Gas-phase pyrolytic reactions of N-ethyl, N-isopropyl, and N-t-butyl substituted 2-aminopyrazine and 2-aminopyrimidine

Article abstract of DOI:10.1002/(SICI)1097-4601(2000)32:7<403::AID-KIN2>3.0.CO;2-P

The rates of gas-phase elimination of N-ethyl (1), N-isopropyl (2), N-t-butyl (3) substituted 2-aminopyrazine and N-ethyl (4), N-isopropyl (5), and N-t-butyl (6) substituted 2-aminopyrimidine have been measured. The compounds undergo unimolecular first-order pyrolytic reactions. The relative rates of the primary:secondary:tertiary alkyl homologues at 600 K are 1:14.4:38.0 for the pyrazines and 1:20.8:162.5 for the pyrimidines, respectively. The reactivities of these compounds have been compared with those of the alkoxy analogues and with each other. Product analyses, together with the kinetic data, were used to outline a feasible pathway for the elimination reaction of the compounds under study.

Full text of DOI:10.1002/(SICI)1097-4601(2000)32:7<403::AID-KIN2>3.0.CO;2-P

Gas-Phase Pyrolytic
Reactions of N-Ethyl,
N-Isopropyl, and
N-t-Butyl Substituted
2-Aminopyrazine and
2-Aminopyrimidine
NOURIA A. AL-AWADI, OSMAN M. E. EL-DUSOUQUI, KAMINI KAUL, HICHAM H. DIB
Chemistry Department, Kuwait University, P.O. Box 5969, 13060 Safat, Kuwait
Received 24 October 1999; accepted 3 February 2000
ABSTRACT: The rates of gas-phase elimination of N-ethyl (1), N-isopropyl (2), N-t-butyl (3)
substituted 2-aminopyrazine and N-ethyl (4), N-isopropyl (5), and N-t-butyl (6) substituted
2-aminopyrimidine have been measured. The compounds undergo unimolecular first-order
pyrolytic reactions. The relative rates of the primary:secondary:tertiary alkyl homologues at
600 K are 1:14.4:38.0 for the pyrazines and 1:20.8:162.5 for the pyrimidines, respectively. The
reactivities of these compounds have been compared with those of the alkoxy analogues and
with each other. Product analyses, together with the kinetic data, were used to outline a
feasible pathway for the elimination reaction of the compounds under study. ᭧ 2000 John Wiley
& Sons, Inc. Int J Chem Kinet 32: 403–407, 2000
INTRODUCTION
In an earlier study, one of the authors showed that both
2-alkoxypyrimidines and 2-alkoxypyrazines react by
a unimolecular first-order thermal elimination process
to give the alkenes and 2(1H)-pyrimidinone and
2(1H)-pyrazinone, respectively, according to the
mechanism shown in Scheme I [1].
Scheme I Cyclic transition state formulation of elimina-
tion pathway of 2-alkoxypyrimidine.
Correspondence to: N. A. Al-Awadi (chesc@kuc01.kuniv.
edu.kw)
Contract grant sponsor: University of Kuwait
Contract grant number: SC 086
The importance of the nucleophilicity of the nitro-
᭧ 2000 John Wiley & Sons, Inc.
gen moiety in the alkoxy-heterocycles and its suscep-

404
AL-AWADI ET AL.
tibility to modification by ring structure has been as-
sessed in part from consideration of the dual pathway
available for transmission of the effect of replacement
substituents in the heteroaromatic ring:
has more carbocationic character, with the two N re-
placement substituents augmenting charge develop-
ment. Examples of gas-phase reactivity of heteroatoms
as replacement substituents in heteroaromatic com-
pounds have been reported [3], and the electron-defi-
cient character of the aza and diazabenzenes has for
sometime been recognized [4]. To provide further in-
sight as to the nature of the transition state of the re-
action, we have in the present study sought to compare
the effect of replacing the oxygen atom of the alkoxy
heterocycles by the NH moiety of the amino analogues
on the rates of pyrolysis of these heteroaromatic com-
pounds. Accordingly, we prepared the ethyl, isopropyl
and t-butylpyrazines and pyrimidines (1–6) and mea-
sured their rates of thermal gas-phase elimination in
what is believed to be the first study of the structural
Further, the spread of rates for the pyrolysis of both
the pyrazines and pyrimidines is found to be wider
than for the pyridines [2]. This suggested that the tran-
sition state for elimination in the former two systems
Table I Kinetic Data and Arrhenius Parameters for Pyrolysis of Compounds (1–6)
Ϫ
1
Ϫ
1
Ϫ1
Cpd.
(1)
T(K)
104 k(s
)
log A(s
)
Ea(kJ mol )
714.4
732.8
750.5
768.8
782.4
786.4
685.5
703.1
721.6
736.9
751.7
764.9
644.8
661.6
678.3
693.5
706.8
719.2
729.4
739.6
755.0
761.9
772.1
786.6
796.7
810.0
726.0
739.6
755.9
771.4
785.7
645.1
666.6
679.7
695.5
708.4
720.2
0.25
0.68
1.68
4.15
7.86
9.45
0.045
1.17
3.04
12.63 Ϯ 0.05
12.28 Ϯ 0.01
11.34 Ϯ 0.01
235.68 Ϯ 0.78
218.20 Ϯ 0.14
202.62 Ϯ 0.15
(2)
(3)
6.51
13.14
24.01
0.08
0.22
0.54
1.19
2.33
4.22
6.78
10.76
1.62
2.26
3.66
7.12
11.14
19.76
5.16
10.06
21.71
43.79
81.75
0.36
(4)
12.21 Ϯ 0.00
231.20 Ϯ 0.04
(5)
(6)
12.49 Ϯ 0.00
12.39 Ϯ 0.00
219.39 Ϯ 0.03
207.92 Ϯ 0.06
1.25
2.58
5.96
11.47
20.46

GAS-PHASE PYROLYTIC REACTIONS OF N-ETHYL, N-ISOPROPYL, AND N-t-BUTYL
405
and electronic effects arising from the replacement of
O (alkoxy group) by NH (amino group) in this type of
compound.
producible first-order kinetics, with strict linearity up
to Ͼ95% reaction over a temperature range of 67 Ϯ
12 K. The homogeneity of the reaction was tested by
comparing the kinetic rate using an empty reaction
tube with that of a similar vessel packed with glass
helices. The results showthat the change in the rate of
reaction was within experimental error. Thus, an in-
crease in surface area of more than 50% caused a neg-
ligible change in reaction rate. It is noteworthy that the
values obtained for the Arrhenius parameters are typ-
ical of polar homogeneous pyrolytic gas-phase reac-
tions [5]. Rates of reaction at 600 K are recorded in
Scheme II.
RESULTS AND DISCUSSION
1
The kinetic data and Arrhenius log A/sϪ and Ea/kJ
1
molϪ for the present series of compounds (1–6) are
given in Table I. The values of log A/sϪ1 lie within a
narrowrange of 12.41 Ϯ 0.21, whereas the values of
the energy of activation vary between 203–236 kJ
1
molϪ . Each of the substrates gave excellent and re-
The rate constants at this temperature allowdi-
rect comparison with earlier results for related com-
pounds and are calculated using the equation: log k ϭ
log A Ϫ Ea/19.148 ϫ 600.
The kinetic data together with the results of analysis
of the products of reaction reveal the following:
2. In both the pyrazine and the pyrimidine series,
the alkylamino compounds are consistently less
reactive than their alkoxy counterparts, involv-
ing rate factors of ca 4.2 ϫ 102 Ϫ 4.2 ϫ 104.
This is explained in terms of the greater contri-
bution to reactivity provided by the more polar
C␣ 9O bond in the alkoxy moiety compared
with the less polar C␣ 9NH bond of the alkyl-
amino group. The effect of bond polarity on rel-
ative reactivity has been observed to followthe
trend: C␣ 9O Ͼ C␣ 9N Ͼ C␣ 9C [6]. Further,
1. The gas-phase elimination reaction of the 2-N-
alkylamino and 2-alkoxypyrazines and their py-
rimidine analogues involve a cyclic 6-mem-
bered transition state (Scheme I).

406
AL-AWADI ET AL.
the polarity of the transition state, as indicated
by the rate ratio of 10 : 20 : 30 N-alkyla-
minopyrazines (ca 1 : 14 : 38) being smaller than
that of N-alkylaminopyrimidines (ca 1 : 21 :
163), is lower for the former group of com-
pounds. This result is to be expected, since elec-
tron withdrawal by the two ortho-N replacement
substituents of the electron-deficient pyrimidine
nucleus is greater than for the ortho- and meta-
nitrogens of the pyrazine isomer. The electronic
effect is both inductive and mesomeric in origin,
and both modes act in favor of the pyrimidine
compounds. The polarity of the transition state
should, therefore, be greater for the pyrimidines,
as appears to be the case. The results for the
considerably more polar transition state of the
corresponding 2-alkoxy analogues indicate
larger magnitudes of relative rates, but closer
ranges of rate ratios: 1 : 27 : 3.7 ϫ 103 for the
alkoxypyrazines, and 1 : 26 : 4.2 ϫ 103 for the
alkoxypyrimidines. Apparently, bond polarity
and the concomitant transition state carbocation
character are advanced well enough in the al-
koxy moiety in both the pyrazine and pyrimi-
dine compounds for the electron-withdrawing
effect of the N replacement substituents to make
much difference to relative reactivity of ana-
logues.
reactor set-up including: (i) HPLC (Bio-rad Model
2700) fitted with a UV/VIS detector (Bio-rad Model
1740); HPLC: Column LC-8, 25 cm, 4.6 mm, 5 ␮m
(Supelco); and CDS custom-made pyrolysis unit for
the thermolysis reactions. The pyrolysis tube is jac-
keted by an insulating aluminum block fitted with a
platinum resistance thermometer and a thermocouple
connected to a Comark microprocessor thermometer.
Kinetic Runs and Data Analysis. Aliquot parts (0.2
ml) of very dilute solutions (ppm) of neat substrates
in acetonitrile as solvent and chlorobenzene as internal
standard were pipetted into the reaction tube, which
was then sealed under vacuum (0.28 mbar) and the
tube then placed inside the pyrolyzer for 600 s at a
temperature where 10–20% pyrolysis is deemed to
occur. The contents of the tube were analyzed using
the HPLC probe.
At least three kinetic runs were repeated for each
5–10ЊC rise in temperature of the pyrolyzer and for
the same time interval until 90–95% pyrolysis was
achieved. The rates were followed over a temperature
range exceeding 55 K, and the rate coefficients were
calculated using the expression for a first-order reac-
tion: kt ϭ ln a0/a. The Arrhenius parameters were ob-
tained from a plot of log k vs. 1/T(K).
Product Analysis
3. The rate factors (Scheme II) of the alkoxy/
alkylamino analogues (k(O)/k(NH)) steadily in-
creases with branching in the alkyl group: 424,
795, 41 640 for the pyrazine series, and 900,
1140, 22 990 for the pyrimidine series. This
trend parallels the relative stabilizing influence
of the alkyl groups on the carbocationic transi-
tion state and reflects the difference in polarity
between the C␣ 9O and C␣ 9NH bonds. The
dramatic drop in the rate factor between the t-
butyl compounds and their ethyl homologues
further confirms the effect of bond polarity and
highlights the much greater stability of the in-
cipient t-butyl carbocation. Similar reactivity
patterns have been reported for compounds of
comparable structure in the alkyl group [6].
Flow Technique. Solutions of substrates in chloro-
benzene were passed down a 1 m reactor column
packed with helices [7]. The column was heated to
temperatures comparable to those used in the kinetic
investigations. The products of pyrolysis were swept
through the column using a stream of nitrogen gas,
and the effluents were trapped in a glass coil sur-
rounded by a jacket of dry ice. The material collected
on the walls of the trap (glass coil) was crystallized
and analyzed by NMR spectroscopy.
Synthesis
2-(N-Ethylamino)pyrazine (1). Reaction of 2-chlo-
ropyrazine in absolute ethanol with a threefold excess
of 2 molar solution of ethylamine in methanol at 110ЊC
for 72 h gave after in vacuo concentration, the amine
hydrochloride salt, which was taken up in ether, fil-
tered, and washed repeatedly with ether. 2-(N-eth-
ylamino)pyrazine (45%) was obtained after concentra-
tion of the ether layer, in vacuo, b.p. 62ЊC at 0.16
mbar. ␦H (CDCl3) 1.1 (3H, t, CH3), 3.3 (2H, q, CH2),
7.0 (1H, s, NH), 7.6–7.9 (3H, m, pyrazine). (Found:
C, 58.6; H, 7.5; N, 33.9. Calc. for C6H9N3: C, 58.5;
H, 7.3; N, 34.1%).
EXPERIMENTAL
Kinetic Studies
Reaction Set-up. Preliminary kinetic results were ob-
tained on a system featuring a Eurotherm 093 pyrol-
ysis unit coupled to a Perkin Elmer Sigma 115 gas
chromatograph. The kinetic data reported are from a

GAS-PHASE PYROLYTIC REACTIONS OF N-ETHYL, N-ISOPROPYL, AND N-t-BUTYL
407
2-(N-Isopropylamino)pyrazine (2). Reaction of 2-
chloropyrazine in absolute ethanol with isopropyla-
mine at 110ЊC for 72 h. gave after in vacuo concen-
tration, the amine hydrochloride salt, which was taken
up in ether, filtered, and washed repeatedly with ether.
2-(N-isopropylamino)pyrazine (40%) was obtained af-
ter concentration of the ether layer, in vacuo, m.p.
53ЊC. ␦H (CDCl3); 1.2 (6H, d, 2Me), 4.0(1H, m,
HCMe2); 6.8 (1H, s, NH), 7.6–7.9 (3H, m, pyrazine).
(Found: C, 61.2; H, 8.2; N, 30.9. Calc. for C7H11N3:
C, 61.3; H, 8.0; N, 30.7%).
crystallization from petroleum ether, m.p. 29–30ЊC,
␦(CDCl3), 1.2 (6H, d, 2Me), 4.1 (1H, m, HCMe2), 6.5
(1H, t, C5-pyrimidine), 6.9 (1H, s, NH), 8.3 (2H, d,
C4- and C6-pyrimidine). (Found: C, 61.5; H, 8.1; N,
30.6. Calc. for C7H11N3: C, 61.3; H, 8.0; N, 30.7%).
2-(N-t-Butylamino)pyrimidine (6). Reaction of 2-
chloropyrimidine with t-butylamine in absolute etha-
nol at 110ЊC for 24 h gave after normal work-up 2-
(N-t-butylamino)pyrimidine (80%) m.p. 69–70ЊC, lit.
m.p. 71ЊC [9].
2-(N-t-Butylamino)pyrazine (3). Reaction of 2-chlo-
ropyrazine in absolute ethanol with t-butylamine at
110ЊC for 15 h in a sealed tube gave after in vacuo
concentration, the amine hydrochloride salt, which
was taken up in ether, filtered, and washed repeatedly
with ether. 2-(N-t-butylamino)pyrazine (36%) was ob-
tained after concentration of the ether layer, in vacuo,
m.p. 86ЊC. ␦H (CDCl3), 1.4 (9H, s, 3Me), 6.7 (1H, s,
NH), 7.6–7.9 (3H, m, pyrazine). (Found: C, 63.9; H,
8.4; N, 27.9. Calc. for C8H13N3: C, 63.7; H, 8.4; N,
27.8%).
The support of the University of Kuwait through research
grant SC 086 and the facilities of Analab and SAF are grate-
fully acknowledged.
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1. Al-Awadi, N. A.; Taylor, R. J Chem Soc, Perkin Trans
1986, 2, 1255.
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Int J Chem Kinet 1997, 29, 289; and earlier papers in the
series.
4. de la Mare, P. B. D.; Ridd, J. H. Aromatic Substitution:
Nitration and Halogenation; Butterworths: London,
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5. Holbrook, K. A. in The Chemistry of Acid Derivatives:
Supplement B, Vol 2; Patai, S., Ed.; Wiley: Chichester,
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6. Al-Awadi, N. A.; Elnagdi, M. H.; Al-Awadhi, H. A.; El-
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2-(N-Ethylamino)pyrimidine (4). Reaction of 2-chlo-
ropyrimidine in absolute ethanol with ethylamine in
methanol at 110ЊC for 5 h gave after normal work-up
2-(N-ethylamino)pyrimidine (90%) m.p. 49–50ЊC.,
lit. m.p. 50–51ЊC [8].
2-(N-Isopropylamino)pyrimidine (5). Reaction of 2-
chloropyrimidine with isopropylamine in absolute eth-
anol at 110ЊC for 18 h gave after in vacuo concentra-
tion, the amine hydrochloride salt, which was taken up
in ether, filtered, and washed repeatedly with ether. 2-
(N-isopropylamino)pyrimidine (80%) was obtained
after in vacuo concentration of the ether layer and re-