Co-reporter:Joseph Clarke, Patrick W. Fowler, Scott Gronert, and James R. Keeffe
The Journal of Organic Chemistry 2016 Volume 81(Issue 19) pp:8777-8788
Publication Date(Web):September 6, 2016
DOI:10.1021/acs.joc.6b01261
Suprafacial sigmatropic shift reactions of 5-substituted cyclopentadienes, 3-substituted cyclopropenes, and 7-substituted cycloheptatrienes have been studied computationally at the MP2/6-31+G* level for structures and energetics and with the ipsocentric method at the CHF/6-31G** level to calculate current–density maps. The hydrogen shifts in cyclopentadienes have a diatropic ring current indicating aromatic, cyclopentadienide anion character. This result stands in contrast to the fluorine shift in 5-fluorocyclopentadiene which requires much more energy and has a paratropic ring current in the TS pointing to antiaromatic, cyclopentadienyl cation character. [1,3] hydrogen shifts in cyclopropenes are very difficult, passing through transition states that have an extended C–C bond. For 3-fluorocyclopropene, the [1,3] fluorine shift is much easier than the hydrogen shift. For 7-fluorocycloheptatriene, the [1,7] hydrogen shift is predicted but requires very high energy and has a paratropic ring current and antiaromatic character. The [1,7] suprafacial fluorine shift is relatively easy, having a TS with cycloheptatrienyl cation character. Patterns of currents, and the reversal for H and F migration, are rationalized by orbital analysis based on the ipsocentric method. Calculated charges and structural features for reactants and transition states support these conclusions.
Co-reporter:Jeannette T. Bowler, Freeman M. Wong, Scott Gronert, James R. Keeffe and Weiming Wu
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 32) pp:6175-6180
Publication Date(Web):25 Jun 2014
DOI:10.1039/C4OB00946K
The “element effect” in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving group order, L = F > NO2 > Cl ≈ Br > I, in activated aryl substrates. A different leaving group order is observed in the substitution reactions of ring-substituted N-methylpyridinium compounds with piperidine in methanol: 2-CN ≥ 4-CN > 2-F ∼ 2-Cl ∼ 2-Br ∼ 2-I. The reactions are second-order in [piperidine], the mechanism involving rate determining hydrogen-bond formation between piperidine and the substrate-piperidine addition intermediate followed by deprotonation of this intermediate. Computational results indicate that deprotonation of the H-bonded complex is probably barrier free, and is accompanied by simultaneous loss of the leaving group (E2) for L = Cl, Br, and I, but with subsequent, rapid loss of the leaving group (E1cB-like) for the poorer leaving groups, CN and F. The approximately 50-fold greater reactivity of the 2- and 4-cyano substrates is attributed to the influence of the electron withdrawing cyano group in the deprotonation step. The results provide another example of β-elimination reactions poised near the E2-E1cB mechanistic borderline.
Co-reporter:Ihsan Erden, Scott Gronert, James R. Keeffe, Jingxiang Ma, Nuket Ocal, Christian Gärtner, and Leah L. Soukup
The Journal of Organic Chemistry 2014 Volume 79(Issue 14) pp:6410-6418
Publication Date(Web):June 30, 2014
DOI:10.1021/jo501157s
The activating effects of the benzyl and allyl groups on SN2 reactivity are well-known. 6-Chloromethyl-6-methylfulvene, also a primary, allylic halide, reacts 30 times faster with KI/acetone than does benzyl chloride at room temperature. The latter result, as well as new experimental observations, suggests that the fulvenyl group is a particularly activating allylic group in SN2 reactions. Computational work on identity SN2 reactions, e.g., chloride– displacing chloride– and ammonia displacing ammonia, shows that negatively charged SN2 transition states (tss) are activated by allylic groups according to the Galabov–Allen–Wu electrostatic model but with the fulvenyl group especially effective at helping to delocalize negative charge due to some cyclopentadienide character in the transition state (ts). In contrast, the triafulvenyl group is deactivating. However, the positively charged SN2 transition states of the ammonia reactions are dramatically stabilized by the triafulvenyl group, which directly conjugates with a reaction center having SN1 character in the ts. Experiments and calculations on the acidities of a variety of allylic alcohols and carboxylic acids support the special nature of the fulvenyl group in stabilizing nearby negative charge and highlight the ability of fulvene species to dramatically alter the energetics of processes even in the absence of direct conjugation.
Co-reporter:Jaya Satyanarayana Kudavalli ; S. Nagaraja Rao ; David E. Bean ; Narain D. Sharma ; Derek R. Boyd ; Patrick W. Fowler ; Scott Gronert ; Shina Caroline Lynn Kamerlin ; James R. Keeffe ;Rory A. More O’Ferrall
Journal of the American Chemical Society 2012 Volume 134(Issue 34) pp:14056-14069
Publication Date(Web):July 25, 2012
DOI:10.1021/ja304366j
Evidence that a 1,2-dihydroxycyclohexadienide anion is stabilized by aromatic “negative hyperconjugation” is described. It complements an earlier inference of “positive” hyperconjugative aromaticity for the cyclohexadienyl cation. The anion is a reactive intermediate in the dehydration of benzene cis-1,2-dihydrodiol to phenol. Rate constants for 3-substituted benzene cis-dihydrodiols are correlated by σ– values with ρ = 3.2. Solvent isotope effects for the reactions are kH2O/kD2O = 1.2–1.8. These measurements are consistent with reaction via a carbanion intermediate or a concerted reaction with a “carbanion-like” transition state. These and other experimental results confirm that the reaction proceeds by a stepwise mechanism, with a change in rate-determining step from proton transfer to the loss of hydroxide ion from the intermediate. Hydrogen isotope exchange accompanying dehydration of the parent benzene cis-1,2-dihydrodiol was not found, and thus, the proton transfer step is subject to internal return. A rate constant of ∼1011 s–1, corresponding to rotational relaxation of the aqueous solvent, is assigned to loss of hydroxide ion from the intermediate. The rate constant for internal return therefore falls in the range 1011–1012 s–1. From these limiting values and the measured rate constant for hydroxide-catalyzed dehydration, a pKa of 30.8 ± 0.5 was determined for formation of the anion. Although loss of hydroxide ion is hugely exothermic, a concerted reaction is not enforced by the instability of the intermediate. Stabilization by negative hyperconjugation is proposed for 1,2-dihydroxycyclohexadienide and similar anions, and this proposal is supported by additional experimental evidence and by computational results, including evidence for a diatropic (“aromatic”) ring current in 3,3-difluorocyclohexadienyl anion.
Co-reporter:Nicholas A. Senger, Bo Bo, Qian Cheng, James R. Keeffe, Scott Gronert, and Weiming Wu
The Journal of Organic Chemistry 2012 Volume 77(Issue 21) pp:9535-9540
Publication Date(Web):October 11, 2012
DOI:10.1021/jo301134q
The “element effect” in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving group order, F > NO2 > Cl ≈ Br > I, in activated aryl halides. Multiple causes for this result have been proposed. Experimental evidence shows that the element effect order in the reaction of piperidine with 2,4-dinitrophenyl halides in methanol is governed by the differences in enthalpies of activation. Computational studies of the reaction of piperidine and dimethylamine with the same aryl halides using the polarizable continuum model (PCM) for solvation indicate that polar, polarizability, solvation, and negative hyperconjugative effects are all of some importance in producing the element effect in methanol. In addition, a reversal of polarity of the C–X bond from reactant to transition state in the case of ArCl and ArBr compared to ArF also contributes to their differences in reactivity. The polarity reversal and hyperconjugative influences have received little or no attention in the past. Nor has differential solvation of the different transition states been strongly emphasized. An anionic nucleophile, thiolate, gives very early transition states and negative activation enthalpies with activated aryl halides. The element effect is not established for these reactions. We suggest that the leaving group order in the gas phase will be dependent on the exact combination of nucleophile, leaving group, and substrate framework. The geometry of the SNAr transition state permits useful, qualitative conceptual distinctions to be made between this reaction and other modes of nucleophilic attack.
Co-reporter:James R. Keeffe
Journal of Physical Organic Chemistry 2004 Volume 17(Issue 12) pp:1075-1083
Publication Date(Web):14 JUN 2004
DOI:10.1002/poc.784
Nucleophilic attack of cyanide anion at the carbonyl carbon was studied computationally at the MP2/6–311+G** level for ketene and at the MP2/6–31+G* and MP2/6–31+G*//HF/6–31+G* levels for all four title compounds. Heats of addition were computed for formation of in-plane adducts and perpendicular adducts where the terms ‘in-plane’ and ‘perpendicular’ indicate the direction of nucleophilic attack relative to the ketene plane. Heats of activation were also computed for the two modes of attack. For ketene (1) the in-plane adduct is favored by 37.6 kcal mol−1 and the in-plane transition state by 18.8 kcal mol−1. For the 6-methylene compound (2) the in-plane adduct is favored by 20.1 kcal mol−1 and the in-plane transition state by 7.3 kcal mol−1. For the 6-oxo compound (3) the in-plane adduct is more stable by 11.2 kcal mol−1 whereas the in-plane transition state is preferred by 8.8 kcal mol−1. For the 4-oxo compound (4) the in-plane adduct is favored by 19.3 kcal mol−1 but its transition state by only 2.8 kcal mol−1. The in-plane adduct for ketene is the enolate of acetyl cyanide while the perpendicular adduct is a pyramidalized carbanion attached to a cyanocarbonyl group. Calculated NPA charges support this conclusion. The perpendicular adduct is actually the transition state for rotation about the CC bond of the ketene moiety in the in-plane adduct, and the 37.6 kcal mol−1 enthalpy difference is closely matched by the calculated activation enthalpy for rotation about the CC bond of acetaldehyde enolate: ΔH‡ = 33.6 kcal mol−1. The smaller differences found for in-plane vs perpendicular adduct formation for the 6-methylene, 6-oxo and 4-oxo compounds are correlated with decreases in bond length alternation within the six-membered rings which occur upon addition of the nucleophile. Less alternation may be associated with an approach to aromaticity, hence an increase in stability. Both modes of attack lead to reduced bond length alternation, but the amount of alternation is lowered more for the perpendicular adducts than for the in-plane adducts. Changes in the CO bond lengths are also diagnostic. For all four ketenes the ketenyl CO length in the in-plane adducts is greater than in the perpendicular adducts reflecting more single bond (enolate) character in the former and more double bond (carbonyl) character in the latter. On the other hand the lengths of the 6-oxo and 4-oxo CO bonds in their in-plane adducts are smaller than in the perpendicular adducts, consistent with increased conjugation with the oxo substituent in the latter. The greater NPA charge on the 6-oxo and 4-oxo oxygens of the perpendicular adducts supports this conclusion. Calculated enthalpies of activation are in the order ketene > 6-methyleneketene > 6-oxoketene, in qualitative agreement with experimentally determined rates of hydration. Copyright © 2004 John Wiley & Sons, Ltd.
Co-reporter:Jeannette T. Bowler, Freeman M. Wong, Scott Gronert, James R. Keeffe and Weiming Wu
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 32) pp:NaN6180-6180
Publication Date(Web):2014/06/25
DOI:10.1039/C4OB00946K
The “element effect” in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving group order, L = F > NO2 > Cl ≈ Br > I, in activated aryl substrates. A different leaving group order is observed in the substitution reactions of ring-substituted N-methylpyridinium compounds with piperidine in methanol: 2-CN ≥ 4-CN > 2-F ∼ 2-Cl ∼ 2-Br ∼ 2-I. The reactions are second-order in [piperidine], the mechanism involving rate determining hydrogen-bond formation between piperidine and the substrate-piperidine addition intermediate followed by deprotonation of this intermediate. Computational results indicate that deprotonation of the H-bonded complex is probably barrier free, and is accompanied by simultaneous loss of the leaving group (E2) for L = Cl, Br, and I, but with subsequent, rapid loss of the leaving group (E1cB-like) for the poorer leaving groups, CN and F. The approximately 50-fold greater reactivity of the 2- and 4-cyano substrates is attributed to the influence of the electron withdrawing cyano group in the deprotonation step. The results provide another example of β-elimination reactions poised near the E2-E1cB mechanistic borderline.
