The three isomers of chlorobenzonitrile (CBN) and the corresponding radical anions are investigated by semiempirical methods in order to Study the regioselectivity of solvated hydrogen and hydroxy radical attacks. Additional negative charge is distributed upon reduction at the chlorine and cyano subunits and in para-position to the cyano group. Most of the negative charge (about 70%) is located in the aromatic ring. The different protonation sites for the negatively charged radical and neutral species are explained by distinctly different electro-negativities. The observed position of a hydroxy radical attack on 2-chlorobenzonitrile is correlated to the relative stabilities of the six possible addition products. The electron density contribution of 2-CBN as calculated by the Mulliken population analysis method is in excellent agreement with the experimentally observed formation of different products: The 2-chloro-5-hydroxybenzonitrile is the preferentially created species, with both the 4- and 6-hydroxy isomers as important sideproducts

Andreas B. J. Parusel

Gottfried K&ouml

Rudolf Schamschule

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ISSN-0011-1643CCA-2651 Original Scientific PaperReduction and Radical Addition:A Theoretical Study on ChlorobenzonitrilesAndreas B. J. Parusel,a,b,* Rudolf Schamschule,b and Gottfried Köhlerba NASA Ames Research Center, MS 239–4, Moffett Field, CA 94035, USAb Institute for Theoretical Chemistry and Structural Biology,University of Vienna, Althanstrasse 14, 1090 Viena, AustriaReceived February 24, 1999; revised June 30, 1999; accepted September 14, 1999The three isomers of chlorobenzonitrile (CBN) and the correspond-ing radical anions are investigated by semiempirical methods in or-der to study the regioselectivity of solvated hydrogen and hydroxyradical attacks. Additional negative charge is distributed upon re-duction at the chlorine and cyano subunits and in para-position tothe cyano group. Most of the negative charge (about 70%) is locatedin the aromatic ring. The different protonation sites for the nega-tively charged radical and neutral species are explained by dis-tinctly different electro-negativities. The observed position of a hy-droxy radical attack on 2-chlorobenzonitrile is correlated to the rela-tive stabilities of the six possible addition products. The electrondensity contribution of 2-CBN as calculated by the Mulliken popula-tion analysis method is in excellent agreement with the experimen-tally observed formation of different products: The 2-chloro-5-hydroxybenzonitrile is the preferentially created species, with boththe 4- and 6-hydroxy isomers as important sideproducts.Key words: chlorobenzonitriles, radical addition, reduction, semi-empirical studyINTRODUCTIONThe reaction of haloarenes with solvated electrons has been subject tointensive experimental studies. A reduction reaction is followed by an intra-* Author to whom correspondence should be addressed. (E-mail: andreas.parusel@univie.ac.at)CROATICA CHEMICA ACTA CCACAA 73 (2) 359¿366 (2000)molecular electron transfer leading to dehalogenated products.1–3 The redu-ction of chlorobenzonitriles (see Figure 1) is an intensively studied reac-tion,4–6 as the presence of an additional electron withdrawing group stabi-lizes the radical anion intermediate. The introduction of a negative chargecompletely changes the electronic properties of the molecule, thus resultingin different sites of radical attack. Both the protonation of a solvated hydro-gen atom and the attack of a solvated hydroxy group is of major interest. Inthe neutral species, addition of the hydrated proton takes place at the aro-matic ring carbon atoms,5 whereas the negatively charged chlorobenzoni-trile radical is selectively protonated at the nitrogen of the cyano group.6According to the estimated electron density of the radical anion, the solva-ted H radical should attack both at the 2- and 4- positions, which cannot beobserved in experiment. No satisfactory explanation could be given for thisresult.6 In this semiempirical study we present an investigation of the elec-tron density for both the 2-, 3-, and 4-chlorobenzonitriles (2-CBN, 3-CBN,and 4-CBN, see Figure 1) and their radical anions. These investigationsyield an insight into regioselectivity of the protonation of chlorobenzonitri-les radical anions.The addition of a hydroxy group represents the second radical reactioninvestigated. After an attack of hydroxy radicals5,6 to chlorobenzonitrile, va-rious isomers of chloro-hydroxy-benzonitriles can be formed. This reactionof OH radicals is of special interest due to the regioselectivity of the possibleproducts. The question whether the chloro or cyano unit determines the po-sition of the hydroxy attack remains still unsettled. Mesomeric effects ofboth the chloro and cyano group favor the OH to attack in ortho and paraposition to the chloro atom, and meta position relative to the cyano group.Experimentally, the following order is found for preferred sites of OH radi-cal attacks on 2-CBN: 5 > 3 > 4 >> 6.5 The attack of OH is thus highly re-gioselective. The presented theoretical investigation of the stability of vari-360 A. B. J. PARUSEL ET AL.165432CNCl165432CNCl165432ClCN2-CBN 3-CBN 4-CBNFigure 1. Molecular structures and enumeration of 2-chlorobenzonitrile (2-CBN), 3-chlorobenzonitrile (3-CBN), and 4-chlorobenzonitrile (4-CBN).ous OH radical adducts on the chlorobenzonitriles gives a closer insight inthe regioselectivity of the OH attack presented at the example of 2-CBN.COMPUTATIONAL METHODSThe ground state geometries of all compounds (neutral and radical) areoptimized using the AM1 (Ref. 7) Hamiltonian with an unrestricted Har-tree-Fock (UHF) method, as implemented in the VAMP program package,version 6.1.8 For the optimization, Baker’s eigenvector following algorithmwas used as described in Ref. 9. The radical anions are defined within theunrestricted formalism by a negative charge equivalent of one electron. Theaddition of a hydroxy radical to the closed shell molecule results in an un-charged radical with 26 alpha and 25 beta electrons, which is also treatedwith an UHF approach. The charge distributions are calculated by multi-pole analysis of the distribution of electronic charge density for the givensystem derived from point charges. The charge densities result as a sum ofmolecular orbital densities, each the square of the orbital wavefunction,with the charges of the hydrogen atoms summed up into the heavy atoms.The Mulliken population analysis as used throughout the work assigns allcharge to the nuclei. We point out, that the absolute values are less mean-ingful than differences between similar molecules. The main emphasis isput on the comparison of charge distribution between the similar CBN iso-mers, indicating trends in charge distributions.10 The Mulliken populationanalysis is also applied to obtain the relative ratio for the location of thenegative charge. The point charges for all six aromatic carbon and attachedhydrogen atoms are summarized and compared to the net point charges forboth the chlorine and cyano subunits.RESULTS AND DISCUSSIONThe calculated partial charges are compared for possible addition sitesof both the neutral and the radical anion systems (see Figure 2).In the neutral forms of 2-, 3-, and 4-CBN (see Figure 2, left), the highestelectron densities of approximately –0.13 electrons is found both at the cy-ano group and the unsubstituted 3-position. The benzene carbon atom nextto the cyano group bears no negative charge independent from the positionof the chlorine atom. The negative charge of the cyano group is mainly lo-cated at the carbon atom. The negative charge at the chlorine is neglectiga-ble, the electron density of the carbon atom directly connected to it is sig-nificantly reduced. A different situation is found for the three correspondingradical anions in contrast to the neutral isomers (see Figure 2, right). TheA THEORETICAL STUDY ON CHLOROBENZONITRILES 361negative charge at the cyano group (–0.27) has a much larger value com-pared to that of the neutral compounds, and the main part of the negativecharge is located on the nitrogen atom. The negative charge of the chlorineatom is increased to ca. –0.13, and a negative charge of –0.27 is found at the4-position for both 2- and 3-CBN.The contribution of the negative charge between the aromatic, cyano,and chloro moiety of the molecule is presented in Figure 3. The major partof the negative charge is located at the benzene moiety with minor contribu-tions divided equally between the cyano and the chloro group (14% and19%). In all cases, a slightly larger negative charge is found at the cyanogroup, indicating its stronger electron withdrawing property. A detailed in-vestigation of the charge distribution within the aromatic subunit shows a362 A. B. J. PARUSEL ET AL.CClN -0.02-0.10+0.01-0.03-0.13-0.10-0.13-0.09-0.01CClN -0.24-0.02-0.12-0.07-0.12-0.27-0.17-0.10-0.24-0.09-0.13-0.10-0.02-0.07-0.090.00-0.10-0.03CNClCNCl-0.25-0.03-0.25-0.11-0.06-0.14-0.27-0.14-0.14-0.04-0.08-0.130.00-0.01-0.10-0.03CNCl-0.19CNCl-0.25-0.03-0.25-0.13-0.15-0.12(A) (B)Figure 2. Negative charge distribution in 2-CBN (top), 3-CBN (middle), and 4-CBN(bottom) for the neutral state (A) and the corresponding radical anions (B).distinct preferred reaction position for this compound. More than 70% of thenegative charge are located at the 1- and the 4-positions within the benzenemoiety. This clearly demonstrates the dominating electronic effect of the cy-ano group compared to the chloro subunit, where no such directing effectscan be observed. The preferences of protonation sites are thus determinedfor both the neutral systems and radical anions. In the three neutral CBNmolecules, the major part of the electron density is located in the aromaticring moiety, favoring a protonation at the aromatic ring carbon atoms.5 Incontrast, the addition of an electron shifts the negative charge from the ringtowards the cyano group, and within this moiety to the nitrogen atom. Inagreement with experiment,6 we find a protonation at the cyano group asthe preferred reaction.The regioselectivity for the addition of the OH radical to the three CBNsystems is mainly related to three aspects: 1) directing influences of theA THEORETICAL STUDY ON CHLOROBENZONITRILES 363CClNCClNCClN(64%) (17%) (19%)CNClCNClCNCl(69%) (14%) (17%)CNClCNClCNCl(65%) (16%) (19%)(A)(B)(C)Figure 3. Positions of the negative charge distribution in 2-CBN (A), 3-CBN (B), and4-CBN (C) radical anion.364 A. B. J. PARUSEL ET AL.Figure 4. Total energies for the 2-chloro-1-hydroxybenzonitrile to 2-chloro-6-hydro-xybenzonitrile addition products.chloro and cyano groups, 2) electron densities, and 3) steric hindrance. 2-CBN is studied as a representative example due to the previously discussedsimilarities between all three systems. All six carbon atoms of the aromaticsystem are considered as possible reactive sites for the addition of the hy-droxy radical. The total energies of all six products are presented in Figure4 along with their molecular structure. The results clearly indicate a pre-ferred addition at the 5-position, yielding the most stable system. Additionsat the 4- and 6-position result in slightly less stable conformations (E = 0.8kJ/mol). Compared to the product of an addition at the 5-position the addi-tion product in 3-position is destabilized by more than 6.3 kJ/mol. Stericalhindrance causes additions both at the chloro and at the cyano positions re-sulting in significantly destabilized compounds. According to our calcula-tions, the 5-position is the preferred position of a hydroxy radical group at-tack, with the chlorine atom as the most effective directing group. The 4-and 6-positions (i.e. ortho and para to CN) are only slightly destabilized.The para addition relative to the cyano unit (4-position) results in a less sta-ble product compared to the para addition relative to the Cl atom. It be-comes clear thereby, that the chloro atom has stronger directing effects com-pared to that of the cyano group. The 3-position (i.e. mesomeric favoredortho position to chlorine) results in a less stable product, due to strong ste-rical hindrance caused by the large halogen atom. This indicates that thecyano group has electron withdrawing properties of the same magnitude asthe chlorine moiety. Sterical hindrance is less important in this case due tothe strong stabilization caused by the low energy of the addition product ofthe reaction at the 6-position.As an electrophilic species, the hydroxy radical preferably attacks thesite with the highest electron density. According to Figure 2, these are the3- and 5-positions, and to a somewhat smaller degree the 4-position. A com-parison of electron densities and stabilities of addition products (see Figure4) is in good agreement with experimental data,5 where both the 3- and 5-position are found as the main sites of addition. Both the 4- and 6-adductsare relevant sideproducts.5 Our calculations of total energies yield the 3-and 5-addition products as the most stable – besides the 4-product – and acorresponding large electron density is found at these positions. A clear dis-advantage of the direct addition to the chloro and cyano ipso position is ob-served, which is in agreement with experimental results.5CONCLUSIONSThe chlorobenzonitriles and their radical anions are investigated by se-miempirical methods. The different protonation sites for neutral and redu-ced CBN are satisfactorily predicted by these quantum mechanical studiesA THEORETICAL STUDY ON CHLOROBENZONITRILES 365of the prevailing charge densities. The electron densities and the relativestability of various hydroxy radical addition products thus allow the expla-nation of the experimentally observed products.Acknowledgments. – ABJP thanks the German Academic Exchange Service(DAAD) for a postdoctoral fellowship. The Fonds zur Förderung der Wissenschaft-lichen Forschung in Österreich (project nr. P11880-CHE) is gratefully acknowledgedfor financial support. We also like to thank Nikola Getoff (University of Vienna) forhis interest in and help with this work.REFERENCES1. M. Anbar, Adv. Phys. Org. Chem. 7 (1969) 115–125.2. J. Lichtscheidl and N. Getoff, Int. J. Radiat. Phys. Chem. 8 (1976) 661–666.3. N. Getoff and S. Solar, Radiat. Phys. Chem. 31 (1988) 121–130.4. P. Neta and D. Behar, J. Am. Chem. Soc. 103 (1981) 103–106.5. W. D. Geppert and N. Getoff, Radiat. Phys. Chem. 51 (1998) 281–292.6. W. D. Geppert, N. Getoff, and K. Sehested, in preparation.7. M. J. S. Dewar, E. G. Zoebisch, E. F. Healy, and J. J. P. Stewart, J. Am. Chem. Soc.107 (1985) 3902–3909.8. G. Rauhut, A. Alex, J. Chandrasekhar, T. Steinke, W. Sauer, B. Beck, M. Hutter,P. Gedeck, and T. Clark, VAMP6.1, Oxford Molecular Ltd., Oxford, 1997.9. J. Baker, J. Comput. Chem. 7 (1986) 385–395.10. S. M. Bachrach in: Reviews in Computational Chemistry, K. B. Lipkowitz and D.B. Boyd (Eds.), Indiana University-Purdue University at Indianapolis (IUPUI),1994, Vol. 5, p. 171.SA@ETAKRedukcija i adicija radikala: Teorijska istra`ivanja klorbenzonitrilaAndreas B. J. Parusel, Rudolf Schamschule i Gottfried KöhlerIzomeri klorbenzonitrila te njihovi anion-radikali istra`ivani su semiempirijskimra~unskim metodama da se do|e do novih saznanja o regioselektivnosti reakcija sol-vatiziranog vodika i hidroksil-radikala. Negativni naboj stvoren tijekom redukcijeraspodijeli se izme|u klora, ciano-substituenta i ugljika u para-polo`aju u odnosu naciano-skupinu. Oko 70% negativnog naboja nalazi se na aromatskom prstenu. Raz-lika u reaktivnim mjestima negativno nabijenog radikala i neutralne molekule mo`ese objasniti razlikama u elektronegativnosti. U reakciji hidroksil-radikala s 2-klor-benzonitrilom mjesto adicije ovisi o relativnoj stabilnosti {est mogu}ih produkata.Elektronske gusto}e, izra~unane Mulliken-ovom populacijskom analizom za 2-klor-benzonitril, vrlo se dobro sla`u s dobivenim primarnim i sekundarnim produktima:2-klor-5-hidroksibenzonitril je primarni produkt, a 4-hidroksi- i 6-hidroksi-izomeriglavni su sekundarni produkti.366 A. B. J. PARUSEL ET AL.

A Theoretical Study on Chlorobenzonitriles

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