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

DOI: 10.1023/B:RUJO.0000034909.58849.e9

Source and publish data:

Russian Journal of Organic Chemistry p. 50 - 56 (2004)

Update date:2022-08-28

Topics:

Authors:

Sadovskii

Solomoichenko

Kas'yan Kas'yan

Golodaeva

Anikanova

Kas'yan Kas'yan

Savelova

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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. Kasyan, Golodaeva, Anikanova, L. Kasyan, Savelova.

Reactivity of Cage-Like Amines

toward p-Toluenesulfonyl Chloride and Diphenyl

Chlorophosphate in Acetonitrile

Yu. S. Sadovskii¹, T. N. Solomoichenko¹, A. O. Kasyan², E. A. Golodaeva¹, S. V. Anikanova¹,

L. I. Kasyan³, and V. A. Savelova¹

¹Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,

Donetsk, Ukraine

²Institut fur organische Chemie, RheinischWestfalische technische Hochschule, Aachen, Germany

Dnepropetrovsk National Universitety, per. Nauchnyi 13, Dnepropetrovsk, 49050, Ukraine

e-mail: cf@ff.dsu.dp.ua

Received April 2, 2003

AbstractThe 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

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

constants k_t(s ) did not change during the process, and

average k_tvalue calculated from 810 measurements was

taken. In a few cases when k_tslightly decreased as the

reaction progressed, the rate constants at the initial mo-

ment k_t=0(s ) were determined by extrapolation of the

curvilinear k_t= f(t) dependences to the zero moment,

assuming k_t=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

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 k₁for 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 c_Bfor 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´10⁶(c), 2.48´10⁵M (d); (3) XIII +

TSC, c(TSC) = 1.15´10⁵(e), 5.71´10⁵M (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):

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 k₁for primary amines of the norbornene

and adamantane series. The k₁values for norbornene

derivatives V and VI almost do not depend on the length

of the (CH₂)_nbridge, 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 E_Nvalues [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 k₁in-

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+ dE_N+ r_H* n_Hs_H*.

Here, E_Nis a parameter which characterizes spatial

accessibility of the amino group in an amine molecule; it

is equal to the Taft steric constant E_Sfor an alkyl sub-

stituent which is isosteric to the given amine [12]; n_His

the number of hydrogen atoms on the nitrogen (n_H= 1

or 2); s_H* = 0.49 is the Taft inductive constant of the hy-

drogen atom; and the coefficients r_Hand s_H* 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 k₁^endoto k₁^exofor

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 carboncarbon 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 k₁are 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

SADOVSKII et al.

Table 1. Second-order rate constants k₁for reactions of cage-like amines IXIV (B) with p-toluenesulfonyl chloride (TSC) and

diphenyl chlorophosphate (DPCP) (acetonitrile, 25°C) and parameters E_Nfor amines IXIV and sterically related alkylamines

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REACTIVITYOF CAGE-LIKEAMINES

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^aLinear correlation coefficient.

^bThe number of points involved in the calculation of k₁.

^cGiven are E_Svalues for alkyl radicals isosteric to the amines.

^dA mixture of exo and endo isomers.

^eAssumed on the basis of the fact that E_Svalues 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 E_Nvalue was assumed to be no less than E_S= 0.97 [9] for the CH₃CH₂CH(CH₃)CH₂substituent, for alkyl groups at the third

carbon atom weakly affect E_S; for example, E_Svalues for CH₃CH₂CH₂CH₂, (CH₃)₂CHCH₂CH₂, and (CH₃)₃CCH₂CH₂are 0.31,

0.32, and 0.33, respectively [9].

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

SADOVSKII et al.

responsible for an appreciable reduction in k₁in 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 k₁for reactions of aliphatic amines

XVXXIV with p-toluenesulfonyl chloride (acetonitrile, 25°C)

and parameters E_Nof amines XVXXIV

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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 k₁values for the reactions with both re-

agents (Fig. 2):

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logk₁^TSC= (0.09 ± 0.03) + (0.80 ± 0.02) log k₁^DPCP

r = 0.998, s₀= 0.06, n= 11.

;

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The rate constant k₁for 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 k₁^TSC= log k₁^DPCP= 0.45, the

reactivity of the amines is inversed: those amines for which

log k₁^TSC> 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 k₁^TSC< 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 k₁for

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 k₁decreases 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., E_N. This

problem may be solved by comparing the reactivity of

common aliphatic amines for which the corresponding

parameters E_Nare known with that of cage-like amines.

In this case, it is necessary to assume that the nucleo

Fig. 2. Correlation between log k₁^TSCand log k₁^DPCPfor 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

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 k₁values 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 E_Nfrom 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 k₁^TSC= (5.53 ± 0.39) + (1.56 ± 0.07)E_N (3.28

± 0.38) 0.49n_H;

(5)

EXPERIMENTAL

R = 0.996, s₀= 0.19, n= 10.

The procedures for conductometric measurements and

calculation of the apparent rate constants k_twere 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 XVIXXIV 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 k₁and n_Hvalues for cage-like amines

into Eq. (5) we calculated the corresponding parameters

E_N(Table 1).^*

Naturally, the parameters E_Ndetermined 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, XIIXIV (Table 1), XVIII, and XXII (Table 2)

gives correlation (6):

log k₁^DPCP= (5.94 ± 0.22) + (1.84 ± 0.05)E_N (3.27

± 0.21)0.49 n_H;

(6)

R = 0.999, s₀= 0.064, n= 12.

However, verification in such a way cannot be re-

garded as reliable, for logk₁^TSCand log k₁^DPCPvalues 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 E_Nvalues for cage-

like amines with E_Nof 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 E_Nare also given in Table 1.

REFERENCES

1. Morozov, I.S., Petrov, V.I., and Sergeeva, S.A., Farmakolo-

giya adamantanov (Pharmacology ofAdamantanes), Volgo-

grad: Volgograd. Med.Akad., 2001.

2. Bagrii, E.M., Adamantany: poluchenie, svoistva, primene-

nie (Adamantanes: Synthesis, Properties, and Application),

Moscow: Nauka, 1989; Indulen, M.K., Kalninya, V.A., Rya-

zantseva, G.M., and Bubovich, V.I., Mekhanizmy anti-

virusnogo deistviya proizvodnykh adamantana (Mechan-

isms of AntiviralAction ofAdamantane Derivatives), Riga:

Zinatne, 1981.

The E_Nvalues for cage-like amines I, II, IVVI, IX,

XII, and XIII and sterically related alkylamines are fairly

similar: the difference in E_Ndoes not exceed 1020%.

The difference observed for amines III, X, XI, and XIV

is more significant: it approaches 4050%. It is difficult

3. Kasyan L.I., Zlenko, O.T., Mamchur, V.I., Kasyan, A.O.,

and Tarabara, I.M., Farm. Zh. 2002, p. 59.

4. Krieger, H., Arzn.-Forsch., 1968, vol. 18, pp. 129, 324, 487.

* The parameters E_Nfor amines VII and VIII were not calculated, for

the procedure used for the calculation should distort their values

because of inductive effect of the oxygen atom.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

SADOVSKII et al.

13. Temnikova, T.I., Kurs teoreticheskikh osnov organicheskoi

5. Kasyan, L.I., Sereda, S.V., Potekhin, K.A., and Kasyan,A.O.,

khimii (Lectures on Theoretical Foundations of Organic

Chemistry), Leningrad: Khimiya, 1968, p. 203.

Heteroatom Chem., 1997, vol. 8, p. 177; Kasyan, A.O.,

Okovityi, S.I., Krasnovskaya, O.Yu., and Kasyan, L.I.,

Russ. J. Org. Chem. 1997, vol. 33, p. 985; Kasyan, L.I.,

Tarabara, I.N., Savelyeva, A.O., and Kasyan, A.O.,

Heteroatom Chem., 2001, vol. 12, p. 119; Kasyan, A.O.,

Russ. J. Org. Chem., 1999, vol. 35, p. 635.

14. Titarenko, I.P., Protsenko, L.D., Tarnavskaya, M.I., and

Kopelnik, M.A., Fiziol. Aktiv. Veshch-va., 1975, p. 6.

15. Kasyan, A.O., Krasnovskaya, O.Yu., Zlenko, E.T., Okovi-

tyi, S.I., and Kasyan, L.I., Russ. J. Org. Chem., 1996, vol. 32,

p. 1113.

16.Alder, K., Krieger, H., and Weib, H., Chem. Ber., 1955, vol. 8,

p. 144; Alder, K., Heimbach, K., and Reubke, R., Chem.

Ber., 1958, vol. 91, p. 1516.

17. Kasyan, L.I., Tarabara, I.N., and Kasyan, A.O., Russ. J.

Org. Chem., 2002, vol. 38, p. 19.

18. Kasyan, A.O., Krasnovskaya, O.Yu., Okovityi, S.I., and

Kasyan, L.I., Russ. J. Org. Chem., 1995, vol. 31, p. 311.

19. Kasyan, L.I., Okovity, S.I., and Kasyan, A.O., Heteroatom

Chem., 1997, vol. 8, p. 177.

20. Polis, L.Yu., USSR Inventors Certificate no. 408 546, 1974;

Ref. Zh., Khim., 1978, no. 20O46 P; Skoldinov, A.P.,

Pushkar, G.V., Shmaryan, M.I., Klimova, N.V., Lavro-

va, L.N., and Kharkevich, D.A., USSR Inventors Certificate

no. 503 851, 1976; Ref. Zh., Khim., 1977, no. 4N129P.

21. Kreshkov,A.P., Bykova, L.N., and Kazaryan, N.A., Kislotno-

osnovnoe titrovanie v nevodnykh rastvorakh (Acid-Base Titra-

tion in Nonaqueous Media), Moscow: Khimiya, 1967, p. 75.

6. Savelova, V.A., Popov, A.F., Solomoichenko, T.N.,

Sadovskii, Yu.S., Piskunova, Zh.P., and Lobanova, O.V.,

Russ. J. Org. Chem., 2000, vol. 36, p. 1465.

7. Bilobrova, A.I., Sharanin, Yu.A., Popov, A.F., and

Litvinenko, L.M., Zh. Org. Khim., 1971, vol. 7, p. 2168;

Litvinenko, L.M., Sharanin, Yu.A., Popov, A.F., and

Bilobrova,A.I., Zh. Org. Khim., 1972, vol. 8, p. 2393.

8. Litvinenko, L.M. and Popov,A.F., Zh. Obshch. Khim., 1968,

vol. 38, p. 1969; Litvinenko, L.M., Bilobrova,A.I., Shara-

nin, Yu.A., and Popov, A.F., Zh. Org. Khim., 1971, vol. 7,

p. 795.

9. MacPhee, J.A., Panaye, A., and Dubois, J.-E., Tetrahedron,

1978, vol. 34, p. 3553.

10. DeTar, D.F., J. Org. Chem., 1980, vol. 45, pp. 5166, 5174.

11. Akshentsev, V.V., Dragalov, V.V., and Chimishkyan, A.L.,

Zh. Org. Khim., 1987, vol. 23, p. 305.

12. Bogatkov, S.V., Popov,A.F., and Litvinenko, L.M., Reakts.

Sposobn. Org. Soedin., 1969, vol. 6, p. 1011.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

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Article Doi

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

DOI: 10.1023/B:RUJO.0000034909.58849.e9

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

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

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