Structure-kinetics relations holding in the amination of six-membered nitrogen-containing heterocyclic compounds

Article abstract of DOI:10.1134/S107042801106011X

Relative rates of the amination of 3-X- and 4-X-substituted pyridines (X = H, 3-Me, 4-Me, 3-F₃C, 3-CN, 4-CN, 3-Cl, 3-Br, 4-MeO, 4-Me ₂N), pyrazine, quinoline, isoquinoline, 2,2′- and 4,4′-bipyridines, and 1,10-phenanthroline with O-

Full text of DOI:10.1134/S107042801106011X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 6, pp. 897–903. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © G.I. Borodkin, A.Yu. Vorob’ev, V.G. Shubin, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 6, pp. 880–886.
Structure–Kinetics Relations Holding in the Amination
of Six-Membered Nitrogen-Containing Heterocyclic Compounds
G. I. Borodkina, b, A. Yu. Vorob’eva, b, and V. G. Shubina
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: gibor@nioch.nsc.ru
b Novosibirsk State University, Novosibirsk, Russia
Received April 30, 2010
Abstract—Relative rates of the amination of 3-X- and 4-X-substituted pyridines (X = H, 3-Me, 4-Me, 3-F3C,
3-CN, 4-CN, 3-Cl, 3-Br, 4-MeO, 4-Me2N), pyrazine, quinoline, isoquinoline, 2,2′- and 4,4′-bipyridines, and
1,10-phenanthroline with O-mesitylenesulfonylhydroxylamine were estimated by NMR spectroscopy. Correla-
tions were found between logarithms of the relative amination rate constants and substituent constants σ or σI
and σR for X-substituted pyridines. A wide series of nitrogen-containing heterocyclic compounds turned out to
fit correlations between logarithms of the relative amination rate constants, on the one hand, and relative
stabilities of N-aminoazinium cations, energies of activation of the amination process, and gas-phase proton
affinities, calculated by the DFT/PBE/3z and DFT/B3LYP/L2 methods, on the other.
DOI: 10.1134/S107042801106011X
Salts containing N-amino cations derived from
nitrogen-containing heteroaromatic compounds are
widely used as reagents for amination of arenes [1] and
for the synthesis of various heterocyclic compounds
through the corresponding imines [2–12]. Salts con-
taining a large number of nitrogen atoms are promising
as energetic compounds [13–15]. Compounds possess-
ing an N-aminopyridinium fragment were proposed as
components of photothermographic elements [16];
they also act as antibiotics [17]. Such salts are usually
obtained by direct amination of nitrogen-containing
heterocycles with various aminating agents; among
the latter, O-mesitylenesulfonylhydroxylamine
(MesSO2ONH2) is the most popular [18–20].
The goal of the present work was to reveal factors
determining the reactivity of nitrogen-containing het-
eroaromatic compounds in the amination with O-me-
sitylenesulfonylhydroxylamine. As model substrates
we selected 3- and 4-substituted pyridines Ia–Ij, pyra-
zine (II), quinoline (III), isoquinoline (IV), 2,2′- and
4,4′-bipyridines V and VI, and 1,10-phenanthroline
(VII). Our choice was based on wide application of
Scheme 1.
X
X
MesSO2ONH2, CH2Cl2
MesSO3
N
N
NH2
Ia–Ij
VIIIa–VIIIj
X = H (a), 3-Me (b), 4-Me (c), 3-F3C (d), 3-CN (e), 4-CN (f), 3-Cl (g), 3-Br (h), 4-MeO (i), 4-Me2N (j).
N
N
N
NH2
N
N
N
N
NH2
N
NH2
N
N
H2N
NH2
NH2
IX
X
XI
XII
XIII
XIV
897

BORODKIN et al.
898
Relative rate constants for amination and alkylation of nitrogen-containing heterocyclic compounds [35–37], their proton
affinities PA [38, 39], and calculated energies of activation (Eacalc) and relative stabilities of the corresponding N-amino
+
cations [ΔA(NH2 )]
ΔA(NH2+), kJ/mol
Comp.
no.
PA,
kJ/mol
Eacalc, kJ/mol,
DFT/PBE/3z
krel(NH2)a
logkrel(Me)b logkrel(Et)c
DFT/B3LYP/L2 DFT/PBE/3z
Ia
Ib
Ic
1
0.000
0.204
–
0.000
930.0
943.4
947.2
892.5
877.0
880.6
903.4
910.0
961.7
997.6
877.1
953.2
951.7
958.9–970.6
–
50.4
46.3
47.1
64.2
69.9
65.1
0.
0.
1.75±0.07
0.168
14.4
16.2
1.81±0.08
0.433
18.2
15.1
Id
Ie
0.0484±0.0012
0.030±0.001
0.0571±0.0016
0.0810±0.0010
0.0790±0.0015
3.12±0.10
–
–
–37.0–
–56.2–
–48.7–
–35.1–
–53.1–
–44.2–
–1.276–
–
–1.316–
If
–1.144–
Ig
Ih
Ii
–0.854–
–1.102–
–
–
60.4
d
–23.3–
–22.8–
d
d
–0.865–
0.629
45.3
36.2
62.8
50.8
47.9
61.7
53.3
39.7
31.7
74.2
29.8
71.0
Ij
22.8±0.40
–
1.379
II
0.0525±0.0010
0.540±0.008
1.06±0.02
–1.444–
–0.959–
0.079
–2.538–
–
–
–
–
–
–
–
–43.8–
19.3
–39.2–
18.0
III
IV
V
24.8
24.4
0.149±0.008
0.375±0.015
9.57±0.13
19.7
26.2
VI
VII
11.5
03.4
–1.328–
–
53.4
61.1
a
1
Average values determined from 3–5 measurements by H NMR spectroscopy. The relative rate constants for the amination of com-
pounds II and V–VII were calculated with account taken of statistical factor.
b
c
d
The reaction with methyl iodide in DMSO at 23°C [35, 36].
The reaction with ethyl iodide in methylene chloride at 25°C [37].
No calculations were performed because of difficulties in the introduction of relativistic correction for bromine atom.
these compounds in the synthesis of N-aminoazinium
salts [18–20].
[27] and 1-amino-1,10-phenanthrolinium mesitylene-
sulfonates [30] in DMSO solution at 100 or 150°C,
respectively, is not accompanied by variation of the
1H NMR spectra. Likewise, no amino group transfer
from the cation to free nitrogen-containing base was
observed when a solution of 1-aminopyrazinium mesit-
ylenesulfonate and pyridine in DMSO was heated for
3 h at 90°C or a solution of 1-amino-1,10-phenanthro-
linium mesitylenesulfonate and 4-methyl-1,10-phenan-
throline in the same solvent was heated for ~1 h at
150°C. These findings indicate that N-amino cations
derived from nitrogen-containing heteroaromatic com-
pounds are inactive in nitrenium ion transfer processes.
By treatment of compounds I–VII with O-mesit-
ylenesulfonylhydroxylamine in methylene chloride at
0°C we obtained N-aminoazinium mesitylenesulfo-
nates VIIIa–VIIIj and IX–XIV (Scheme 1). Salts
VIIIa–VIIIc, VIIIe–VIIIi, IX–XII, and XIV were
reported previously [21–31]. The structure of salts
VIIId, VIIIj, and XIII was confirmed by comparing
1
their H and 13C NMR spectra with those of struc-
turally related compounds [13, 21–24]. The relative
reactivity of nitrogen-containing heterocycles I–VII
was estimated by the competitive reactions method,
which was successfully used previously while studying
quaternization of nitrogen-containing heterocycles
The data in table show that electron-donating sub-
stituents X in 3- and 4-substituted pyridines I accel-
erate amination and that electron-withdrawing groups
inhibit the reaction, which is typical of quaternization
of pyridines [32]. Comparison of logarithms of the
relative rate constants for the amination of pyridines
1
[32]. The product ratios were determined by H NMR
(see table). Obviously, these ratios reflect kinetically
controlled processes. As shown previously, heating of
1,2-diamino- and 1-amino-3-acetylaminopyrazinium
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

STRUCTURE–KINETICS RELATIONS HOLDING IN THE AMINATION
899
Ia–Ij with the Hammett substituent constants σ [33]
gave the following correlation:
Amination of a larger series of nitrogen-containing
heteroaromatic compounds can be described on
a quantitative level with the aid of their proton affini-
ties (PA) or logarithms of the relative rate constants for
their alkylation. The following correlation was found
between the logarithms of the relative rate constants
for amination of compounds I–IV and proton affinities
[38] (see table).*
log(kX/kH) = –(0.17±0.07) – (2.09±0.16)σX;
r = 0.98, s = 0.22, n = 10.
(1)
Separate correlations for the series of 3- and 4-sub-
stituted pyridines are characterized by better quality:
log(k3-X/kH) = (0.01±0.04) – (2.88±0.11)σm-X
r = 0.997, s = 0.06, n = 6;
;
(2)
logkrel(NH2) = (0.023±0.002)PA – (21.4±1.8);
r = 0.96, s = 0.26, n = 13.
(8)
log(k4-X/kH) = –(0.04±0.03) – (1.75±0.06)σp-X
r = 0.999, s = 0.06, n = 5.
;
(3)
The use of logarithms of the relative rate constants
for alkylation of nitrogen-containing heterocycles as
kinetic parameters is limited by the available data (see
table). Comparison of logkrel for the amination and
alkylation shows that these reactions are not similar.
For example, the relative rate constants for amination
and alkylation of substituted pyridines fit the following
correlations:
The use of polar constants σ+ and σ– (σ+m and σ–m
were assumed to be equal to σm) [33] instead of
Hammett substituent constants σ did not improve the
above correlations (r = 0.94 and 0.85, respectively).
The relative contributions of the inductive and reson-
ance effects may be estimated using constants σI and
σR [33]. The inductive constant for CF3 group was
σI(CF3) = 0.40 [34].
logkrel(NH2) = (1.21±0.03)logkrel(Me) – (0.01±0.03); (9)
r = 0.999, s = 0.04, n = 4;
log(k3-X/kH) = (0.02±0.10) – (2.67±0.26)σI
– (0.89±0.46)σR;
(4)
(5)
logkrel(NH2) = (1.05±0.04)logkrel(Et) – (0.09±0.04); (10)
r = 0.995, s = 0.10, n = 8.
r = 0.989, s = 0.14, n = 6;
log(k4-X/kH) = –(0.03±0.14) – (1.38±0.39)σI
– (2.60±0.31)σR;
logkrel(NH2)
1.0
VII
r = 0.991, s = 0.18, n = 5.
As might be expected, the contribution of reson-
ance effect of substituent X in 4-substituted pyridines
is larger than in 3-substituted pyridines (ρR/ρI = 1.88
and 0.33, respectively). In the ethylation of 4- and
3-substituted pyridines the ratio ρR/ρI was 0.83 and
0.43, respectively [32]. The larger ρR/ρI value for the
amination of 4-substituted pyridines as compared to
their ethylation is likely to be determined by the larger
positive charge on the pyridine ring in the amination
transition state. The use of substituent constants σR+
instead of σR somewhat improves the two-parameter
correlations, which is consistent with the assumption
implying appearance of positive charge on the pyridine
ring in the transition state.
0.5
Ib
IV
Ia
0.0
III
–0.5
–1.0
–1.5
V
Ig
II
Ie
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
0.5
logkrel(Me)
Fig. 1. Correlation between the logarithms of the relative
rate constants for the amination and methylation of com-
pounds Ia, Ib, Ie, Ig, II–V, and VII. The data for com-
pounds II, III, V, and VII were excluded.
log(k3-X/kH) = (0.01±0.09) – (2.93±0.22)σI
– (1.76±0.73)σR+;
(6)
(7)
r = 0.991, s = 0.12, n = 6;
* The US National Institute of Standards and Technologies (NIST)
database (http://webbook.nist.gov) contains no proton affinities
for compounds V–VII. Only a range of PA values for compound
V was estimated in [39]; therefore, the corresponding point was
not included in the correlation.
log(k4-X/kH) = (0.01±0.01) – (2.19±0.03)σI
– (2.70±0.02)σR+;
r = 0.999, s = 0.01, n = 5.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

BORODKIN et al.
(a)
900
However, extension of the substrate series reveals
considerable differences between the amination and
alkylation. The points corresponding to quinoline,
2,2′-bipyridine, and 1,10-phenanthroline strongly
deviate from the correlation drawn for compounds Ia,
Ib, Ie, Ig, and IV (Fig. 1). In going from pyridine to its
benzo-fused derivative, quinoline, the reactivity of the
latter in the methylation reaction decreases more
strongly than in the amination process, which may be
due to steric hindrances caused by interaction of MeI
with 8-H (cf. [40]). It should be noted that the amina-
tion rate constants for pyridine and isoquinoline are
fairly similar. Higher rate of N-amination of 2,2′-bipyr-
idine and 1,10-phenanthroline as compared to their
methylation may be rationalized by formation of intra-
molecular hydrogen bond N···H···N between the NH2
group and endocyclic nitrogen atom in the transition
state, which should reduce the energy barrier. This
assumption is confirmed by the results of DFT/PBE/3z
quantum-chemical calculations of the transition states
for the reactions of 2,2′-bipyridine and 1,10-phenan-
throline with O-mesitylenesulfonylhydroxylamine
(Fig. 2). It is seen that the corresponding nitrogen
atoms are involved in short hydrogen bond.
1.927
1.960
2.013
(b)
1.903
1.960
1.950
As shown previously, the DFT/PBE/3z method
properly describes regioselectivity of the amination of
2-substituted pyrazines [26, 27]. We used this method
to calculate the energies of activation Ecaalc for the reac-
tions of compounds I–VII with O-mesitylenesulfonyl-
hydroxylamine (see table). The amination transition
states are characterized by one imaginary frequency in
the corresponding Hessian matrix, and the vibrational
vector conforms to the motion of the NH2 group from
the oxygen atom in the SO3NH2 group to the nitrogen
atom in the heteroring. Application of the IRC (internal
reaction coordinate) procedure converts the system
from the transition state directly to reaction product or
initial reactants. The interacting atoms [N1, N(NH2),
and O(SO3NH2)] in all identified transition states fit
almost straight line (∠NNO 171–176°), which is typi-
cal of SN2 reactions [26, 27, 41, 42]. The relative rate
constants for N-amination are linearly related to the
calculated energies of activation Eacalc (Fig. 3).
Fig. 2. Transition states in the amination of (a) 2,2′-bipyri-
dine and (b) 1,10-phenanthroline with O-mesitylenesulfonyl-
hydroxylamine. Some interatomic distances (Å) are given.
logkrel
1.5
Ij
1.0
0.5
VII
Ii
Ic
Ib
Ia
III
0.0
IV
–0.5
–1.0
–1.5
–2.0
VI
V
If
Ig
Ie
II
We showed previously [31] that regioselectivity in
the N-amination of 3-bromo-, 4-methyl-, and 5-nitro-
1,10-phenanthrolines with O-mesitylenesulfonylhy-
droxylamine is determined by the relative stability of
isomeric N-amino cations thus formed. We compared
the relative rates of N-amination of compounds I–VII
with the stability of the corresponding cations. The
relative stabilities of N-amino cations [ΔA(NH2+)] were
Id
35
40
45
50
55
60
65
70
75
Eacalc, kJ/mol
Fig. 3. Correlation between the logarithms of the relative rate
constants for the amination of compounds I–VII and calcu-
lated (DFT/PBE/3z) energy barriers Eacalc; r = 0.99, s = 0.15.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

STRUCTURE–KINETICS RELATIONS HOLDING IN THE AMINATION
901
estimated using the isodesmic reaction shown in
Scheme 2.
[45, 46] and L2 basis sets [47] (PRIRODA software).
Critical points on the potential energy surface were
identified by calculating the corresponding Hessian
matrix [48].
Scheme 2.
The following reagents and solvents were used:
pyrazine (99%), 3-trifluoromethylpyridine (98%), pyri-
dine-3- and -4-carbonitriles (98%), 2,2′- and 4,4′-bi-
pyridines (99%), 1,10-phenanthroline (99%), and iso-
quinoline (99%) from Lancaster, 4-methoxypyridine
(99%) and isovaleric acid (99%) from Acros Organics,
and 4-dimethylaminopyridine (>98%) from Fluka;
DMSO-d6 contained 99% of deuterium. Pyridine, quin-
oline, and 3- and 4-methylpyridines of chemically pure
grade were distilled over potassium hydroxide and
were stored over 4 Å molecular sieves.
+
+
N
N
N
N
NH2
NH2
ΔA(NH2+) = E(1-NH2Az+) + E(Py) – E(Az) – E(1-NH2Py+),
where Az = Ib–Ij, II–VII; Py = Ia.
The results obtained by the DFT/PBE/3z and DFT/
B3LYP/L2 methods are given in table. Comparison of
the logarithms of the relative rate constants for amina-
tion of compounds I–IV, VI, and VII with the
ΔA(NH2+) values calculated by the DFT/PBE/3z
method gave the following correlation**:
Methylene chloride was purified according to
standard procedure [49] by washing with a saturated
solution of potassium carbonate, heating under reflux
with activated charcoal, drying, and distillation over
calcium chloride.
logkrel = (0.023±0.002)ΔA(NH2+) – (0.34±0.06); (11)
r = 0.98, s = 0.21, n = 14.
N-Aminoazinium mesitylenesulfonates VIIId,
VIIIj, and XIII (general procedure). A solution of
~0.75 mmol of O-mesitylenesulfonylhydroxylamine in
2 ml of methylene chloride (preliminarily dried over
anhydrous sodium sulfate) was added dropwise under
stirring at 0°C to a solution of ~0.5 mmol of the corre-
sponding nitrogen-containing heteroaromatic com-
pound in 1 ml of methylene chloride. The mixture was
stirred for 1 h at that temperature and diluted with
10 ml of diethyl ether, and the precipitate was filtered
off, washed with diethyl ether, dried under reduced
pressure, and recrystallized from ethanol (VIIId,
VIIIj) or ethanol–hexane (1:1 by volume; XIII).
Analogous correlation was obtained between logkrel
and ΔA(NH2+) calculated by the B3LYP/L2 method**:
logkrel = (0.022±0.002)ΔA(NH2+) – (0.33±0.06); (12)
r = 0.97, s = 0.23, n = 14.
Thus, amination of nitrogen-containing hetero-
aromatic compounds features some specificity, which
distinguishes this reaction from alkylation of the same
substrates. The effect of substituents in positions 3 and
4 of pyridine ring is well described in terms of correla-
tion analysis. Quantum-chemical calculations at the
DFT level of theory provide quantitative description of
relative reactivity of a wider series of nitrogen-con-
taining heterocycles.
1-Amino-3-trifluoromethylpyridinium mesity-
lenesulfonate (VIIId). Colorless needles, mp 133–
134°C. 1H NMR spectrum (DMSO-d6), δ, ppm: cation:
8.22 d.d (1H, 5-H, J = 8.4, 6.5 Hz), 8.67 d (1H, 4-H,
J = 8.4 Hz), 8.83 br.s (2H, NH2), 9.02 d (1H, 6-H, J =
6.5 Hz), 9.35 s (1H, 2-H); MesSO3–: 2.17 s (3H, CH3),
2.50 s (6H, CH3), 6.75 s (2H, Harom). 13C NMR spec-
trum (DMSO-d6), δC, ppm: cation: 121.1 q (CF3, J =
273.3 Hz), 129.0, 135.7 q (J = 4.5 Hz), 136.0 q (J =
3.0 Hz), 141.0; MesSO3–: 20.2, 22.7 (CH3), 129.9,
135.9, 136.4, 142.5; the C3 signal was not observed
because of its low intensity. 19F NMR spectrum
(DMSO-d6): δF –62.08 ppm. Found, %: C 49.9;
H 4.73; N 7.79. C15H17F3N2O3S. Calculated, %:
C 49.72; H 4.73; N 7.73.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Bruker AC-200 and AV-300 spectrometers at room tem-
perature using DMSO-d6 (δ 2.50 ppm, δC 39.50 ppm)
and CFCl3 (δF 0 ppm) as internal references.
Quantum-chemical calculations in terms of the
density functional theory (DFT) were performed using
PBE [43] and B3LYP/L2 functionals [44] with 3z
** The point for 2,2′-bipyridine was not taken into account, for
its deviation from the calculated value exceeded 2s. A probable
reason is overestimation of the hydrogen bond energy in the
ground state of the N-amino cation in terms of DFT.
1-Amino-4-dimethylaminopyridinium mesity-
lenesulfonate (VIIIj). Colorless needles, mp 162–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

BORODKIN et al.
902
164°C. 1H NMR spectrum (DMSO-d6), δ, ppm: cation:
3.14 (6H, CH3), 6.92 d (2H, 3-H, 5-H, J = 7.0 Hz),
7.14 br.s (2H, NH2), 8.16 d (2H, 2-H, 6-H, J = 7.0 Hz);
MesSO3–: 2.17 s (3H, CH3), 2.50 s (6H, CH3), 6.75 s
(2H, Harom) (cf. [13]). 13C NMR spectrum (DMSO-d6),
δC, ppm: cation: 39.7 (CH3), 107.3, 139.6, 154.9;
MesSO3–: 20.3, 22.8 (CH3), 129.9, 135.9, 136.3, 142.4.
Found, %: C 57.23; H 6.85: N 12.33. C16H23N3O3S.
Calculated, %: C 56.95; H 6.87; N 12.45.
[MesSO2ONH2]0
[Het1]0
R
log 1 –
log 1 –
k1
k2
R + 1
1
krel
=
=
.
[MesSO2ONH2]0
[Het2]0
R + 1
Here, [MesSO2ONH2]0, [Het1]0, and [Het2]0 are the
initial concentrations of the aminating reagent and
heterocyclic substrates, respectively; R = [Het1NH2+]/
[Het2NH2+]. The concentration ratio of the resulting
1
4-Amino-4,4′-bipyridinium mesitylenesulfonate
(XIII). Light yellow crystals, mp 135–137°C. 1H NMR
spectrum (DMSO-d6), δ, ppm: cation: 7.96 d.d (2H,
J = 4.5, 1.7 Hz), 8.47 d.d (2H, J = 5.3, 1.8 Hz),
8.67 br.s (2H, NH2), 8.82 d.d (2H, J = 4.5, 1.7 Hz),
8.88 d.d (2H, J = 5.3, 1.8 Hz); MesSO3–: 2.15 s (3H,
CH3), 2.50 s (6H, CH3), 6.74 s (2H, Harom). 13C NMR
spectrum (DMSO-d6), δC, ppm: cation: 121.5, 125.4,
138.2, 141.2, 146.2, 150.7; MesSO3–: 20.3, 22.8 (CH3),
130.0, 136.0, 136.6, 142.3. Found, %: C 61.68, H 5.79,
N 11.20. C19H21N3O3S. Calculated, %: C 61.44;
H 5.70; N 11.31.
N-aminoazinium cations was determined by H NMR
spectroscopy from the intensities of several non-over-
lapping signals, and the intensity ratios were averaged.
In addition, the data obtained in several parallel runs
were also averaged.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00116-a) and by the Chemistry and Mate-
rials Science Department of the Russian Academy of
Sciences (project no. 5.1.4).
REFERENCES
Preparation of anhydrous O-mesitylenesulfonyl-
hydroxylamine for studying the kinetics of compet-
itive reactions. A solution of 1 g of moist O-mesity-
lene-sulfonylhydroxylamine [18] in 5 ml of methylene
chloride was dried for 1 h over anhydrous sodium
sulfate, the solution was filtered, and the filtrate was
diluted with 20 ml of hexane. The mixture was kept for
3–5 h at –19°C, and the precipitate was filtered off,
dried, and used immediately.
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1
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