(4)–H of the pyridine
ring in 2 and 4. This is seen by examining the preferred
conformations of these and related model compounds,
as determined by theory. The side chain of 3 is perpen-
dicular to the plane of the pyridine ring, i.e. ~1[C(2 or 4)–
C(ipso)–Ca–N]=ca. 90°, similar to that found for
ethylbenzene,6 propylbenzene,6 and isobutylbenzene7 7
The loss of 43 u from either the (M+CH3)+ or (M+CD3)+
ions of 2 cannot be readily rationalized if deuteriomethy-
lation had occurred on the sp3-nitrogen to form 6. In
that case, a mixture of CH3–NꢀCH2, CD3–NꢀCH2 and
CH3NꢀCD2 fragments would have resulted from the
(M+CD3)+ ion, corresponding to loss of 43, 46, and 45 u,
because the two methyl and one deuteriomethyl groups
have equivalent chances of being eliminated when all are
bound to the same nitrogen. The alkylating methyl
group is not directly involved in the fragmentation pro-
cess.
Scheme 2.
Scheme 3.

J. S. Brodbelt et al. / Tetrahedron Letters 42 (2001) 6949–6952
6951
the C(2)–H and presumably C(4)–H. In addition, as 4 is
significantly more stable than 3, thermodynamic consid-
erations also favor pyridine methylation.
and the monoprotonated 8 (see Fig. 1). However, in the
pyridine ring methylated 4 and 3-(dimethylamino)-
methylpyridine 2, a very different conformation is
found. Here, the lone pair on the side chain nitrogen
points towards either the C(2)– or C(4)–hydrogen (see
data in Fig. 1). The torsional angle found for N,N-
dimethylbenzylamine 9 in this work is consistent with
the literature experimental data and the highest level of
theory in the earlier calculations.12 The sp3-nitrogen
lone pair is within hydrogen bonding distance to the
C(2)– and C(4)–hydrogens. This is reminiscent of the
formyl hydrogen bond recently identified by Corey et
al.8,9 and investigated computationally by one of us
(J.G.).10,11
Acetonitrile is known to more effectively solvate pyri-
dine than either ammonia or trimethylamine.7 By anal-
ogy, acetonitrile would more effectively solvate the
pyridine ring nitrogen than the dimethylaminomethyl
nitrogen in 2. In acetonitrile, pyridine methylation may
be energetically less favored in part because pyridine
desolvation must occur first.
In conclusion, a reversal in regiochemistry is observed
for gas-phase13 and condensed methylations: A coun-
terbalancing of effects explain the results.14 In the gas
phase, sp2-nitrogen methylation is explained by a weak
hydrogen bonding interaction between the sp3-nitrogen
lone pair and the C(2)- and C(4)-hydrogen atoms
which acts against sp3-methylation. In acetonitrile,
preferential pyridine solvation acts against sp2-nitrogen
methylation.
If this analysis is correct, the strength of the nitrogen
lone pair–aromatic ring hydrogen interaction would
increase as the polarization of the C(aromatic)ꢁH bond
increases. This would lead to a decrease in the torsional
angle, as the acyclic nitrogen lone-pair–ring hydrogen
interaction would be more able to counteract the steric
effects pushing the side chain out of the plane. The
calculated geometries are consistent with this interpre-
tation. As the ortho aromatic-hydrogen increases its
positive charge, the torsional angle shifts from perpen-
dicular toward the plane of the aromatic ring, indicat-
ing an increased nitrogen lone pairꢁhydrogen bond.
This trend is shown in Fig. 1. The nitrogen lone pairs in
4, 2 and 9 are oriented to point in the direction of an
aromatic hydrogen. The calculations show that for 4,
the nitrogen lone pair prefers to interact with the
C(2)–H by ca. 5 kJ/mol. For 2, it prefers the C(4)–H by
ca. 2 kJ/mol. This switch in orientation is consistent
Acknowledgements
The Royal Society is thanked for its support to J.M.G.
and the Robert A. Welch Foundation for its support to
J.S.B. J.I.S. thanks E. B. Sanders and R. Walk for
support of this work.
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Figure 1. Torsion angles ~1(Caromatic–Cipso–Ca–N) or
~1(Caromatic–Cipso–Ca–Cb) from RHF/3-21G calculations and
[in brackets] RHF/6-31G** calculations.

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14. The two reactions being compared herein (Scheme 1) differ
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tional issues will be discussed in detail in our full paper.