action of electrophiles on 2-aminopyridines: a charge sensitivity and electrostatic potential study

Journal of MoIecuIar Structure (Theochem), 288 (1993) 119-131 0166-1280/93/$06.00 0 1993 - Elsevier Science Publishers B.V. All rights reserved

119

Action of electrophiles on 2-aminopyridines: a charge sensitivity and electrostatic potential study

Piotr Kowalski *Ta, Jacek Korchowiecb aInstitute of Organic Chemistry and Technology, Politechnical University, Warszawska 24, 31-15.5 Cracow, Poland bK. Gumiriski Department of Theoretical Chemistry, Jagiellonian University, R. Ingardena 3, 30-060 Cracow, Poland

(Received 10 March 1993; accepted 30 April 1993)

Abstract

Charge sensitivity analysis (CSA) and molecular electrostatic potential (MEP) data are applied to predict the most sensitive centers for electrophilic attack in five 2-aminopyridine structures. The analysis is focused on the electrostatic (ES) (responsible for hard-hard interaction) and charge transfer (CT) (responsible for soft-soft interaction) contributions to the overall interaction energy. Rigid and relaxed hardness and chemical potential parameters, and Fukui function indices of atoms-in-molecules (AIM) are discussed. The 2-aminopyridine molecules are considered in both isolated and reactive systems. The analysis indicates that the C-5 carbon atom can be clearly distinguished as an electron donating center from the whole subset of carbon atoms in four of the structures (imino, amino, second monocation, dication), whereas the C-3 carbon atom acts this way in the first monocation structure. The sensitivity of the exocyclic N atom is greater than that of the annular N atom for the imino and first monocation forms, whereas for the amino and second monocation forms the opposite is observed. The AIM hardness values predict the C-5 and C-3 carbon atoms to be less hard than the annular and exocyclic nitrogen atoms for all five structures; hence electrophilic attack on the carbon atoms is mainly CT controlled, whereas on the nitrogen atoms it is ES controlled. The calculated data are compared with experimental data in the literature.

Introduction

The reactions of 2-aminopyridine with electrophiles have been known for a long time, but relatively little work has been reported on their mechanisms. Experimental results [ 1 -IO] and theoretical calculations [ 11,121 indicate four electron donating centers in a molecule of 2-aminopyridine (exocyclic and annular nitrogen atoms, NeXc and Nad respectively and the C-3 and C-5 carbon atoms), which cause electrophilic attack at these positions.

The composition of the compound formed depends on the reaction conditions (kind of

*Corresponding author.

solvent, temperature, reaction time) and on the nature of the electrophilic agent.

In an inert solvent the equilibrium between the imino (I) and amino (II) forms of 2-aminopyridine is possible [12-141 (see Fig. 1). In acidic solutions 2-aminopyridine can exist in monocation (III and IV) and dication (V) forms [15-171 (see Fig. 1). In order to explain which of the structures are responsible for observed chemical behavior trends in reactions with electrophilic agents, we have examined all five structures. The influence of the nature of the electrophilic agent on the substitution of 2-aminopyridines has also been qualitatively considered.

The aim of this paper is to reinvestigate the mechanism of electrophilic substitution in 2-amino-

120 P. Kowalski and J. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131

*

I \

9

N.

a I \ 0 0 V

Fig. 1. Structural formulas of the investigated 2-aminopyridines I-V.

pyridines in terms of charge sensitivity analysis (CSA) and molecular electrostatic potential (MEP) data.

2-Aminopyridines, both isolated (M) and in a reactive system (M . . H+) with a proton as a model electrophilic agent, have been used for CSA and MEP data. The basic concepts of CSA, such as hardness, softness, Fukui function (FF) indices and electronegativity (the negative of the chemical potential) have special meaning for quantifying intuitive chemical concepts and ration- alizing reactivity and stability trends [18-241. It has been shown that the group chemical potential (GCP) parameters and FF indices are the best reactivity criteria for discussing reactions with electrophiles in classical aromatic systems [25-271.

Method

The theory of CSA has been described elsewhere [24,25,28,29], so here only some basic definitions are summarized. The semiempirical atoms-in- molecules (AIM) CSA is based upon the canonical AIM hardness tensor

qg = #E/aNiaNj = dpi/dNj = apj/aNi , (1)

where N = (N1, N2,. . .) is the AIM electron popu-

lation vector, E(N) is the system electronic energy, and p= aE/aN is the vector of the AIM rigid chemical potential. The hardness tensor can be approximated by the valence shell electron repul- sion integrals estimated from the atom ionization potential and electron affinity data, via the Pariser [30] and Ohno [31] formulas. Both the rigid chemical potential and the diagonal AIM hardness depend on the actual valence state of the AIM characterized by the net charge q, and are interpolated to give the actual AIM charges.

Among charge sensitivity parameters the AIM FF indices are of the greatest importance [l&21,24-26,28,29], given by f= dN/aN= (~N/~/.L)/(~N/@.A) es/S=s~ (2)

where N = Ci Ni is the global number of electrons, s is the vector of the AIM softness and S is the global softness of the system (the inverse of the global hardness r]). All these parameters charac- terize the global equilibrium state in a system. This means that there are no constraints on the flow of electrons between a system’s constituent parts (e.g. atoms). One can also define CSA parameters for a constraint equilibrium state, which is equivalent to partition of the system into closed subsystems (with equilibrium only inside sub-

p. Kowalski and .I. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131 121

systems). Such a partition allows one to define either fewer or more relaxed parameters and to investigate the electronic mechanism (the intermediate stages of electronegativity equalization (EE) in the system). All the parameters mentioned can be obtained from the hardness tensor via combination formulas [21,24,25,28,29]. The crucial role in calculating more condensed hardness matrix parameters is played by FF indices, e.g.

rlX,Y = C C fkyrlkjfj” (3) jcX kcY

where f> is the FF index of the kth atom in fragment Y. The importance of CSA parameters is connected with their relationship to the polar- ization and charge transfer (CT) contributions to the overall interaction energy.

The interaction energy AE,, between two reac- tants, say A (an acid, electrophile) and B (a base, nucleophile) for a “frozen” geometry of both reac- tants consists of three components [ 18,24,28], i.e.

AE,, = Et; + EIB f E:; (4)

where EES, EP and ECT are the electrostatic, polar- ization and charge transfer energies, respectively. In the present analysis we focus on the ES and CT contributions to the interaction energy because the former is responsible for stabilizing hard-acid-hard-base interactions [19], and the latter is responsible for stabilizing soft-acid- soft-base interactions [18], in the spirit of the hard- soft-acid-base (HSAB) principle and recent qualitative papers [25,26]. The global characteristics, including all mentioned contributions to the interaction energy, are presented elsewhere.

The electrostatic component in Eq. (4) includes the usual electrons-nucleus (en), electron-electron (e,e) and nucleus-nucleus (n,n) interaction energies, i.e.

ES EAB = U?; + U;; i- lJ2;

= U:; + (nAvB f nBvA) dr+ s ss

- dr dr’ ,,“-“,“, ,

= q” - C~A$B+~B~AI~~ (5)

where nA, VA, 4A are the electronic density, the external potential due to the bar nuclei and the electrostatic potential

4Ak) = VA(r) + Jdr’& of the reactant A.

The last term in Eq. (4) Es is associated with the tranSfer of NCT = dNA = -dNB > 0 electrons between base B and acid A. To the second order and for dw = 0, the CT energy is given by

Ezi = -$ ApAB NCT (6)

where A/JAB = pa - PA (/.J = dE/dN) is the initial chemical potential difference. This quantity (ApAB) can be interpreted as the “motive power” of the chemical reaction. Of course, NCT depends on ApAa and the condensed hardness matrix elements vu, QBB and n~,a, which we omit because we want to know the change of CT energy in units of NCT (i.e. Ezi/NcT).

We are interested in the site selectivity of a chemical reaction, so we quote here one of the alternative expressions (the so-called B-resolved expression) for Ezz [24], namely

1 =- 2 (

pANCT - C/LB dN,B i )

= ;-&(P: - PA) dNiB I

=$Ap:dN; = ce:’ (7) I i

where dNi = A. NCT is the contribution of the ith atom to the overall amount of CT, and eFT is the local CT stabilization energy. One should observe that the quantity Cif;‘pF in the expression above is merely the combination formula for calculating pa. We wish to point out here that {&} calculated for a given oxidation state of atoms in B (standard SCF MO schemes) are not equalized [27]. This expression allows one to discuss the contribution


Table 1 The rigid (unrelaxed) atomic electronegativities xi (a.u.) (negative of the chemical potential pi), for selected positions (see Fig. 1) in all the investigated structures of 2-aminopyridine

Structure Xl = -Pi

Annular 2 3 4 5 6 ext.

I 0.218 0.196 0.208 0.221 0.215 0.232 0.177

II 0.184 0.198 0.209 0.217 0.209 0.208 0.217

III 0.441 0.422 0.401 0.405 0.396 0.412 0.431

N 0.375 0.403 0.393 0.380 0.374 0.373 0.564 V 0.639 0.613 0.591 0.575 0.569 0.595 0.738

to EA”;f from the interaction between A (treated as a whole) and individual local sites in B. The first term in Eq. (7) pANCT/2 represents the charge stabilization in the acid, and the second term - Ci~B~BNCT/2 is the charge activation of the base. The local CT stabilization energy is the highest for an atom which has the highest ApF (which is equivalent to the highest py for a constant pA) andhB. When we consider the interaction between atoms i in B and A we must include the population relaxation in B (outside the attacked atom i) to the chemical potential and hardness matrix elements [24,25]. In such a picture of the interaction, molecule B is divided into two parts, i.e. B = (XIY), where X = i and Y = B # i. Thus, the modified relaxed chemical potential is given by

keY (8)

and the modified hardness matrix element is

given by

iji,i = Tji,i + C 7)ijTJ(y”) I I (9) jER

where the relaxational matrix T(W) =

Wk’/W%, can be derived from the relevant EE equations. We would like to mention here that relaxational effects have no influence on FF indices [24]. One should also notice that if fragment Y reduces to one atom then the relaxational corrections to the hardness and chemical potential parameters are equal to zero in the considered AIM resolution of the CSA so there is no relaxation within the acid (A = Hf) in the reactive system M...H+.

Results

All calculations on structures I-V were performed using the standard MNDO method, with full geometry optimization (gradient norm less than 0.1 kcal mol-’ A-‘); structures with minimum

Table 2 The relaxed atomic electronegativities zi (a.u.) (negative of the relaxed chemical potential pi) for selected positions (see Fig. 1) in all the investigated structures of 2-aminopyridine

Structure

I II III N V

gj = xi + 6Xi(6N,) = -/Iii

Annular 2 3 4 5 6 Ext.

0.214 0.256 0.211 0.240 0.211 0.236 0.193 0.220 0.251 0.225 0.241 0.225 0.240 0.223 0.436 0.447 0.413 0.439 0.415 0.422 0.418 0.423 0.415 . 0.427 0.429 0.426 0.433 0.491 0.648 0.592 0.617 0.618 0.610 0.612 0.687

p. Kowalski and J. Korchowiec/J. Mol. Struct. (Theochem) 288 (1993) 119-131 123

energy were used; the MNDO geometry and atomic charges were the input data in the calculations.

In Table 1 we list rigid chemical potential parameters of the 7r electron system atoms of the 2-aminopyridines I-V, and in Table 2 we list their relaxed equivalents.

The FF indices (Table 3) give additional information about the reactivity of the atoms in systems I-V.

General comparison of the data in Tables 1 and 2 indicates the great importance of the relaxational correction. The relaxed chemical potential fi more clearly distinguishes electron donating centers (atoms with the highest chemical potential) in the molecules. Hence, in structure I for example, the rigid chemical potential favors especially the exocyclic nitrogen atom N,,, and to a smaller degree the C-2, C-5, C-3 and Nan, atoms as the most reactive positions (see Table 1). After including relaxation, the N,,,, C-3, C-5 and NanI atoms of I appear as the most reactive centers, and the C-2, C-4 and C-6 atoms appear as the non-reactive centers (see Table 2). Analogously, in structure II, the rigid chemical potential favors Nan,, C-2, C-6, C-3 and C-5, and the relaxed parameter favors NanI, N exe 3 C-3 and C-5 as the preferred reaction sites. Thus, for both forms I and II the same groups of reactive and non-reactive atoms are obtained.

The sign of the FF index is responsible for local donor/acceptor behavior. Thus, when a molecule as a whole acts as a base, atoms with a positive FF index show local donor properties, whereas those with a negative FF index show local acceptor properties.

Differences between the relaxed chemical potentials for AIM disappear in the cationic forms III-V. In the case of III, the relaxed chemical potentials of atoms C-5 and C-3 are slightly different from the others; the reactivity of the atoms in structures IV and V is almost the same, except for the protonated nitrogen atoms, which have the smallest value of chemical potential.

In structures I and II, the nitrogen atoms, and the C-3 and C-5 carbon atoms show local donor properties (positive FF indices), whereas C-2, C-4 and C-6 show local acceptor properties (negative FF indices). In the protonated structures III, IV and V, the FF indices of the nitrogen atoms and the C-3 and C-5 carbon atoms generally decrease in comparison with the corresponding atoms in I and II. Additionally, in the case of IV and V a change in the local properties of the protonated nitrogen atoms from basic to acidic is observed. The other atoms (C-2, C-4 and C-6) increase their FF indices on passing from the neutral molecules (I and II) to the cationic forms (III-V); nevertheless, they still have lower FF index values than the remaining atoms (except the protonated nitrogen atoms and the C-2 carbon atom in V).

It should be observed that the general trends in the AIM FF indices (Table 3) are similar to those of the relaxed chemical potentials (Table 2). Hence, this leads to the conclusion that the nitrogen atoms and the C-3 and C-5 carbon atoms are generally the preferred reaction sites for electrophilic attack in molecules I-V.

The data presented in Tables l-3 concern

Table 3. The Fukui function indices f; for selected positions (see Fig. 1) in all the investigated structures of 2-aminopyridine

Compound h

Annular 2 3 4 5 6 Ext.

I 0.083 -0.117 0.218 -0.09 1 0.273 -0.056 0.281 II 0.136 -0.054 0.167 -0.046 0.185 -0.029 0.085 Ill 0.041 -0.071 0.222 -0.052 0.154 0.006 0.169 N 0.083 0.043 0.055 0.032 0.075 0.030 -0.065 V -0.004 0.063 0.045 0.033 0.087 0.042 -0.060

124 P. Kowalski and .I. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131

isolated molecules (M = I - V) (one reagent reactivity criteria). For a better illustration of the reactivity differences between the N,,, Nad, C-3 and C-5 atoms in molecules I-V, FF indices for atoms in the reactive system M . . . Hf were obtained (Fig. 2-6).

All plots were prepared by probing the surface parallel to the ring surface at a distance of 1 A with a proton.

The values of the FF indices in the asymptotic regions (see Figs. 2-6) correspond to the respective value listed in Table 3. In the region close to the reaction site, a rapid increase of the FF indices for the atoms which make an essential contribution to ECT was observed. Hence, it appears that C-3 and C-5 carbon atoms in structures I, II and III make a greater contribution to ECT than do the nitrogen

Fig. 2. Contour diagrams of the atomic Fukui functiohf;, (r) in the reactive system M . . H+(r); M is structure I; i = C-5 (a), C-3 (b), %I 6) and N, (4.

P. Kowalski and J. Korchowiec/J. Mol. Struct. (Theoehem) 288 (1993) 119-131 125

Fig. 3. As Fig. 2, with M as structure II.

atoms. The FF indices of Nan,, C-3 and C-5 in structure IV are nearly the same; in the structure V the FF indices are greatest for the C-3 and C-5 carbon atoms.

Investigations of the AIM reactivity in I-V, carried out for the reactive systems M. . . Hf indicate that the CT component (responsible for the soft-soft interaction) clearly favors the C-3 and C-5 atoms as the preferred reaction sites.

From this it follows that the nitrogen atoms in I-V are not significant in the soft-soft interaction. This suggestion confirms the AIM diagonal data listed in Table 4, for which, in all respective structures, the C-3 and C-5 carbon atoms are softer than the nitrogen atoms; the same trends are observed for the relaxed diagonal hardnesses ijii, because the relaxational correction (which is always negative according to

126 P. Kowalski and .I. KorchowieclJ. Mol. Struci. (Theochem) 288 (1993) 119-131

Fig. 4. As Fig. 2, with M as structure III.

Le Chatelier’s principle [24]) is more or less the same for all atoms.

For the hard-hard interaction, the ES component is the one mainly responsible. Figure 7 shows MEP plots for all structures; all plots were prepared in the surface parallel to the ring surface at a distance of 1 A.

The MEP plots have a qualitative character, because they were prepared according to

MNDO data. It is seen, that the exocyclic nitrogen atom in structure I (Fig. 7(a)) and the annular nitrogen atom in structure II (Fig. 7(b)) are the preferred reaction sites for electrophilic attack, from the wide and deep basin in the region closed to these atoms. The remaining atoms in structures I and II and all atoms in structures III-V are not clearly favored and they each make a destabilizing contribution to

p. Kowalski and J. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131 12-l

Fig. 5. As Fig. 2, with M as structure IV.

the interaction energy, which increases with increasing charge of the systems.

Discussion

The investigations indicate that the relative AIM reactivity depends on CT and ES contributions, but it is not entirely clear which of these is dominant [ 181.

In model considerations, one can adopt the HSAB principle. According to this, the reaction of hard species (hard-hard interaction) is electro- statically controlled (the ES contribution to the overall interaction is the largest), whereas the reaction of soft species (soft-soft interaction) is CT controlled (the CT contribution to the overall interaction is the largest).

Hence, the reaction of a hard electrophile such as

P. Kowalski and J. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131

4 d)

7th -0. 1

0 I P

&

Fig. 6. As Fig. 2, with M as structure V.

Table 4 Rigid (unrelaxed) and relaxed diagonal hardness (a.u.) in systems M = (i IR), where M is one of structures I-V (see Fig. 1) and R is the molecular remainder (all atoms except the ith atom)

M Unrelaxed Relaxed

c-3 c-5 N ad N exe c-3 c-5 N ad N exe

I 0.3170 0.3032 0.3769 0.3528 0.2214 0.2135 0.2567 0.2474 II 0.3226 0.3178 0.3873 0.4072 0.2313 0.2278 0.2906 0.2678 III 0.3148 0.3304 0.4111 0.3681 0.2231 0.2340 0.2846 0.2717 Iv 0.3559 0.3533 0.4199 0.5336 0.2571 0.2530 0.3145 0.3391

’ V 0.3712 0.3548 0.4564 0.5330 0.2674 0.2534 0.3203 0.4584

p. Kowalski and J. KorchowieclJ. Mol. Slruct. (Theochem) 288 (1993) 119-131 129

b)

Fig. 7. Molecular electrostatic potential plots (kcal mol-‘) corresponding to structures I (a), n @I, Ill (c). IV (d) and V 69.

a proton with the free base I should occur easily on Table 3 and Fig. 2(d)). By analogy, it can be shown the exocyclic nitrogen atom, because both contri- that the annular nitrogen atom in structure II is the butions stabilize the system (the deep negative preferred hard electrophilic reaction site. In these basin close to N,,, (see Fig. 7(a)); FF indices (see cases both contributions stabilize the systems, so


proton addition to I or II becomes exothermic and leads to 2-aminopyridinium cation formation.

Electrophilic substitution at the carbon atoms in I or II is controlled by the CT contribution (the ES term is destabilizing). The process becomes harder when passing from the free bases to the cationic forms: 2-aminopyridine cations have smaller chemical potentials (see Table 2) and thus relatively smaller values of CT stabilization energies (see Eq. (7)). The carbon atoms C-3 and C-5 are the softest in the respective structures (see Table 4) so the reaction with soft electrophiles should occur easily. Thus, chlorination of 2-aminopyridine to give 5-chloro-2-aminopyridine runs in a short time and under mild conditions [6], whereas deuterium exchange at the C-3 carbon atom in 5-bromo-4-methyl-2-aminopyridine with sulphuric acid-& requires heating at 100°C for 3 days [17].

In the reaction of the free base of 2-aminopyridine with alkyl halides, the ratio of annular adducts to exocyclic substitution decreases on passing from hard methyl to soft ally1 or benzyl substituents [9,32]. These trends remain in agree- ment with our calculations, where it was found that in the case of soft electrophilic agent attack the exocyclic N derivatives form more easily with the greater participation of structure I (cf. Figs. 2(c), 2(d) and (3c), 3(d); Tables 3 and 4). The greater participation of the imino form of 2-aminopyridine (I) is also visible in the formation of C-5 derivatives; nevertheless, both structures direct the electrophilic agent attack to the C-5 carbon atom mainly (cf. Figs. 2(a) and 3(a)).

In the case of the cationic forms of 2-aminopyridine the chemical potential data and FF indices indicate that cation III should favor the electrophilic attack at the 3-position mainly (see Tables 2 and 3; cf. Figs. 4(a) and 4(b)) and only structures IV and V can explain the primary electrophilic attack at the C-5 carbon atom (Tables 2 and 3; Figs. 5(a), (b) and 6(a), 6(b)). Hence, if the cation III takes part in C-substituted derivative formation, compounds with the substituent at the 3-position should be formed in significant amounts. Such compounds, however,

were not detected in the reaction of 2-aminopyridines carried out in a slightly acidic medium, and in a highly acidic medium the quantity of the 3-substituted isomer clearly differs from that of the 5-substituted one. Hence, for example, the bromin- ation reaction of 2-aminopyridine carried out in 20% sulfuric acid [33] or in an acidic medium [34] yielded only 5-bromo derivatives. Similarly, in a slightly acidic medium, 5-substituted benzyl derivatives are obtained by benzylation reaction [35-371. Nitration carried out in a mixture of concentrated nitric and sulfuric acids gives 3- and 5-nitro isomers in the ratio 1 : 8 [5,10].

It is stressed that structure III of 2-aminopyridine, commonly quoted in the literature as the intermediate responsible for C-5 electrophilic substitution, is in the light of SCA mainly responsible for electrophilic attack at the C-3 position. The calculated reactivity of the carbon atoms in III, however, corresponds especially well with the kinetic experimental data, which shows that the 1-methyl-2-dimethylaminopyridinium cation (parallel to structure III) was five times less reactive in high acidity and 4000 times less reactive in ‘low’ acidity during nitration than was 2-dimethylaminopyridine [ 11.

It was found that in 33.3N (90%) sulfuric acid 2-dimethylaminopyridine existed in dication form and in 2.2 N (10%) sulfuric acid solution it existed in annular N monocation form [15]. It was found that in 100% sulfuric acid 2-amino-4-methyl- pyridine appeared in the dication form and in more dilute sulfuric acid (95%) in the exocyclic N monocation form [ 161. It is therefore apparent that for the nitration of 2-dimethylaminopyridine described in the literature, when carried out in high acidity medium (98.2% H2S04) [38] occurs with the dication structure (parallel to structure V), whereas when carried out in low acidity medium (81.8% H2S04) it occurs with the exocylic N monocation form (parallel to structure IV).

Comparing the data obtained from the CSA analysis with the literature information indicates that the reaction carried out in low acidity medium in which 5-substituted derivatives are obtained

p. Kowalski and J. KorchowieclJ. Mol. Struct. (Theochem) 288 (1993) 119-131 131

takes place with structures different from structure 111. This may lead to the conclusion that in low acidity medium electrophilic substitution occurs with the free base of 2-aminopyridine, and there is progressively more support confirming this fact [1,39]. The analysis performed indicates that in high acidity medium preferred substitution at the 5-position requires the participation of structures IV and V of 2-aminopyridine.

15

16

17

18

19

Acknowledgment 20 21 22

The financial support of the State Committee for Scientific Research (Warsaw) is gratefully acknowledged.

23

24

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action of electrophiles on 2-aminopyridines: a charge sensitivity and electrostatic potential study

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