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Electrophilic Substitution of Heteroaromatic Compounds with Six-Membered Rings.

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Electrophilic Substitution of Heteroaromatic Compounds with Six-Membered
Rings I**’
BY A. R. KATRITZKY AND C. D. JOHNSON 1’1
IN COLLABORATION WITH
G. P. BEAN, P. BELLINGHAM, P. J. BRIGNELL, B. J. RIDGEWELL, N. SHAKIR, 0. TARHAN,
M. VINEY, AND A. M. WHITE
The limited amount of quantitative data available on the electrophilic substitution of
heterocycles is surveyed. Initial objectives are first to determine the species undergoing
substitution and then to find out the amount by which the heterocyclic atom or group
activates or deactivates the ‘ring by comparison with the corresponding benzenoid compound. When suflcient data’are availabk it is hoped to correlate this by means of-a Haiiimett-type treatment or by MO methods.
The mechanism of electrophilic substitution in benzenoid compounds is now comparatively well understood
and the subject has been comprehensively reviewed 111
On the other hand our knowledge of the mechanism
of heteroaromatic electrophilic substitution is meager
and it was therefore considered important to study
this mechanism both to rationalize the mass of qualitative information, and to aid the prediction of the
feasibility of new reactions.
For example it is a familiar fact that the nitration of
pyridines proceeds only under vigorous conditions
and that product yields are poor. At present it is
not known whether this is due to the low reactivity
of the positively charged conjugate acid of pyridine
toward the electrophile NO2@,or whether the rea-tion
took place on the very small amount of free base
present under the strongly acidic conditions.
The present review summarizes the results obtained in
our studies together with results obtained by other
workers, notably J. Ridd at University College, London, and K. Schofield at the University of Exeter.
There are two major questions to be answered regarding the quantitative aspects of the substitution of heterocycles: 1) What species are involved; for example
as above does the heterocyclic compound react in the
form of free base or as the conjugate acid? 2) In what
way does the annular heteroatom affect the rate of
substitution at carbon atoms in the various ring
positions?
Several criteria may be used to decide which species is
reacting:
[*I Prof. A. R. Katritzky and Dr. C. D. Johnson
School of Chemical Sciences, University Plain
University of East Anglia
Norwich, Norfolk (England)
[**I Based on lectures given at the Heterocyclic Conference for
College Teachers, Bozeman, Montana; I. C. I. Petrochemical and
Polymer Laboratory, Runcorn ; University of California, Los
Angeles; Groningen, Warsaw, Berlin, Rome, Exeter, and elsewhere, 1964-1967.
[l] C. K. Ingold: Structure and Mechanism in Organic Chemistry. Cornell University Press, New York 1953, Chapter VI.
608
l a ) The most direct is to compare the kinetic rate with
that for model compounds in which the possibilities of
ionisation or tautomerism are eliminated.
l b ) The “rate profile” may be determined, i.e. the
manner in which the rate depends on the acidity of the
medium. Then, if the manner in which the ratio of the
concentration of base to conjugate acid varies over the
acidity range in question is known (i.e. the acidity
function followed by the base), the theoretical change
of rate for reaction via each of the possible reacting
forms may be calculated and compared with that
found.
lc) The entropy of activation, determined by Arrhenius plots, is expected to be considerably greater
for reactions between two singly charged species of the
same sign (Frosl and Pearson predict [21 ca. -20 e.u.)
than for reaction between a neutral species and one
with a single charge.
Id) The encounter rate criterion can be applied in
those cases where the concentration of a free base in a
strongly acid solution is so low that, even if every
molecalar collision resulted in reaction, the calculated
reaction rate would be lower than that measured. This
limiting rate, the encounter rate, is given by:
(where 3 is the viscosity of the medium, k is Boltzmann’s constant, N is
Avagadro’s number, and rA and rB are the radii of the ions).
The rate constant (k’) for reaction on the free base
may be calculated from
n log k‘ = n log k
(where n is unity for a Hammett base
constant).
[‘I, and
+ pKa-Ho
(2)
k is the observed rate
121 A. A. Frost and R. G. Pearson: Kinetics and Mechanism.
Wiley, New York 1953, p. 132.
[ * ] Such Hammet bases are defined in [ 8 ] ; reference base is e.g.
o-nitroaniline.
Angew. Chem. internat. Edit.
Vol. 6 (1967) NG. 7
When the nature of the reactive species in an electrophilic substitution has been elucidated, the question
of the quantitative effect of the heteroatom can be
considered. The rate of reaction for a heterocyclic
compound is compared with that for the correspondingly substituted benzene at the same temperature (to
d o this, considerable extrapolation is often required).
The effect of the heteroatoni may be treated in two
main ways:
2a) The Hammett equation approach 131 attempts to
assign Hammett sigma constants op and om to each
\
\
obtained showed that the reaction was a first order
reaction and that it occurred, as is suggested by the
following criteria, on the conjugate acid:
a) 1,2,4,6-Tetramethylpyridinium ion ( 1 ) reacted
slightly faster than the 2,4,6-trimethylpyridine (2) ;
an N-methylpyridinium cation would be expected to
react faster than the corresponding protonated pyridinium cation, just as a methyl group causes a rate enhancement in benzenes.
c Ii,
&
\
type of hetero group (e.g. ,N, ,N@H, ,O@, >N@-Oo,
erc.) and a p value for each type of electrophilic substitution.
2b) The molecular orbital approach [41 assigns to each
heteroatoni X a Coulomb integral CI,
and for bonds
C-X a resonance integral p,. These values are used to
derive a variety of molecular orbital parameters with
which the partial rate factors may be compared.
As yet there are insufficient data for the application of
either of the above approaches. It is the aim of work
being presently carried out to remedy this deficiency,
and to enable a test of some of the diverse theoretical
treatments which are possible.
A. Pyridines
Extensive preparative work on the electrophilic substitution
of pyridines has been reviewed by Abramovitch 151. The strongly deactivating and metu-directing influence of the heteroatom is apparent; other substituents exert influences qualitatively similar to their behavior in benzenoid systems. A complicating factor is the catalysis caused by various metal salts
which is thought to result from coordination of the metal
with the pyridine nitrogen atom and possible back-donation
of electrons to the ring.
c €i3
€13C NI'
CH,
H,C
c H,
&
'N
H,
(2)
(1)
b) Plots (cf. Fig. 1) show that log k increased linearly
with -Ho, slopes of 0.45 to 0.77 being found. Although
these slopes are smaller than those found for benzenoid
derivatives [71, the evidence indicates that the magnitudes of the slopes increase as the temperature is lowered, and rough extrapolations give reasonable roomtemperature slopes. Further, the slopes for the bases
and the N-methyl derivative ( 1 ) are similar. If reaction
had been occurring on the free base, the variation of
rate with acidity would have been much less, as the increasing activity of hydrogen ions (H+ and T+) would
be counterbalanced by a decreasing amount of free
base available for reaction.
-22
i \
1. Acid-Catalysed Hydrogen Exchange
Acid catalysed hydrogen exchange of pyridines was
initially studiedt6.101 by use of tritium as a tracer.
Although pyridine and 4-picoline were found to be
unreactive under the most vigorous conditions studied,
exchange proceeded smoothly with 2,6-di- and 2,4,6tri-methylpyridine. The reactions were investigated by
heating aliquots of sulfuric acid, tritiated water, and
the substituted pyridine at predetermined temperatures in sealed tubes for a known time. The base was
isolated as the picrate, and the water produced on
combustion of the picrate was monitored. The results
[3] H. H. Jafe and H. Lloyd Jones in A. R. Kutritzky: Advances
in Heterocyclic Chemistry. Academic Press, New York-London,
1964, Vol. 3, Chapter 2.
[4] J . H. Ridd in A . R. Kutritzky: Physical Methods in Heterocyclic Chemistry. Academic Press, New York-London 1963,
Vol. 1, p. 209.
[ S ] R . A. Abramovitch and J. G. Sahain A. R . Katritzky: Advances
in Heterocyclic Chemistry. Academic Press, New York-London
1966, Vol. 6.
[6] A. R . Katritzky and B. J. Ridgewell, J. chem. SOC.(London)
1963, 3143.
Angew. Chem. internat. Edit.
1 Vol. 6 (1967) J No. 7
L
I
-
-8 2
-72
Ho
Fig. 1. Rate profiles for the acid-catalysed hydrogen exchange of 2.4.6trirnethylpyridine.
c) Calculated colIision frequency factors, assuming
reaction woceeds on the free base, are quite unreasonable, and exclude reaction via the free base (for details.
examples, and discussion cf. [61).
Rate comparisons with benzenoid compounds to obtain
63
values for the deactivating effect of the =NH- group, as
compared with =CH-, are as yet approximate because of
lack of data, but indicate a deactivating factor of ca. 10-18
at the meta position.
[7] V. Gold et al., J. chem. SOC.(London) 1965, 3609.
609
The acid-catalysed hydrogen exchange of aminopyridines is
potentially more complicated. Here reaction could occur via
free base, first conjugate acid, or second conjugate acid. For
ideal behavior, where equilibrium and kinetic protonation
both follow Ho, we should expect a rate profile as in Figure 2.
l2
t
0'
I
-8
-10
-9
Ho
Fig. 3. Rate profile for the nitration of 2,4,6-trimethylpyridineat 101 "C.
P!,"
I
0
pH-
Hn
-
Fig. 2. Idealized rate profile for acid-catalysed hydrogen exchange of
various highly protonated aromatic bases.
A: free base; B: first conjugate acid; C: second conjugate acid.
For other cases it can be shownC7al that for exchange on a
species, the concentration of which is not changing rapidly
with acidity, slog kl6Ho = 6HJ6Ho where Hx is the acidity
function for kinetic C-protonation. For exchange of a species
mainly present as its conjugate acid:
where Hy is the acidity function followed for equilibrium
protonation of the species in question. The study of the hydrogen exchange of 4-amino-, 4-amino-2,6-dichloro-, and 2amino-5-methyl-pyridine has shown rate profiles corresponding to the portions b-c, c-d, and d-e of Figure 217=l.
The above treatment requires assumptions about the acidity
functions followed by pyridines, and the variation of acidity
functions with temperatures. Polyhalogeno-pyridines have
been shown to be Hammett bases[*]. Available data on the
effect of temperature on acidity functions is sparse and does
not include observations for temperatures above 80 "C.
There is an indication, however, that such effects are neither
large nor discontinuous [91.
2. Nitration
with acidity. For nitration as free base a different
shape is expected; the curve should be tilted in a clockwise direction because of the decreasing concentration
of the substrate available for nitration as the acidity
increases (cf. Fig. 4). In addition, calculated encounter
rates show that there is insufficient free base present
for its nitration to explain the results obtained. Again,
rate comparisons with benzenoid compounds are complicated by lack of data, but a rough estimate gives a
deactivating factor of ca. 10-12 for =NH@at the meta
position; however, derivation of this value necessitates
assumptions regarding the constancy of the effect of
methyl groups.
Nitration of a pyridine derivative via the free base
might be expected (if the basicity of the pyridine
nitrogen were low).
2,6-Dichloropyridine (pKa = -2.8 181) was found to
undergo nitration in the 3-position smoothly at 100O C ,
and 3 partial rate profile for nitration at this position,
(3)122 7°C ( x = 3)
\
3
m
1,2,4,6-Tetramethylpyridinium ion can be nitrated
under the same reaction conditions as 2,4,6-trimethylpyridine, indicating that the latter compound reacts
as the conjugate acidrll]. This is confirmed by the
kinetic results; a rate profile for 2,4,6-trimethylpyridine at 101.3 "C is shown in Fig. 3. The general shape
of the plot indicates conjugate acid nitration. This
shape is characteristic1121for a nitration in which the
substrate concentration does not change significantly
[7a] G. P. Bean, C. D . Johnson, A . R. Katritzky, B. J. Ridgewell,
and A. M . White, J. chem. SOC.(London), in press.
[8] c! D . Johnson, A. R. Katritzky, B. J. Ridgewell, N. Shakir,
and A . M . White, Tetrahedron 21, 1055 (1965).
191 A . I. Gel'bshtein, G. G. Shcheglova, and M . I. Temkin, 2.
neorg. Chirn. I , 596 (1956).
[lo] C. Muntescu and A . T.Buluban, Canad. J. Chem. 41. 2120
(1963).
[ll] A. R. Katritzky and B. J. Ridgewell, J. chem. SOC.(London)
1963, 3882.
1121 P. B. de la Mare and J. Ridd: Aromatic Substitution. Butter-
worths, London 1959, p. 64.
610
1
-8
-9
-10
a Ho
Fig 4. Rate profiles for the first and second nitrations of 2,ddimethoxypyridine (the broken curve was calculated for the free base).
together with a low entropy of activation (-10 e.u. in
98.3 % €I2SO4), indicated reaction as the free base. 2,6Dimethoxypyridine (3) could be nitrated to yield
successively the 3-mono- ( 4 ) and 3,s-di-nitro derivative ( 5 ) [131. The rate profiles (Fig. 4) show that the
first of these nitrations occurs on ihe conjugate acid
of 2,6-dimethoxypyridine, and that the introduction
of the first nitro-group lowers the basicity such that
1131 C. D. Johnson, A. R. Katritzky, and M . Viney, J. chem. SOC.
(London), in press.
Angew. Chem. internat. Edit. f Val. 6 (1967) f Nu. 7
H 3 C 0f i ONC
important discoveries in pyridine chemistry, and led
to further work on the electrophilic substitution reactions of pyridine N-oxides [ S , 171.
H3
(3)
(5)
(4)
sufficient of the free base of (4) is present for it to
compete successfully with the corresponding conjugate
acid in the second nitration stage.
Fig. 4 also shows a “corrected” line which has been obtained
from the conjugate acid curve by incorporating the concentration of free base, assuming that it is still a Hammett base at
these acidities. This closely parallels the curve obtained for 3nitro-2,6-dimethoxypyridine,indicating that the latter undergoes further nitration via the free base, or conversely, we may
consider it as an indication that pyridine compounds follow
the Hammett acidity function in very strong sulfuric acid
medium.
By measuring the rates of nitration of 1,3-dichloro- and 1,3dimethoxy-benzene, the deactivation relative to benzene of
the >N “substituent” may be calculated. These rates have
been measured, giving vatues of
The electrophilic substitutions
of pyridine N-oxide
t o yield the 4-nitro derivative on nitration, but the 3SulfoniC acid on sulfonation, has given rise to some
speculation. Kinetic evidence is now available which
Q
1
OH
(9)
I
log
kp (dichlorobenzene)
___=
kZ (dichloropyridine)
1.5 and log
kz (dimethoxybenzene)
- =2.3;
k2 (dimethoxypyridine)
where kz is the bimolecular rate constant.
These values are far smaller than is expected, and suggest that
the same substituent may exert a different mesomeric effect
in the pyridine than in the benzene system.
3. Bromination C141
5-Substituted 2-aminopyridines (6) are brominated
smoothly at the 3-position in aqueous sulfuric acid
and the rates may be conveniently measured by the
decrease in the bromine/bromide potential. At acidities
in the range +0.5 (pH) to -3.5 (H,) straight line rate
profiles with approximately unit slopes are found,
indicating that bromination is occuring on the free
base species (6),and not on the conjugate acids (7).
xrJ
$ NH2
xQNH2
(7)
(6)
proves that 4 substitution is a reaction of the free base
(8),and that 3 substitution occurs on the conjugate
acid (9). This evidence is detailed below.
1. Acid-Catalysed Hydrogen Exchange r
1 9 ~ ~
Hydrogen exchange in 2,4,6 trimethylpyridine N oxide was found to proceed smoothly in the 3- and 5positions at 200 “C without decomposition. Plotting
log k against Ho gave a slope of 0.35 which, although
less than the slopes for the pyridine series, nevertheless
suggests that exchange proceeds through the conjugate
acid. Entropies of activation are consistent with this
conclusion. Attempts to measure the exchange on 1methoxy-2,4,6-trimethylpyridiniumion failed due to
decomposition of this substrate. 2,6-Dimethylpyridine
N-oxide proved difficult to study because of concurrent decomposition ; however, exchange was shown to
occur in the 3-position at an Ho of -8.15. There is
some indication from the NMR spectrum that at
sufficiently low acidities there is a change in mechanism leading to exchange in the 4-position.
3,5-Dimethylpyridine N-oxide was found to undergo
ready exchange of the 2- and 4-position protons.
X = CH,, C1, NO2
By comparison with corresponding para-substituted
anilines, it is found that the \N “substituent” de/
activates by a factor of ca. 0.54 for this particular
reaction 1151.
Numerous examples of other electrophilic substitution reactions are known to occur in pyridines, but no kinetic work
has been carried out on them. The qualitative work reported
has been well reviewed by Abrarnovitch [51 and includes sulfonation, mercuration, nitration and diazo coupling.
I
+I
B. Pyridine N-Oxides
The discovery by Ochiair161 that pyridine N-oxide is
easily nitrated in the 4-position was one of the most
__
[14] P. J. Brignell, P. E. Jones, and A . R . Katritzky, unpublished
work.
[151 R. P . Bell and E. N . Ramsden, J. chem. SOC. (London) 1958,
161 ; R. P . Bell and T. Spencer, ibid. 1959, 1156; R . P. BeN and
D. J. Rawlinson, ibid. 1961, 63.
[16] E. Ochiui, J. org. Chemistry 18, 534 (1953); A . R. Katritzky,
Quart. Rev. (Chem. SOC.,London) 10, 395 (1956).
Angew. Chem. internat. Edit.
Vol. 6 (1967) J No. 7
I
0
-
I
-L
pH.Ho
Fig. 5. Rate profile for the acid-catalysed hydrogen exchange of
methylpyridine N-oxide.
I
-a
3,5-di-
[17] A . R . Katritzky and J . M . Lagowski: N-Oxides. Methuen,
London, in press.
[I81 T . Okamoto and T . Kawazoe, Bull. chem. SOC.Japan 1964,
1384.
[191 C. D . Johnson, A . R. Katritzky, and A . White, J. chem. SOC.
(London), in press.
I201 A . R. Katritzky, B. J. Ridgewell, and A . M . White, Chem.
and Ind. 1964,1576.
61 1
Exchange rates for these positions vary little with
acidity (Fig. 5 ) ; the rate profiles rescemble that for4pyridone (Fig. 7), which is known to exchange as the
free base (see section C 1). At low acidities the exchange rate at the 2-position increases rapidly, probably due to the formation of increasing amounts of
zwitterions of type X; similar zwitterions are formed
by deprotonation of pyridine N-oxide itself 1181.
Comparison of rates of exchange of 2,4,6-trimethylpyridine and 2,4,6-trimethylpyridine N-oxide indicates
that >N@-OH is slightly more deactivating than
‘Nf H; this is probably due to the electron-attracting
/
effect of the hydroxyl group [201.
Preliminary studies have also been made on 3-hydroxypyridine, for which the rate profile shows that reaction
proceeds via the free base. It is not yet certain, however, whether the 2- or 6-hydrogen is exchanging [191.
3,5-Dimethoxypyridine N-oxide exchanges in the 2position; below about Ho -3.5, the reaction proceeds
via the free base, and at higher acidities on the conjugate acid [19J.
2. Nitration
Schofield has shown that the N-methoxypyridinium
cation does not undergo nitration under the conditions
which allow easy reaction of pyridine N-oxide and
concluded that the latter is nitrated as the free base [211.
lower basicity than those originally reported modified
this conclusion and showed that the pyridine N-oxides
follow approximately the HAfunction1251. Adjustment
of the rate profiles (Fig. 6), using this information to
correct for the variation in concentration of free
base, gives a curve which is similar in shape to that
obtained for the concentration of nitronium ion, confirming reaction via the free base.
Nitration of a pyridine N-oxide in the 3-position was
achieved in the case of the 2,6-dimethyl-4-methoxy
derivative (11) + (12); here the rate profiles indicateIl31 nitration on the conjugate acid. The partial
rate factor for nitration at the 4-position in pyridine
N-oxide is estimated as lO-4[2ll. Nitration in the 2position has also been achieved[21al221 in the case of
3,5-dimethoxypyridine N-oxide (13). The 3,Sdirnethoxy-2-nitropyridine N-oxide (14) then undergoes 6rather than 4-nitration to yield the 2,6-dinitro compound (15). Rate profile data indicate that reaction in
both cases is via the conjugate acid.
H3’
3. Substitution Orientation
\
I
-8
-9
-
-10
-11
HO
Fig. 6. Rate profile for the nitration of pyridine N-oxides [A: 2,6-dichloropyridine N-oxide; B: pyridine N-oxide; C: 3,s-dimethylpyridine
N-oxide; D: 3,5-dichloropyridineN-oxide]. The broken curve represents
the corrected rate profile ( H A function) forl2.6dichloropyridine Noxide.
The rate profiles have been measured (Fig. 5)[221 for
the nitration of 2,6-dichloro-, 3,5-dichloro-, and 33dimethylpyridine N-oxide together with that for the
parent compound. A recent paper 181 indicates that
pyridine N-oxides are Hammett bases; a reappraisal
of this work involving pyridine N-oxides of much
1211 R . B. Moodie, K. Schofield, and M . J . Williamson, Chem.
and Ind., 1964, 1577.
[21a] H . J . den Hertog, M . van Ammers, and S. Schukking,
Recueil Trav. chim. Pays Bas 74,1171 (1955).
[22] C. D . Johnson, A . R. Katritzky, and X. Shakir, J. chem. SOC.
(London), in press.
612
The nitration of pyridine N-oxides occurs preferentially in the 4-position while the slower, and therefore
usually more selective, reaction of electrophilic hydrogen exchange attacks the more abundant but less
reactive conjugate acid molecule in the 3-position. A
possible explanation for this difference in substitution
orientation is that the electron withdrawing effect of
the nitro group in the Wheland intermediate (16) for
4-substitution is acceptable, whereas this inductive
effect causes a large decrease in stability for the doublycharged Wheland intermediate (17) for 3 substitution.
I
OH
(17)
In these reactions, the transition state is probably close
to the Wheland intermediate, and it could be that the
inductive effects mentioned cause nitration to proceed
via (16) whereas acid-catalysed hydrogen exchange
can occur via (17).
Angew. Chem. internat. Edit. 1 Vol. 6 (1967) 1 No. 7
As a test of this hypothesis weI231 measured the first
and second pK, values of the pyrimidines (18) and
(19). The structure of the mono- and di-cations are of
types(20) and (21) [23al; a larger effect of the nitro group
on the second pKa than on the first PIC; would be expected if the above hypothesis were valid. The effect
on the second pKa due to the nitro group is 1.0 p K
unit greater than its effect on the first pKa, which is in
the right direction, but smaller than expected.
-1 I
-6
,
L
0
-4
1
I
-8
-12
~H.HD
t-
Fig. 7. Rate profile for the acid-catalysed hydrogen exchange of
Ppyridone (23) and for I-methyl-4-pyridone (continuous line).
C. Pyridones and Pyrones 124.261
The mechanism of substitution of the pyridones is of
particular interest both because of the ease with which
such compounds are attacked by electrophiles and
because of the large number of forms which could
undergo reaction. For 4-pyridone these include the
anion (22), the 0x0 form (23), the hydroxy form (24)
and the cation (25).
00
(22)
Q
(23)
facts show that 4-pyridone undergoes reaction on the
0x0 form (22). The hydroxy form is further excluded
by encounter rate calculations, which were made
assumin2 that N-protonation of the hydroxy form
(24) would follow the Hammett acidity function and
that 0-protonation of the 0x0 form (19) would follow
the amide acidity function (HA)1251.
Consideration of the rate of ex-hange of the phenoxide anion shows ihat the introduction of N H @ for
CH in this ion meta to the reacting site lowers the rate
by a factor of about 107.
Preliminary studies of deuterium exchange in the 3position of 5-methyl-2-pyridone (26) and in the 5position of 3-methyl-2-pyridone (27) indicate that in
both these cases also the reaction proceeds via the
neutral 0x0 form shown.
It has also been shown that 4-quinolone at low acidities (Ho ( - 7 ) exchanges as the neutral species (29)
at the 3-position. On increasing the acidity, reaction
via the conjugate acid occurs successively in the 3-, 6-,
8-, and 5-positions (30).
N
''
1. Acid-Catalysed Hydrogen Exchange
Rate profiles for the deuteration of 4-pyridone at two
temperatures (Fig. 7) show that the rate varies by less
than a factor of 4 over 14 logarithm units of acidity
(pH=4 to H, =-lo). This indicates that the reaction
proceeds via a neutral form of pyridone; a conclusion
which is supported by the low entropy of activation
(ca. -8. e.u.).
The rate profile of I-methyl-4-pyridone (Fig. 7) is
similar to that of 4-pyridone, whereas 4-methoxypyridine does not react under these conditions: these
1231 P. J . Brignell, A. R. Katritzky, and 0 . Tarhan, unpublished
work.
[23a] A . R . Katritzky and J. M . Lagowski in A . R . Katritzky:
Advances in Heterocyclic Chemistry. Academic Press, New YorkLondon 1963, Vol. 1, p. 339.
[24] P . Bellingham, C . D . Johnson, and A . R . Katritzky, Chem.
and Ind., 1384 (1965).
Angew. Chem. internat. Edit. / VoI. 6 (1967) / No. 7
For 2,6-dimethyl-4-pyridone there is a changeover
from conjugate acid to free base reaction on lowering
the acidity to H, = -3 which indicates a deactivation
of ca. l o 7 on protonation.
Investigation of the hydrogen-exchange reactions of pyrones
and thiopyrones is also being carried out 1261.
4-Pyrone is converted to the 3,5-dideuterio-derivative(28) in
neutral or weakly acidic solution; however, this reaction is
not a simple electrophilic substitution [271, but proceeds via
a base-catalysed mechanism.
[25] A . R . Katritzky, A . J. Waring, and K. Yates, Tetrahedron 19,
465 (1963).
[26] P . Bellingham, C. D . Johnson, and A . R. Katritzky, J. chem.
SOC.(London), in press.
1271 P . Beak and G . A. Carls, J. org. Chemistry 29, 2678 (1964);
D . W . Mayo, P . J. Sapienza, R . C. Lord, and W. D . Phillips, ibid.
29, 2682 (1964).
613
Preliminary results indicate that compounds (31a) and (31b)
exchange as the conjugate acids.
/31u/, 2 = 0
(316). Z = S
2. Nitration 1231
4-Pyridone can be nitrated in mixed acids to yield
successively 3-nitro- (32) and then 3,5-dinitro-4pyridone. A spectrophotometric study of the first
nitration gave a rate profile (Fig. 8) indicating reaction
(32)
(33)
on a species whose concentration was not altering
significantly in the range Ho = -8.2 to -10.5. This can
only be the conjugate acid (25) ;a conclusion supported by the large negative entropy of activation (-20.3
e.u.) found from an Arrhenius plot at Ho = -9.33.
The nitration rate was found to be comparable with
that for the nitration of 4-methoxypyridine, and that
for 1-methyl-Cpyridone.
Maitlis[2*] using MO methods, but this work is outside the scope of the present review. Data enabling the
determination of the nature of the species reacting,
and absolute partial rate factors are very much more
sparse. In addition, as discussed in detail by Riddr41,
only very limited success has attended attempts to
correlate available rate data with MO parameters.
Austin and RiddC291 have examined the kinetics of
nitration of quinoline, which yields 5- and 8-nitroquinoline in approximately equal amounts. The slope
of the rate profile, encounter-rate calculations, and the
entropy of activation (-19.3 e.u.) in reactions with
85-98% sulfuric acid, all indicate that the reaction
proceeds via the conjugate acid. Stepwise comparisons
led to partial rate factors of ca. 10-7. Independent work
by Schofield et al. confirmed these conclusions by investigations in the lower acidity region (71 -84 P:, sulfuric acid); they also reported results for N-methyl
quinolinium ions Q11. Similar work [21,301 with isoquinoline and the N-methylisoquinolinium cation
again indicated reaction via the conjugate acid.
Schofield has also examined the nitration in the 5- and
8-positions of isoquinoline N-oxide in the acidity
range 76.4-83.1 % sulfuric acid. This compound has a
rate profile which indicates reaction via the N-hydroxyisoquinolinium cation; this is borne out by the
similar kinetics found for N-methoxyisoquinolinium
perchlorate [211.
Johnson and Ridd [3*1 have clarified the mechanism
whereby N-cyanoquinolinium ion (34) with aqueous
solutions of bromine gives 3-bromoquinoline (39).
The reaction involves intermediate formation of the
pseudo-base 1-cyano-l,2-dihydro-2-hydroxyquinoline
(35), which then undergoes bromination via an addition elimination ((35)
(36)) rather than a substitution mechanism, although straightforward electrophilic substitution may occur with excess bromine in
the benzene ring, finally yielding 3,6-dibromoquinoline (37).
J . Ridd et al. have demonstrated a 100-fold enhansement of the rate of nitration of o-phenanthroline [321 at
--f
I
-8
-9
I
I
-10
-11
Ho
F i g . 8.
Rate profile for the nitration of 4-pyridone (23) at 86 "C.
It is of interest that 4-pyridone is nitrated as theconjugateacid
within an acidity range in which it undergoes acid-catalysed
hydrogen exchange as the free base. This must be due to the
greater selectivity of the hydrogen-exchange reaction compared to the nitration ahich involves the more reactive NOze
ion. This behavior serves to emphasize the abnormality of
the reverse sequence already described for the pyridine Noxides.
D. Polycyclic Heteroaromatic Compounds
with Six-Membered Rings
Much work has been done in determining the position
of substitution in polycyclic heteroaromatics, and in
some cases accurate ratios of the various isomers
formed have been determined. The positions of substitution within individual compounds have been
correlated with considerable success by Dewar and
614
(34)
(35)
'N
(37)
(38) C N
/
CN
(36)
(39)
[28] M. J. S. Dewar and P. M. Muitlis, J. chem. SOC.(London)
1957, 2.521.
(291 M. W. Austin and J. H . Ridd, J. chem. SOC. (London), 4204
(1963).
[30] R. B. Moodie, K . Schofield, and M . J. Williamson, Tetrahedron 20, Suppl. 1, 89 (1964).
[31 J M . D . Johnson and -7. H . Ridd, J. chem. SOC.
(London) 1962,
283, 291.
[32] A. F. Richards, J. H. Ridd, and M . L. Tobe, Chem. and Ind.
1963, 1721.
Angew. Chem. internat. Edit.
1 VoI. 6 (1967) / No. 7
the 5-position over that of the parent compound by
coordination with cobalt(1n) cations. Studies are in
progress to determine whether the difference in reactivity derives from reduction of the effective charge on
the nitrogen or whether there is also an important
degree of x-electron donation to the ring from the
filled Co de orbitals.
E. Conclusion
Phenazine 5-oxide undergoes nitration at the 3-(and
to a minor extent the 1-)position; kinetic criteria show
that the monocation (40) is the reactive speciesL331.
Very much remains to be accomplished. On the experimental side it is necessary to gain quantitative data
as to the effect on rate of substitution (by a wide variety
of electrophiles) of the replacement of a CH-group by
an uncharged nitrogen atom, by various types of
group incorporating a partially charged nitrogen
(N@H,Ne-00, N@- R,N@-OH,etc.), and by charged
==S@- or =O@-. Only when more is known of the effects of these replacements towards the ortho, meta, and
para positions, as well as effects relayed from one ring
to another, will it be possible to develop and test the
theoretical treatments, and, hopefully, to gain a real
understanding of the field.
[33] A . R. Katritzky and B. Swedlund, unpublished.
Received: February 28th, 1966; revised: March 10th. 1967 [A 579 IEI
German version: Angew. Chem. 79,629 (1967)
AcetylcholinesteraseI**
BY N. ENGELHARD, K. PRCHAL,, AND M. NENNER I*]
Acetylcholinesterase plays a vifalpart in the functioning of nerves, andseriousphysioIogica1
damage arises from its blockage by esters ofphosphonic andphosphoric acid used e.g. in
pesticides. The properties and the mechanism of action of acetylcholinesterase, which
show many similarities to those of other hydrolases, are described. Therapeutic agents
(reactivators) for the toxic phosphorus compounds specified are also discussed.
A. Introduction
The mechanism by which impulses are conducted
along nerves and transferred from one nerve to another
or to an end organ entails a complex interplay of electrical and chemical processes 11-33.
A nerve cell or neuron ordinarily consists of a nucleated
cytoplast, short and extensiveiy branched fibers (dendrites)
projecting from it together with a filament (axon or neurite),
up to 1 m long and generally branched at its end, and finally
a membrane enveloping a11 these. During the conduction of
a n exciting impulse, an electric potential (action potential)
travels along the neuron. This potential is produced by
I
[*I Dr. N. Engelhard
Physiologisch-chemisches Institut der Universitat Gottingen,
Strahlenbiochemisches Laboratorium
Present address:
Merle Allee 45
5301 Rottgen (Germany)
Dip1.-Chem. K. Prchal
Breddestr. 17
43 Essen (Germany)
Dip1.-Chem. M. Nenner
Physiologisch-chemischesInstitut der Universitat Gottingen,
Strahlenbiochemisches Laboratorium
Humboldtallee 7
34 Gottingen (Germany)
[**I Delivered in part as a lecture on June 2nd, 1964, at the
Medizinische Forschungsanstalt der Max-Planck-Gesellschaft,
Gottingen and on May 19th, 1965, at Max-PIanck-Institut fur
Kohlenforschung, Abteilung Strahlenchemie, Muhleim/Ruhr.
Angew. Chem. internat. Edit.
1 Vol. 6 (1967) No. 7
selective diffusion of Na+ and Kt through the membrane, as
a result of which the concentration of these ions is changed
on either side of the membrane. The transfer of an impulse to
other excitable elements (neurons, muscles, or glands) occurs
at meeting places (synapses) between the axons of one nerve
[l] For reviews of neuro-physiology and -chemistry, see: a) J.
P. Schade‘ and D . H . Ford: Basic neurology, an introduction to
the structure and function of the nervous system. Elsevier, Amsterdam-London-New York 1965;b) W. Blasius in Landois-Rosemann: Lehrbuch der Physiologiedes Menschen, 28 th Edit., Urban
u. Schwarzenberg, Munchen-Berlin 1962, Vol. 2, p. 629; c ) H.-D.
Henatsch in [I b], Vol. 2, p. 547; d) A. Y. Muralf : Die Signalubermittlung im Nerven. Birkhauser, Base1 1946; e) Neue Ergebnisse
der Nervenphysiologie. Springer, Berlin-Gottingen-Heidelberg
1958; f) J. C. Eccles, Ergebn. Physiol., biol. Chem. exp. Pharmakol. 51, 299 (1961); g) The physiology of synapses. Springer,
Berlin-Gottingen-Heidelberg 1964; h) A . L. Hodgkin, Angew.
Chem. 76, 661 (1964); i) A . F. Huxley, ibid. 76, 668 (1964);
k) J. C. Eccles, ibid. 76, 674 (1964); 1) J . del Castillo and B. Kart,
Progr. Biophysics biophysic. Chem. 6, 122 (1956), cf. p. 126;
m) C. G. Schmidt in B. Flaschentrager and E. Lehnartz: Physiologische Chemie. Springer, Berlin-Gottingen-Heidelberg 1956,
Vol. II12a, p. 613; n) H . McIlwain, Annu. Rep. Progr. Chem.
1960,57, 367 (1961); 0) R. Whittam, ibid. 57, 379 (1961); p) Lectures delivered at “Symposium on the function of acetylcholine
as a synaptic transmitter”. Vancouver 1962, Canad. J. Biochem.
Physiol. 41,2553-2653 (1963).
[2] a) D . Nackmonsohn, Ergebn. Physiol., biol. Chem. exp.
Pharmakol. 48, 575 (1955); b) Chemical and molecular basis of
nerve activity. Academic Press, New York-London 1959; c) Bull.
SOC.Chim. biol. 45, 29 (1963); d) in M. Sela: New perspectives
in biology. Elsevier, Amsterdam-London-New York 1964, p. 176.
[3] G. B. Koelle in Hefter-Heubners Handbuch der experimenteIlen Pharmakologie. Springer, Berlin-Gottingen-Heidelberg
1963, Supplement, Vol. 15.
615
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