Reactivity of cage-like amines toward p-toluenesulfonyl chloride and diphenyl chlorophosphate in acetonitrile

Article abstract of DOI:10.1023/B:RUJO.0000034909.58849.e9

The nucleophilic reactivity of amines of the norbornane, norbornene, and adamantane series toward p-toluenesulfonyl chloride and diphenyl chlorophosphate in acetonitrile at 25°C is determined mainly by the steric factor. Parameters characterizing spatial accessibility of the reaction center in the amine molecule have been determined. Cage-like substituents show no appreciable effect on the amine reactivity, as compared to common alkyl groups.

Full text of DOI:10.1023/B:RUJO.0000034909.58849.e9

Russian Journal of Organic Chemistry, Vol. 40, No. 1, 2004, pp. 50-56. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 1, 2004,
pp. 59-65.
Original Russian Text Copyright Ó 2004 by Sadovskii, Solomoichenko, A. Kas’yan, Golodaeva, Anikanova, L. Kas’yan, Savelova.
Reactivity of Cage-Like Amines
toward p-Toluenesulfonyl Chloride and Diphenyl
Chlorophosphate in Acetonitrile
Yu. S. Sadovskii1, T. N. Solomoichenko1, A. O. Kas’yan2, E. A. Golodaeva1, S. V. Anikanova1,
L. I. Kas’yan3, and V. A. Savelova1
1 Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
Donetsk, Ukraine
2 Institut fur organische Chemie, Rheinisch–Westfalische technische Hochschule, Aachen, Germany
3
Dnepropetrovsk National Universitety, per. Nauchnyi 13, Dnepropetrovsk, 49050, Ukraine
e-mail: cf@ff.dsu.dp.ua
Received April 2, 2003
Abstract—The nucleophilic reactivity of amines of the norbornane, norbornene, and adamantane series toward p-
toluenesulfonyl chloride and diphenyl chlorophosphate in acetonitrile at 25°C is determined mainly by the steric
factor. Parameters characterizing spatial accessibility of the reaction center in the amine molecule have been determined.
Cage-like substituents show no appreciable effect on the amine reactivity, as compared to common alkyl groups.
Cage-like amines, primarily of the norbornane,
norbornene, and adamantane series, exhibit a wide spec-
trum of biological activity. 1-Aminoadamantane hydro-
chloride and 1-(1-aminoethyl)adamantane hydrochloride
(amantadine and remantadine) have found application in
medical practice as antiviral and anti-Parkinson agents
[1, 2]. The biological activity of compounds of this group
is believed to originate from the presence of a highly
lipophilic bulky cage-like fragment which is capable of
directly interacting with biological membranes containing
a lipid layer, as well as with hydrophobic fragments of
proteins [1]. Antiviral activity is typical of amines of the
norbornene and norbornane series acyl derivatives of
amines exhibit neurotropic (specifically analgetic, antis-
pasmodic, antihypoxic, and tranquilizing), antiphlogistic,
antiglycemic, and other kinds of biological activity [3, 4].
For comparison, we also examined the kinetics of
the reactions of common aliphatic amines RR'NH (where
R, R' = H, Alk) with p-toluenesulfonyl chloride. The re-
actions were carried out in acetonitrile at 25°C under
pseudozero-order conditions with respect to the reagent
([RR'NH] >> [AcylCl]); here, the concentration ofAcylCl
–6
–5
was 10 to 10 M. In this case, the conversion in reac-
tion (1) is almost complete. The reaction rate was moni-
tored by conductometry, following decrease in the electric
resistance of the solution as a result of accumulation of
ionic species.As a rule, the apparent pseudofirst-order rate
–1
constants kt (s ) did not change during the process, and
average kt value calculated from 8–10 measurements was
taken. In a few cases when kt slightly decreased as the
reaction progressed, the rate constants at the initial mo-
–1
ment kt=0 (s ) were determined by extrapolation of the
curvilinear kt = f(t) dependences to the zero moment,
assuming kt=0 = k (cf. [6]).
Although a considerable progress was achieved in
the field of synthesis of cage-like amines and their acyl
derivatives [5], quantitative aspects of their reactivity
were studied very poorly. In the present work we used
kinetic methods to estimate the nucleophilic reactivity of
cage-like amines toward acyl halides. As electrophiles
we selected p-toluenesulfonyl chloride and diphenyl
chlorophosphate:
The rate constants k are linearly related to the amine
concentration [B] (Fig. 1). This relation suggests the over-
all second reaction order:
(2)
k = k1[B].
–1 –1
Here, k1 (l mol s ) is the second-order rate con-
stant which characterizes the amine reaction with
p-toluenesulfonyl chloride or diphenyl chlorophosphate.
The fact that the straight lines shown in Fig. 1 include
R is a cage-like substituent; R' = H, Me; Acyl =
p-MeC6H4SO2, (PhO)2PO.
1070-4280/04/4001-0050Ó2004 MAIK “Nauka/Interperiodica”

REACTIVITY OF CAGE-LIKE AMINES
51
points corresponding to different substrate concentrations
provides an additional support for the first order of the
reaction with respect to the substrate. Thus, from the
kinetic viewpoint, reaction (1) is analogous to reactions
of aliphatic amines with arenesulfonyl halides in a polar
aprotic solvent [7] (unlike the reactions of alkylamines in
weakly polar media, where autocatalytic effect of the
two reaction products and the initial amine is observed
[8]). Tables 1 and 2 contain the values of k1 for cage-like
aliphatic amines, calculated by Eq. (2) using the least-
squares procedure.
Fig. 1. Plots of the pseudofirst-order rate constants k versus
amine concentration cB for reactions of cage-like amines with
p-toluenesulfonyl chloride (TSC) and diphenyl
chlorophosphate (DPCP) in acetonitrile at 25°C: (1) III +
TSC, c(TSC) = 1.22´10 (a), 2.41´10 M (b); (2) VII +
DPCP, c(DPCP) = 2.48´10–6 (c), 2.48´10–5 M (d); (3) XIII +
TSC, c(TSC) = 1.15´10–5 (e), 5.71´10–5 M (f). Plot 2 corre-
While discussing the obtained results, it is reasonable
to consider spatial accessibility of the reaction center in
the amine molecule as the main factor. There is a
hypothesis according to which the inductive effect of
an alkyl group attached to a reaction center is almost
equal to zero while change in the reactivity upon varia-
tion of alkyl substituents is determined exclusively by steric
hindrances created by those substituents [10, 11]. There-
fore, the reactivity of primary and secondary alkylamines
depends only on the steric properties of the amine mol-
ecule and inductive effect of hydrogen atoms on the ni-
trogen. This assumption was convincingly proved by cor-
relation analysis of more than 20 reaction series including
reactions of primary and secondary alkylamines with vari-
ous electrophiles, for which the attack by amine was re-
liably shown to be the rate-determining stage [11]. Ac-
cording to [11], the rate constants k for the above series
are well described by two-parameter correlation (3):
–1
–5
sponds to the right y axis.
for the reactivity of cage-like amines to increase was
revealed in going from the exo to the endo isomer.
The number of methylene units between the cage-
like fragment and the amino group differently affects the
rate constants k1 for primary amines of the norbornene
and adamantane series. The k1 values for norbornene
derivatives V and VI almost do not depend on the length
of the (CH2)n bridge, where n = 1 or 2 (Table 1). Here,
we have a complete analogy with structurally related pri-
mary alkylamines (provided that the norbornenyl group is
assumed to be formally equivalent to isopropyl):
alkylamines in which the nitrogen atom is separated from
the isopropyl group by one or more methylene units are
characterized by almost equal EN values [9] and hence
by similar reactivities [11]. Amines of the adamantane
series behave differently in reactions with p-toluenesulfonyl
chloride. In going from 1-aminoadamantane (IX) to
1-aminomethyladamantane (X), the rate constant k1 in-
creases by a factor of ~40, and in going from amine X
to 1-aminoethyladamantane (XI), by a factor of 2.5
(Table 1). Increase in the reaction rate upon introduction
of the second methylene unit into adamantane deriva-
tives (unlike amines of the norbornene series) is explained
by the larger size of the adamantyl group.
(3)
logk = log k0 + dEN + rH* nH sH*.
Here, EN is a parameter which characterizes spatial
accessibility of the amino group in an amine molecule; it
is equal to the Taft steric constant ES for an alkyl sub-
stituent which is isosteric to the given amine [12]; nH is
the number of hydrogen atoms on the nitrogen (nH = 1
or 2); sH* = 0.49 is the Taft inductive constant of the hy-
drogen atom; and the coefficients rH and sH* character-
ize the magnitude of the effect of the respective factor
(steric and inductive) on logk.
Let us consider the data in Table 1. For each sub-
strate of both norbornane and norbornene series we ob-
served only a small difference in the rate constants for
the exo and endo isomers. In the reactions with
p-toluenesulfonyl chloride, the ratio of k1endo to k1exo for
amines II and I is 1.18, and for amines V and IV this
ratio is equal to 1.27; in the reactions with diphenyl
chlorophosphate, the corresponding ratios are 1.13 and
1.39, respectively (Table 1). Nevertheless, some tendency
The double carbon–carbon bond is known to act as
an electron-withdrawing moiety [13]. Therefore,
norbornene amines IV and V were expected to be less
reactive than the corresponding saturated norbornane
derivatives I and II. However, according to the experi-
mental data (Table 1), the rate constants k1 are almost
similar for a given electrophile and each pair of amines (I
and IV or II and V). It seems reasonable to explain the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

52
SADOVSKII et al.
Table 1. Second-order rate constants k1 for reactions of cage-like amines I–XIV (B) with p-toluenesulfonyl chloride (TSC) and
diphenyl chlorophosphate (DPCP) (acetonitrile, 25°C) and parameters EN for amines I–XIV and sterically related alkylamines
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

REACTIVITYOF CAGE-LIKEAMINES
53
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a Linear correlation coefficient.
b The number of points involved in the calculation of k1.
c Given are –ES values for alkyl radicals isosteric to the amines.
d A mixture of exo and endo isomers.
e Assumed on the basis of the fact that –ES values for hydrocarbon groups R(CH2)2CH2 (R = H, Me, Et, i-Pr), which are isosteric to
R(CH2)2NH2, are equal to 0.31 [9].
The –EN value was assumed to be no less than –ES = 0.97 [9] for the CH3CH2CH(CH3)CH2 substituent, for alkyl groups at the third
f
carbon atom weakly affect –ES; for example, –ES values for CH3CH2CH2CH2, (CH3)2CHCH2CH2, and (CH3)3CCH2CH2 are 0.31,
0.32, and 0.33, respectively [9].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

54
SADOVSKII et al.
responsible for an appreciable reduction in k1 in going
from 2-aminomethyl-norbornanes I and II to 2-(1-amino-
ethyl)norbornane (III). Accessibility of the amino group
in compound III is reduced as a result of replacement of
methylene hydrogen atom by a methyl group. An analo-
gous pattern is observed in the reactions of amines X and
XIII of the adamantane series with p-toluenesulfonyl
chloride (Table 1).
Table 2. Rate constants k1 for reactions of aliphatic amines
XV–XXIV with p-toluenesulfonyl chloride (acetonitrile, 25°C)
and parameters EN of amines XV–XXIV
$PLQHꢀN ꢀ
0HWK\ODPLQHꢀꢂ;9ꢃꢀ
$OO\ODPLQHꢀꢂ;9,ꢃꢀ
%XW\ODPLQHꢀꢂ;9,,ꢃꢀ
OꢀPRO ꢀV ꢀ
ꢄꢅꢆꢀrꢀꢄꢇꢀ
ꢋꢄꢉꢊꢀrꢀꢄꢉꢇꢀ
ꢅꢈꢉꢇꢀrꢀꢄꢉꢇꢀ
±( >ꢁ@ꢀ
ꢈꢉꢈꢊꢀ
ꢈꢉꢆꢇꢀ
ꢈꢉꢇꢄꢀ
,VREXW\ODPLQHꢀꢂ;9,,,ꢃꢀ
ꢀ
ꢈꢉꢇꢋꢀ
ꢀ
ꢌꢁꢉꢋꢀrꢀꢄꢉꢊꢀ
ꢂꢄꢇꢄꢀrꢀꢆꢃ ꢀ
ꢄꢉꢋꢁꢀrꢀꢈꢉꢈꢋꢀ
ꢅꢉꢌꢋꢀrꢀꢈꢉꢌꢌꢀ
ꢊꢉꢈꢎꢀrꢀꢈꢉꢌꢄꢀ
As repeatedly noted above, the effects of the struc-
ture of cage-like amines on their reactions with
p-toluenesulfonyl chloride and diphenyl chlorophosphate
are essentially similar. A statistical substantiation of this
statement is given by the existence of linear correlation
(4) between log k1 values for the reactions with both re-
agents (Fig. 2):
WHUWꢍ%XW\ODPLQHꢀꢂ;,;ꢃꢀ
&\FORKH[\ODPLQHꢀꢂ;;ꢃꢀ
'LHWK\ODPLQHꢀꢂ;;,ꢃꢀ
ꢄꢉꢎꢇꢀ
ꢈꢉꢊꢁꢀ
ꢋꢉꢈꢈꢀ
'LSURS\ODPLQHꢀꢂ;;,,ꢃꢀ
ꢀ
ꢋꢉꢈꢇꢀ
ꢀ
ꢅꢉꢄꢇꢀrꢀꢈꢉꢋꢁꢀ
ꢂꢇꢉꢌꢁꢀrꢀꢈꢉꢋꢇꢃ ꢀ
'LEXW\ODPLQHꢀꢂ;;,,,ꢃꢀ
ꢋꢉꢈꢊꢀ
ꢌꢉꢈꢄꢀ
ꢆꢉꢈꢎꢀrꢀꢈꢉꢅꢅꢀ
logk1TSC = (0.09 ± 0.03) + (0.80 ± 0.02) log k1DPCP
r = 0.998, s0 = 0.06, n= 11.
;
'LLVRSURS\ODPLQHꢀꢂ;;,9ꢃꢀ
(4)
ꢂꢁꢉꢁꢎꢀrꢀꢈꢉꢋꢌꢃîꢄꢈ ꢀ
a
ꢀ
The rate constant k1 for the reaction with diphenyl chlorophosphate.
In the general case, equations like (4) indicate that
the reactivity of compounds in both reaction series is con-
trolled by the same factors and that the ratios between
the efficiency of these factors in one reaction series and
the corresponding factors in the other reaction series are
similar. The existence of correlation (4) for the reaction
series under study provides an indirect proof for the as-
sumption that the reactions of cage-like amines with TSC
and DPCP involve transition states having similar
bipyramidal structures. Taking into account that the slope
of correlation (4) is close to unity and that the intercept
on the y axis is small, the substrate selectivity of cage-
like amines for the examined acyl chlorides is low.At the
point corresponding to log k1TSC = log k1DPCP = 0.45, the
reactivity of the amines is inversed: those amines for which
log k1TSC > 0.45 are more reactive toward diphenyl
chlorophosphate than toward p-toluenesulfonyl chloride;
the reverse pattern is observed for amines IX and XII
for which log k1TSC < 0.45.
absence of electron-withdrawing effect of the double bond
in amines IV and V by its remoteness from the reaction
center. Oxidation of the double bond in IV to oxirane ring
(amine VII) leads to decrease in the rate constant k1 for
reactions with both electrophiles. Presumably, this is
caused by a stronger negative inductive effect of the
oxirane oxygen atom, as compared to the double bond.
In reactions with both TSC and DPCP, the rate con-
stant k1 decreases in going from primary amine, 1-amino-
adamantane (IX), to secondary amine, 1-methylamino-
adamantane (XII). Naturally, this is due to lesser spatial
accessibility of the reaction center in the secondary amine,
as compared to the primary one. The steric factor is also
The above qualitative analysis of the kinetic data led
us to conclude that the main factor determining the reac-
tivity of cage-like amines is spatial accessibility of the
reaction center, the amino nitrogen atom. Therefore, we
made an attempt to estimate on a quantitative level steric
structure parameters of cage-like amines, i.e., EN. This
problem may be solved by comparing the reactivity of
common aliphatic amines for which the corresponding
parameters EN are known with that of cage-like amines.
In this case, it is necessary to assume that the nucleo
Fig. 2. Correlation between log k1TSC and log k1DPCP for the
reactions of (a) cage-like amines and (b) with p-toluenesulfonyl
chloride (TSC) and diphenyl chloro-phosphate (DPCP) in ac-
etonitrile at 25°C. The numbers of points correspond to
compound nos. in Tables 1 and 2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

REACTIVITYOF CAGE-LIKEAMINES
55
philic reactivity of cage-like amines is also described by
Eq. (3) and that cage-like and aliphatic amines of the
same type (such as primary and secondary) with similar
spatial accessibilities of the amino group are character-
ized by similar reactivities. Treatment of k1 values for
aliphatic amines (Table 2) by Eq. (3) leads to the follow-
ing correlation:
to rationalize these findings unambiguously. A probable
reason may be both insufficient similarity between cage-
like amines and the corresponding model and large errors
in the calculation of EN from the kinetic data obtained for
only one reaction series [Eq. (5)].
On the whole, we can state that cage-like substitu-
ents do not bring appreciable specificity to the nucleo-
philic reactivity of amines in comparison with common
alkyl groups.
log k1TSC = (5.53 ± 0.39) + (1.56 ± 0.07)EN – (3.28
± 0.38) 0.49nH;
(5)
EXPERIMENTAL
R = 0.996, s0 = 0.19, n= 10.
The procedures for conductometric measurements and
calculation of the apparent rate constants kt were described
previously [6]. p-Toluenesulfonyl chloride was heated in a
boiling mixture of carbon tetrachloride with petroleum ether
(1:1) with addition of charcoal A; after cooling, the crys-
tals were separated and dried in a vacuum desiccator.
Diphenyl chlorophosphate was synthesized and purified by
the procedure reported in [14]. Saturated amines I and II
were prepared as described in [15], and unsaturated stere-
oisomeric amines IV and V were obtained as reported in
[16]. Amine VI was synthesized according to the proce-
dure described in [17]. Epoxy amine VII [18] and tricyclic
amine VIII [19] were prepared by known methods.Amines
of the adamantane series were synthesized by the proce-
dures described in [20]. Liquid amines were purified by
distillation of the dry crude products, and crystalline amines,
by recrystallization from appropriate dry solvents. Liquid
aliphatic amines XVI–XXIV were purified via conversion
into the corresponding hydrochlorides; the free bases were
dried over potassium hydroxide and distilled over metallic
sodium. Methylamine of analytical grade was dried over
potassium hydroxide.Acetonitrile was purified by the pro-
cedure described in [21].
By substituting k1 and nH values for cage-like amines
into Eq. (5) we calculated the corresponding parameters
EN (Table 1).*
Naturally, the parameters EN determined in such a
way require for an additional checking by applying to other
reaction series. One of such series may consist of reac-
tions of cage-like and aliphatic amines with diphenyl
chlorophosphate. Here, inclusion of the data for amines I–
VI, IX, XII–XIV (Table 1), XVIII, and XXII (Table 2)
gives correlation (6):
log k1DPCP = (5.94 ± 0.22) + (1.84 ± 0.05)EN – (3.27
± 0.21)0.49 nH;
(6)
R = 0.999, s0 = 0.064, n= 12.
However, verification in such a way cannot be re-
garded as reliable, for logk1TSC and log k1DPCP values for
cage-like amines are linearly related to each other through
Eq. (6) which also covers alkylamines XVIII and XXII
included in correlation (4) (Fig. 2). We believe it more
reasonable to compare the calculated EN values for cage-
like amines with EN of aliphatic amines which can be
considered to be steric analogs of the former. Here, we
can assume that 2-norbornyl and 5-norbornenyl substitu-
ents correspond to isopropyl group and that 1-adamantyl
moiety is spatially analogous to tert-butyl. The structures
of these model aliphatic amines and their respective pa-
rameters EN are also given in Table 1.
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