Predicting regioselectivity in nucleophilic aromatic substitution.

We have investigated practical and computationally efficient methods for the quantitative prediction of regioisomer distribution in kinetically controlled nucleophilic aromatic substitution reactions. One of the methods is based on calculating the relative stabilities of the isomeric σ-complex intermediates using DFT. We show that predictions from this method can be used quantitatively both for anionic nucleophiles with F(-) as leaving group, as well as for neutral nucleophiles with HF as leaving group. The σ-complex approach failed when the leaving group was Cl/HCl or Br/HBr, both for anionic and neutral nucleophiles, because of difficulties in finding relevant σ-complex structures. An approach where we assumed a concerted substitution step and used such transition state structures gave quantitatively useful results. Our results are consistent with other theoretical works, where a stable σ-complex has been identified in some cases, whereas others have been indicated to proceed via a concerted substitution step.

[1]  T. Brinck,et al.  A pragmatic procedure for predicting regioselectivity in nucleophilic substitution of aromatic fluorides , 2011 .

[2]  N. Nudelman,et al.  Hydrogen-bonded nucleophile effects in ANS: the reactions of 1-chloro and 1-fluoro-2,4-dinitrobenzene with 2-guanidinobenzimidazole, 1-(2-aminoethyl)piperidine and N-(3-aminopropyl)morpholine in aprotic solvents , 2011 .

[3]  I. C. Jones,et al.  Base‐dependent selectivity of an SNAr reaction , 2010 .

[4]  Patrik Rydberg,et al.  Application of Q2MM to Stereoselective Reactions , 2010 .

[5]  T. Brinck,et al.  Validation of a computational model for predicting the site for electrophilic substitution in aromatic systems. , 2010, The Journal of organic chemistry.

[6]  Gernot Frenking,et al.  Rate-determining factors in nucleophilic aromatic substitution reactions. , 2010, The Journal of organic chemistry.

[7]  E. Würthwein,et al.  Di‐ and Trifluorobenzenes in Reactions with Me2EM (E = P, N; M = SiMe3, SnMe3, Li) Reagents: Evidence for a Concerted Mechanism of Aromatic Nucleophilic Substitution , 2010 .

[8]  D. Berger,et al.  Dramatic effect of solvent hydrogen bond basicity on the regiochemistry of S(N)Ar reactions of electron-deficient polyfluoroarenes. , 2009, Organic letters.

[9]  S. O. N. Lill.  Application of Dispersion-Corrected Density Functional Theory , 2009 .

[10]  L. Désaubry,et al.  Regioselectivity of fluorine substitution by alkoxides on unsymmetrical difluoroarenes , 2008 .

[11]  S. Buchwald,et al.  Palladium‐Catalyzed Aromatic Carbon‐Nitrogen Bond Formation , 2008 .

[12]  I. Um,et al.  Choice of solvent (MeCN vs H(2)O) decides rate-limiting step in S(N)Ar aminolysis of 1-fluoro-2,4-dinitrobenzene with secondary amines: importance of Brønsted-type analysis in acetonitrile. , 2007, The Journal of organic chemistry.

[13]  E. A. Luk'yanets,et al.  Phthalocyanines and related compounds: XLIII. Synthesis of poly[phenyl(alkyl)sulfanyl]-substituted phthalonitriles and some phthalocyanines based thereon , 2007 .

[14]  P. Corona,et al.  Synthesis of Substituted Aminoquinolines as Useful Intermediates for Preparation of Aromatic N-Tricyclic Systems , 2006 .

[15]  Raju Mondal,et al.  Effects of ortho- and para-Ring Activation on the Kinetics of SNAr Reactions of 1-Chloro-2-nitro- and 1-Phenoxy-2-nitrobenzenes with Aliphatic Amines in Acetonitrile , 2006 .

[16]  C. Isanbor,et al.  Electronic and steric effects in the SNAr substitution reactions of substituted anilines with 2,4‐dinitrophenyl 2,4,6‐trinitrophenyl ether in acetonitrile , 2006 .

[17]  P. Mancini,et al.  A mechanistic viewpoint of the reaction between 1‐fluoro‐2,6‐dinitrobenzene and alicyclic amines in the ethyl acetate–chloroform system , 2005 .

[18]  Alejandro Toro-Labbé,et al.  New dual descriptor for chemical reactivity. , 2005, The journal of physical chemistry. A.

[19]  J. Schomaker,et al.  2,4,6-Trifluoropyrimidine. Reactions with nitrogen nucleophiles , 2004 .

[20]  William L Jorgensen,et al.  Solvent effects and mechanism for a nucleophilic aromatic substitution from QM/MM simulations. , 2004, Organic letters.

[21]  J. Riveros,et al.  An unusually fast nucleophilic aromatic displacement reaction: the gas-phase reaction of fluoride ions with nitrobenzene. , 2004, Angewandte Chemie.

[22]  Alejandro Toro-Labbé,et al.  Condensation of Frontier Molecular Orbital Fukui Functions , 2004 .

[23]  Donald G. Truhlar,et al.  Effectiveness of Diffuse Basis Functions for Calculating Relative Energies by Density Functional Theory , 2003 .

[24]  Kiyoshi Tanaka,et al.  Ab initio Study of Nucleophilic Aromatic Substitution of Polyfluorobenzene , 1999 .

[25]  S. Buchwald,et al.  Palladium-catalyzed amination of aryl halides and sulfonates , 1999 .

[26]  B. Gierczyk,et al.  Reaction of fluoronitrobenzenes with tetramethylguanidine in acetonitrile , 1999 .

[27]  P. Geerlings,et al.  Local Softness and Hardness Based Reactivity Descriptors for Predicting Intra- and Intermolecular Reactivity Sequences: Carbonyl Compounds , 1998 .

[28]  M. Glukhovtsev,et al.  Single-Step and Multistep Mechanisms of Aromatic Nucleophilic Substitution of Halobenzenes and Halonitrobenzenes with Halide Anions: Ab Initio Computational Study , 1997 .

[29]  K. Butin,et al.  Regioselectivity of methoxydebromination of substituted pentabromobenzenes C6Br5X in pyridine , 1995 .

[30]  M. Bower,et al.  Remarkable orientational effects in the displacement of the fluorine from heptafluoro-isoquinoline and -quinoline towards sulfur nucleophiles. Further reactions with oxygen nucleophiles , 1993 .

[31]  R. Bacaloglu,et al.  MECHANISM OF REACTION OF HYDROXIDE ION WITH DINITROCHLOROBENZENES , 1991 .

[32]  S. Cai,et al.  New reagents for photoaffinity labeling: synthesis and photolysis of functionalized perfluorophenyl azides , 1990 .

[33]  H. Yoshizawa,et al.  MNDO (Modified Neglect of Diatomic Overlap) Study of the Nucleophilic Substitution Reactions of Chloropyrimidines , 1989 .

[34]  R. Chambers,et al.  Mechanisms for reactions of halogenated compounds. Part 5. Orientating effects of fluorine substituents on nucleophilic substitution in naphthalene and other polycyclic systems , 1988 .

[35]  R. Bacaloglu,et al.  Single-electron transfer in aromatic nucleophilic addition and substitution in aqueous media , 1988 .

[36]  R. Chambers,et al.  Mechanisms for reactions of halogenated compounds. Part 6. Investigations into the activating effect of ortho-fluorine in nucleophilic aromatic substitution , 1988 .

[37]  G. Clark,et al.  A palladium-catalyzed rearrangement of 1-vinyl-1-cyclobutanols , 1985 .

[38]  R. Chambers,et al.  Mechanisms for reactions of halogenated compounds. Part 4.[1] activating influences of ring-nitrogen and trifluoromethyl in nucleophilic aromatic substitution , 1982 .

[39]  R. Banks,et al.  Studies in azide chemistry. Part IX [1]. Investigations involving fluorinated azidopyrimidines and 4-azido-3-chloro-2,5,6-trifluoropyridine , 1980 .

[40]  J. Burdon,et al.  A recent attempt to apply frontier orbital theory to nucleophilic aromatic substitution , 1977 .

[41]  W. Cherry,et al.  AN MO STUDY OF THE ORIENTATIONAL SELECTIVITY IN NUCLEOPHILIC SUBSTITUTION REACTIONS OF POLYHALOBENZENES , 1976 .

[42]  J. Zoltewicz.  New directions in aromatic nucleophilic substitution , 1975 .

[43]  R. Chambers,et al.  Polyhalogenoheterocyclic compounds. Part XXVI. Nucleophilic substitution in trifluoropyrazines , 1974 .

[44]  I. Collins,et al.  Polyhalogeno-aromatic compounds. Part XIV. Nucleophilic substitution and peroxy-acid oxidation of pentabromopyridine and some of its NN-dialkylamino- and bis-(NN-dialkylamino)-derivatives , 1970 .

[45]  I. Collins,et al.  Polyhalogeno-aromatic compounds. Part VIII. Reactions of hexabromobenzene with nucleophiles , 1969 .

[46]  R. Haszeldine,et al.  Synthesis and reactions of pentachloropyridine , 1967 .

[47]  J. Burdon.  A rationalization of orientation and reactivity in the nucleophilic replacement reactions of aromatic polyhalo-compounds , 1965 .

[48]  G. Marino,et al.  Meta-substituent effects on the kinetics of methoxydechlorination of some 2- and 4-chloroquinolines , 1963 .