Solution and gas-phase acidities of all-trans (all-E) retinoic acid: an experimental and computational study.

Retinoic acid is of fundamental biological importance. Its acidity was determined in the gas phase and in acetonitrile solution by means of mass spectrometry and UV/Vis spectrophotometry, respectively. The intrinsic acidity is slightly higher than that of benzoic acid. In solution, the situation is opposite. The experimental systems were described theoretically applying quantum chemical methods (wave function theory and density functional theory). This allowed the determination of the molecular structure of the acid and its conjugate base, both in vacuo and in solution, and for computational estimates of its acidity in both phases.

Synthesis of δ-oxo-1,1-bis(triflyl)alkanes and their acidities.

The reaction of 1,1-bis(triflyl)ethylene generated in situ with enolizable carbonyls yielded δ-oxo-1,1-bis(triflyl)alkane derivatives. Their acidities in both the gas and solution phases were determined.

Kinetic and theoretical studies on alkaline ethanolysis of 4-nitrophenyl salicylate: effect of alkali metal ions on reactivity and mechanism.

Pseudo-first-order rate constants (k(obsd)) for reactions of 4-nitrophenyl salicylate (7) with alkali metal ethoxides (EtOM, M = K, Na, and Li) in anhydrous ethanol have been measured spectrophotometrically. Interestingly, the k(obsd) value decreases significantly as the concentration of EtOM increases. Because the phenolic moiety of substrate 7 would be deprotonated and exist as an anionic form (i.e., 7(-)) under kinetic conditions, the ground-state stabilization of 7(-) through formation of a six-membered cyclic complex with M(+) (i.e., 8) is proposed to be responsible for the decreasing k(obsd) trend. The k(obsd) value at a given concentration of EtOK increases steeply upon addition of [18]crown-6 ether (18C6) up to [18C6]/[EtOK] = 1 in the reaction mixture and then remains relatively constant thereafter. In contrast, k(obsd) decreases upon addition of salts (e.g., LiClO(4) or KSCN) to the reaction mixture, which indicates that M(+) ions inhibit the reaction. However, in the presence of 18C6, the k(obsd) value is independent of the concentration of EtOK but remains constant, which indicates that the reaction proceeds through a unimolecular mechanism in the presence of the complexing agent. Although two conceivable unimolecular pathways (formation of ketene 9 and lactone 10) can account for the kinetic results, the reaction has been concluded to proceed via formation of ketene 9 as the reactive intermediate on the basis of theoretical calculations.

Highly effective vinylogous Mukaiyama-Michael reaction catalyzed by silyl methide species generated from 1,1,3,3-tetrakis(trifluoromethanesulfonyl)propane.

Silyl methide species in situ generated from 1,1,3,3-tetrakis(trifluoromethanesulfonyl)propane (Tf(2)CHCH(2)CHTf(2)) performed as an excellent acid catalyst for the vinylogous Mukaiyama-Michael reaction of alpha,beta-unsaturated ketones with 2-silyloxyfurans. Notably, the required loading of Tf(2)CHCH(2)CHTf(2) to obtain the 1,4-adducts in reasonable yield was significantly low (from 0.05 to 1.0 mol %). This carbon acid-mediated VMM reaction provides a powerful synthetic methodology to construct highly substituted gamma-butenolide structure.

Gas-phase basicities around and below water revisited.

This work employs Fourier transform ion cyclotron resonance (FT-ICR) and the Gaussian quantum chemistry composite methods W1 and G2 to experimentally and computationally analyze gas-phase basicities (GB) for a series of weak bases in the basicity region around and below water. The study aims to clarify the long-standing discrepancy between reported GB values for weak bases obtained via high-pressure mass spectrometry (HPMS) and ICR; the ICR scale is observed to be more than 2 times contracted compared to the HPMS scale. The computational results of this work support published HPMS data. This agreement improves with increasing sophistication of the computational method and is excellent at the W1 level. Several equilibria were also re-examined experimentally using FT-ICR. In the experiments with some polyfluorinated weak bases (hexafluoro-2-propanol and nonafluoro-2-methyl-2-propanol), it was found that two protonation processes compete in the gas phase: protonation on oxygen and protonation on fluorine. In these species, protonation on fluorine proceeds faster and is statistically favored over protonation on oxygen but leads to cations that are thermodynamically less stable than oxygen-protonated cations. The process may also lead to the irreversible loss of HF. The rearrangement of fluorine-protonated cations to oxygen-protonated cations is very slow and is further suppressed by the process of HF abstraction. These results at least partially explain the discrepancy between published HPMS data and earlier FT-ICR findings and call for the utmost care in using FT-ICR for gas-phase basicity measurements of heavily fluorinated compounds. The narrower dynamic range of ICR necessitates the measurement of several problematic bases and produces some differences between the ICR results in the present work and the published HPMS data; the wider dynamic range allows HPMS to overcome these difficulties in connecting the ladder.

Structural effect on the stability of acetophenone-B(OMe)2 complexes in the gas phase. The nature of the bond between the boron cation and neutral molecules.

The free energy changes (DeltaG, boron cation basicity; BCB) for the reaction [(MeO)2B]L+ = (MeO)2B+ + L (L = acetophenones) were determined in the gas phase by measuring ligand exchange equilibria using an FT-ICR mass spectrometer. On the basis of the correlation analysis by the Yukawa-Tsuno equation, DeltaG = rho(sigma degrees + r+DeltasigmaR+), the substituent effect on DeltaBCB of acetophenone was characterized by a rho value (in kJ mol(-1) sigma(-1) unit) of -43.2 and an r+ value of 0.89. Both the rho and r+ values were found to be similar to the corresponding values for protonation, indicating that the bond between (MeO)2B+ and the oxygen atom of the carbonyl group has a high covalent character similar to the H+-O=C bond. This conclusion was consistent with the geometrical features and the charge distribution calculated at DFT-B3LYP/6-311+G(d,p) level of theory. A comparison with the results for a series of Lewis cation basicity of the acetophenone system showed that the r+ value decreases in the order of H+ = (MeO)2B+ > Me3Si+ > Me3Ge+ > Cu+ > Li+. This decreasing order is related to increasing ionic (ion-dipole interaction) nature of the bonding interaction between Lewis cations and the carbonyl oxygen atom. This was also supported by the theoretical calculations.

Revision of the gas-phase acidity scale below 300 kcal mol(-1).

The gas-phase acidity (GA) scale from (CF(3)CO)(2)NH to (C(2)F(5)SO(2))(2)NH--about a 24 kcal mol(-1) range of gas-phase acidities--was reexamined using the Fourier transform ion cyclotron resonance equilibrium measurement approach. Some additions and modifications to the standard methodology of GA measurements were introduced (estimation of partial pressures from mass spectra of the compounds, instead of the pressure gauge readings and use of long reaction times) to achieve higher reliability. Gas-phase acidities of 18 compounds were determined for the first time. The results reveal a contraction of the previously published values in this part of the scale. In particular, the GA values of (CF(3)SO(2))(2)NH and (C(2)F(5)SO(2))(2)NH (important components of lithium ion battery electrolytes and ionic liquids) were revised toward stronger acidities from 291.8 kcal mol(-1) to 286.5 kcal mol(-1) and from 289.4 kcal mol(-1) to 283.7 kcal mol(-1) (i.e., by 5.3 and 5.7 kcal mol(-1)), respectively. Experimental and computational evidence is presented in support of the current results.

Isomeric solid enols on ring- and amide-carbonyls of substituted 2-carbanilido-1,3-indandiones.

Both isomeric enols on ring carbonyl (5b) and on amide carbonyl (6b) derived from N-p-methoxyphenyl-2-carbamido-1,3-indandione (4b) were isolated, and their X-ray structures were determined. X-ray diffraction of the N-o,p-dimethoxy analogue indicated a disorder ascribed to the presence of a 6:4 mixture of 5c and 6c. Calculation (B3LYP/6-31+G*) gave good agreement with observed geometries. The calculated energies indicated that enols 6 are more stable by <1 kcal/mol than enols 5 and much more stable than amides 4.

Regioselective carbon-carbon bond cleavage in the oxidation of cyclopropenylcarbinols.

The strained double bond of cyclopropenylcarbinols undergoes a facile oxidation reaction to lead to unsaturated carbonyl derivatives. The distribution of the formed products depends on the relative stability of carbon-centered radical species, and the Sharpless kinetic resolution leads to enantiomerically pure Baylis-Hillman enal adducts.

Structural effects on interconversion of oxygen-substituted bisketenes and cyclobutenediones.

Cyclobutenediones 5 disubstituted with HO (a), MeO (b), EtO (c), i-PrO (d), t-BuO (e), PhO (f), 4-MeOC6H4O (g), 4-O2NC6H4O (h), and 3,4-bridging OCH2CH2O (i) substituents upon laser flash photolysis gave the corresponding bisketenes 6a-i, as detected by their distinctive doublet IR absorptions between 2075 and 2106 and 2116 and 2140 cm-1. The reactivities in ring closure back to the cyclobutenediones were greatest for the group 6b-e, with the highest rate constant of 2.95 x 10(7) s-1 at 25 degrees C for 6e (RO = t-BuO) in isooctane, were less for 6a (RO = OH, k = 2.57 x 10(6) s-1 in CH3CN), while 6f-i were the least reactive, with the lowest rate constant of 3.8 x 10(4) s-1 in CH3CN for 6h (RO = 4-O2NC6H4O). The significantly reduced rate constants for 6f-i are attributed to diminution of the electron-donating ability of oxygen to the cyclobutenediones 5f-h by the ArO substituents compared to alkoxy groups and to angle strain in the bridged product cyclobutenedione 5i. The reactivities of the ArO-substituted bisketenes 6f-h in CH3CN varied by a factor of 50 and gave an excellent correlation of the observed rate constants log k with the sigma p constants of the aryl substituents. Computational studies at the B3LYP/6-31G(d) level of ring-closure barriers are consistent with the measured reactivities. Photolysis of squaric acid (5a) in solution provides a convenient preparation of deltic acid (7).

Pentakis(trifluoromethyl)phenyl, a sterically crowded and electron-withdrawing group: synthesis and acidity of pentakis(trifluoromethyl)benzene, -toluene, -phenol, and -aniline.

A general route to functionalized pentakis(trifluoromethyl)phenyl (C6(CF3)5) derivatives, promising building blocks for designing novel stable carbenes, radical species, superacids, weakly coordinating anions and other practically and theoretically useful species, is presented. This pertrifluoromethylation route proceeds via conveniently pregenerated (trifluoromethyl)copper (CF3Cu) species in DMF, stabilized by addition of 1,3-dimethyl-2-imidazolidinone (DMI). These species react with hexaiodobenzene at ambient temperature to give the potassium pentakis(trifluoromethyl)phenoxide along with hexakis(trifluoromethyl)benzene and pentakis(trifluoromethyl)benzene in a combined yield of 80%. A possible reaction pathway explaining the formation of pentakis(trifluoromethyl)phenoxide is proposed. Pentakis(trifluoromethyl)phenol gives rise to easily functionalized pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)aniline. Pertrifluoromethylation of pentaiodochlorobenzene and pentaiodotoluene allows straightforward access to pentakis(trifluoromethyl)chlorobenzene and pentakis(trifluoromethyl)toluene, respectively. XRD structures of several C6(CF3)5 derivatives were determined and compared with the calculated structures. Due to the steric crowding the aromatic rings in all C6(CF3)5 derivatives are significantly distorted. The gas-phase acidities (Delta Gacid) and pKa values in different solvents (acetonitrile (AN), DMSO, water) for the title compounds and a number of related compounds have been measured. The origin of the acidifying effect of the C6(CF3)5 group has been explored using the isodesmic reactions approach.

Structural effect on the stability of (pyridine)(2)Cu(+) complexes in the gas phase: nature of the bond between copper(I) ion and neutral molecules.

Free energy changes (DeltaG degrees , copper cation basicity) for the reaction L(2)Cu(+) = Cu(+) + 2L were obtained in the gas phase for substituted pyridines based on the measurement of ligand-exchange equilibria in a Fourier transform ion cyclotron resonance (FT-ICR) spectrometer. For 3- and 4-substituted pyridines, the relative copper cation basicities (DeltaCCB[L(2)Cu(+)]) were linearly correlated with the corresponding gas-phase proton basicities (DeltaGB) with a slope of 1.01. On the basis of a linear relationship between the calculated copper cation basicities of dimeric and monomeric complexes at MP2/6-311+G(2p,2d)//B3LYP/6-311G*, DeltaCCB[L(2)Cu(+)](calcd) = 1.54DeltaCCB[LCu(+)](calcd), the substituent effect on the DeltaCCB for the first ligand was estimated to be 0.66 times smaller than the corresponding DeltaGB. A comparison with the corresponding results for other Lewis cation basicity of the pyridine system showed that the magnitude of the substituent effect decreases in the order H(+) (1.00) > Me(3)Si(+) (0.95) > Cl(+) (0.83) > Cu(+) (0.66) > Li(+) (0.47). This change was associated with the natural charges at the Lewis cation moiety and the natural atomic orbital (NAO) bond order of the M+-N bond of the complex ion, indicating the decrease in covalent character of the M(+)-N bond in this order. Furthermore, when a variety of neutral bases such as amines, carbonyl compounds, and ethers were included in a comparison between CCB[L(2)Cu(+)] and GB, it was found that there is a good linear relationship with significant deviations of small molecules and bulky tributylamine, which is attributed to their different steric environment at the binding sites from others, while there is no simple linear relationship with the lithium cation basicities (LCB). The similarity of the substituent effect between CCB[L(2)Cu(+)] and GB reflects the covalent character in the Cu(+) interaction. In conclusion, although the ionic (ion-dipole interaction) nature of the Cu(+) interaction results in a smaller substituent effect than that for the protonation, the covalent nature also plays an important role in the Cu(+) interaction with neutral molecules.

Aminolysis of Y-substituted phenyl X-substituted cinnamates and benzoates: effect of modification of the nonleaving group from benzoyl to cinnamoyl.

A kinetic study is reported for reactions of Y-substituted phenyl X-substituted cinnamates (1a-e and 3a-g) and benzoates (2a-e and 4a-g) with a series of alicyclic secondary amines in 80 mol % H2O/20 mol % DMSO at 25.0 +/- 0.1 degrees C. Reactions of 2,4-dinitrophenyl X-substituted cinnamates (1a-e) and benzoates (2a-e) with amines result in linear Yukawa-Tsuno plots. The rho(X) values are much smaller for the reactions of 1a-e than for those of 2a-e. A distance effect and the nature of the reaction mechanism (i.e., a concerted mechanism for 1a-e) have been suggested to be responsible for the small rho(X) values. The Brønsted-type plots for the reactions of 2,4-dinitrophenyl X-substituted cinnamates (1a, 1c, and 1e) with amines are curved with a decreasing betanuc value from 0.65 to 0.3-0.4. The reactions of Y-substituted phenyl cinnamates (3a-g) with morpholine also result in a curved Brønsted plot, while the corresponding reactions of Y-substituted phenyl benzoates (4a-e) exhibit a linear Brønsted plot. It has been concluded that the curved Brønsted plots found for the reactions of the cinnamates (1a, 1c, 1e, and 3a-g) are not due to a change in the rate-determining step (RDS) but due to a normal Hammond effect for a concerted mechanism, that is, an earlier transition state (TS) for a more reactive amine or substrate.

Observable azacyclobutenone ylides with antiaromatic character from 2-diazoacetyl-azaaromatics.

Azacyclobutenone ylides 2 and 11 were generated in solution by laser flash photolysis of 2-diazoacetylpyridine (1) and 3-diazoacetylpyridazine (10), respectively, together with the corresponding ketenes. The ylides were identified by their characteristic IR and UV spectra: 2, nu (CH3CN) 1725 cm(-1), lambdamax 360 and 550 (br) nm; 11, nu (CH3CN) 1776 cm(-1), lambdamax 370 and 550 (br) nm. 2-Triisopropylsilyldiazoacetylpyridine 20 upon photolysis at 5 degrees C in CH3CN forms the ylide 21 as a rather persistent (T1/2 2 h at 25 degrees C) purple solution, nu (CH3CN) 1718 cm(-1), lambdamax 245, 378 and 546 (br) nm, but no ketene is observed. Quinolyl ylide 14 and pyridyl ylides 17 and 19 with Me and 2-pyridyl substituents, respectively, with characteristic IR and UV spectra were also generated. The 1H NMR spectrum of the pyridyl ring of 21 shows substantial upfield shifts relative to those of 20. Calculated nucleus-independent chemical shifts (NICS) for 2, 11, and 21 are comparable to those for benzocyclobutadiene (22) and benzocyclobutenone enolate (23), with substantial positive values for the 4-membered rings, while the NICS values for the 6-membered rings are significantly more positive than for benzene or pyridine. Significant bond alternation is also found in the calculated ylide structures, and these results suggest strong antiaromatic character for the 4-membered rings of 2, 11, 14, 17, 19, and 21, and greatly reduced aromatic character for the 6-membered rings.

Brønsted basicities of diamines in the gas phase, acetonitrile, and tetrahydrofuran.

A comprehensive basicity study of alpha,omega-alkanediamines and related bases has been carried out. Basicities in acetonitrile (AN, pK(a) values), tetrahydrofuran (THF, pK(alpha) values), and gas phase (GP, GB values), were measured for 16, 14, and 9 diamine bases and for several related monoamines. In addition the gas-phase basicities and equilibrium geometries were computed for 19 diamino bases and several related monoamines at the DFT B3LYP 6-311+G** level. The effects of the different factors (intrinsic basicity of the amino groups, formation of intramolecular hydrogen bonds, and molecular strain) determining the diamine basicities were estimated by using the method of isodesmic reactions. The results are discussed in terms of molecular structure and solvation effects. The GP basicity is determined by the molecular size and polarizability, the extent of alkylation, and the energy effect of intramolecular hydrogen bond formation in the protonated base. The basicity trends in the solvents differ very much from those in GP: 1) The solvents severely compress the basicity range of the bases studied (3.5 times for the 1,3-propanediamine family in AN, and 7 times in THF), and 2) while stepwise alkylation of the basicity center leads to a steady basicity increase in the gas phase, the picture is complex in the solvents. Significant differences are also evident between THF and AN. The high hydrogen bond acceptor strength of THF leads to this solvent favoring the bases with "naked" protonation centers. In particular, the basicity order of N-methylated 1,3-propanediamines is practically inverse to that in the gas phase. The picture in AN is intermediate between that of GP and THF.

Experimental gas-phase basicity scale of superbasic phosphazenes.

Seventeen superbasic phosphazenes and two Verkade's bases were used to supplement and extend the experimental gas-phase basicity scale in the superbasic region. For 19 strong bases the gas-phase basicity values (GB) were determined for the first time. Among them are such well-known bases as BEMP (1071.2 kJ/mol), Verkade's Me-substituted base (1083.8 kJ/mol), Et-N=P(NMe2)2-N=P(NMe2)3 (Et-P2 phosphazene, 1106.9 kJ/mol), and t-Bu-N=P(NMe2)3 (t-Bu-P1 phosphazene, 1058.0 kJ/mol). For the first time experimental GB values were determined for P2 phosphazenes. Together with our previous results self-consistent experimental gas-phase basicity scale between 1020 and 1107 kJ/mol is now established. This way an important region of the gas-phase basicity scale, which was earlier dominated by metal hydroxide bases, is now covered also with organic bases making it more accessible for further studies. The GB values for several superbases were calculated using density functional theory at the B3LYP/6-311+G** level. For the phosphazene family the standard deviation of the correlation between the experimental and theoretical values was 6.5 kJ/mol.

Amino substituted bisketenes: generation, structure, and reactivity.

Hitherto unknown diamino-substituted bisketenes with both free (14) and tethered (16) amino substituents have been generated by using laser flash photolysis for ring opening of the corresponding cyclobutenediones. The time-resolved kinetics of ring closure of the amino bisketenes back to the cyclobutenediones were measured by IR or UV spectroscopy, and give first-order rate constants which vary by a factor of 7.5x10(4), and the bis(Me2N) bisketene 14 is the most reactive in ring closure that has been reported. Rate constants for ring closure of these and previously observed bisketenes vary by a factor of 10(13). The dialkylamino bisketenes 16 (R=Me, n-Bu) with tethered substituents and restricted geometries are less reactive than the bis(Me2N) bisketene 14 by factors of 1700 and 540, respectively. Computational results obtained with DFT methods suggest angle strain in the tethered cyclobutenediones 15 inhibits facile cyclization of bisketenes 16.

Aminolysis of Y-substituted phenyl diphenylphosphinates and benzoates: effect of modification of electrophilic center from C=O to P=O.

The effect of modification of the electrophilic center from C=O to P=O on reactivity and reaction mechanism has been investigated for aminolysis of Y-substituted phenyl diphenylphosphinates (1a-j) and benzoates (2a-i). The phosphinates 1a-j are less reactive than the benzoates 2a-i. The reactions of 2,4-dinitrophenyl diphenylphosphinate (1a) with alicyclic secondary amines resulted in a linear Brønsted-type plot with a beta(nuc) value of 0.38, while the corresponding reactions of 2,4-dinitrophenyl benzoate (2a) yielded a curved Brønsted-type plot. Similarly, a linear Brønsted-type plot with a beta(lg) value of -0.66 was obtained for the reactions of 1a-j with piperidine, while the corresponding reactions of 2a-i gave a curved Brønsted-type plot. The linear Brønsted-type plots for the reactions of 1a-j have been taken as evidence for a concerted mechanism, while the curved Brønsted-type plots for the reactions of 2a-i have been suggested to indicate a change in the rate-determining step of a stepwise mechanism. The Hammett plot for the reactions of 1b-j exhibited a poor correlation with sigma(-) constants (R(2) = 0.962) but slightly better correlation with sigma(o) (R(2) = 0.986). However, the Yukawa-Tsuno plot for the same reactions resulted in an excellent correlation (R(2) = 0.9993) with an r value of 0.30. The aminolysis of 1a-j has been suggested to proceed through a concerted mechanism with an early transition state on the basis of the small beta(nuc) and small r values.

Gas-phase acidities of disubstituted methanes and of enols of carboxamides substituted by electron-withdrawing groups.

The gas-phase acidities DeltaG degrees (acid) of some 20 amides/enols of amides RNHCOCHYY'/RNHC(OH)=CYY' [R = Ph, i-Pr; Y, Y' = CO(2)R', CO(2)R' ', or CN, CO(2)R', R', R' ' = Me, CH(2)CF(3), CH(CF(3))(2)], the N-Ph and N-Pr-i amides of Meldrum's acid, 1,3-cyclopentanedione, dimedone, and 1,3-indanedione, and some N-p-BrC(6)H(4) derivatives and of nine CH(2)YY' (Y, Y' = CN, CO(2)R', CO(2)R' '), including the cyclic carbon acids listed above, were determined by ICR. The acidities were calculated at the B3LYP/6-31+G//B3LYP/6-31+G level for both the enol and the amide species or for the carbon acid and the enol on the CO in the CH(2)YY' series. For 12 of the compounds, calculations were also conducted with the larger base sets 6-311+G and G-311+G. The DeltaG degrees (acid) values changed from 341.3 kcal/mol for CH(2)(CO(2)Me)(2) to 301.0 kcal/mol for PhNHC(OH)=C(CN)CH(CF(3))(2). The acidities increased for combinations of Y and Y' based on the order CO(2)Me < CO(2)CH(2)CF(3) < CN, CO(2)CH(CF(3))(2) for a single group and reflect the increased electron-withdrawal ability of Y,Y' coupled with the ability to achieve planarity of the crowded anion. The acidities of corresponding YY'-substituted systems follow the order N-Ph enols > N-Pr-i enols >> CH(2)YY'. Better linear relationships between DeltaG degrees (acid) values calculated for the enols and the observed values than those for the values calculated for the amides suggest that the ionization site is the enolic O-H of most of the noncyclic trisubstituted methanes. The experimental DeltaG degrees (acid) value for Meldrum's acid matches the recently reported calculated value. The calculated structures and natural charges of all species are given, and the changes occurring in them on ionization are discussed. Correlations between the DeltaG degrees (acid) values and the pK(enol) values, which are linear for the trisubstituted methanes, excluding YY' = (CN)(2) and nonlinear for the CH(2)YY' systems, are discussed.

Linear free energy relationship and kinetic isotope effects as measures for the transition state variation. A computational study.

Linear free energy relationship (LFER) and kinetic isotope effects (KIEs) are frequently used experimental means to study reaction mechanisms, in particular the nature of transition states (TSs). Density functional theory (B3LYP/6-311+G**) calculations were carried out on a model reaction, acid-catalyzed ionization of phenylethyl alcohol, to analyze how experimentally observable properties, such as nonlinearity in the Hammett and Brønsted relations and variation in KIE, are related to a variation of the transition state structure and the mechanism. Several conclusions and insights were obtained: (1) Linear Hammett plots with a dual parameter treatment may not be evidence for an invariable TS structure for a series of reactions. (2) Variations of KIEs indeed reflect the variations of TS structures. (3) Nonlinear Brønsted plots cannot always be taken as evidence for a stepwise mechanism. (4) A TS structure in the gas phase may change much more easily than a TS structure in solution.