Recent advances in our mechanistic understanding of S(N)V reactions.

Nucleophilic vinylic substitution (S(N)V), in which a leaving group such as halogen is replaced by a carbon, oxygen, nitrogen, sulfur, or other nucleophile, is an important synthetic tool. It generates compounds with a carbon- or heteroatom-substituted carbon-carbon double bond, such as vinyl ethers, enamines, a variety of heterocyclic systems, and intermediates to pharmaceutically important compounds. The S(N)V reaction has many mechanistic variants, which depend on the substituents, nucleophile, leaving group, and solvent, among other factors. Among these mechanisms, the "addition-elimination" S(N)V route is the most important to synthetic chemists. S(N)V reactions are involved in several biological processes, notably (i) in the inactivation of proteases, (ii) in intermediates of herbicide metabolism, and (iii) in the formation of mutagenic intermediates by reaction of glutathione with the environmental pollutant trichloroethylene. A variant involving a tetrahedral intermediate was found in the enzymatic transfer of an enolpyruvyl group of phosphoenolpyruvate. The main S(N)V mechanism was previously analyzed in terms of a variable transition state with perpendicular nucleophilic attack. Electron-withdrawing groups Y and Y' in the beta position adjacent to the C(alpha) reaction site increase the nucleophilic attack rate; the retention of stereochemistry was mostly ascribed to formation of carbanionic intermediate 1, in which internal rotation is slower than nucleofuge expulsion (k2). As predicted, poor nucleofuges and high activation led to partial or complete stereoconvergence, and an intramolecular element effect in polyhaloethylenes gave competition ratios, kF/kBr < 1. Evidence for a zwitterionic intermediate comes from amine-catalyzed substitutions with amines. The mechanistic spectrum investigated is wide in terms of rate constants, electron-withdrawing groups, nucleophiles, leaving groups, and solvents. However, the two extremes, that is, the very slightly activated systems where in-plane invertive substitution is feasible and conversely the highly activated systems carrying poor nucleofuges where the intermediate may be observable and kinetics examined, remained almost unexplored for a long time. In this Account, we describe the progress during the last two decades in these areas. Computations on low-reactivity systems showed that the in-plane invertive single-step nucleophilic sigma attack can have a lower barrier than the pi-perpendicular retentive attack. A kBr/kCl > 1 could be deduced for the H2C=CHX (X = Cl, Br) system. Several inverted substitution-cyclizations or inverted ring openings were observed. Alkenyl iodonium salts with superb nucleofuges, showed in-plane substitutions by various nucleophiles. In parallel, we demonstrated that several highly activated systems carrying poor nucleofuges enabled a direct detection of the intermediate 1 when attacked by strong nucleophiles. Poor correlation between the equilibrium constants K1(RS) for RS- attack and pKa(CH2YY') indicates large nucleofuge steric effects (SPr > SMe > OMe >> H). Rate and equilibrium constants for RS- attack as a function of YY' also correlate poorly owing to differences in intrinsic barriers caused by different resonance effects of YY'. The expulsion of either the nucleofuge (k2) or the nucleophile (k(-1)) from 1 was analyzed with respect to several factors. Challenges still remain, including acquiring experimental data for unactivated systems and observing an intermediate carrying a good nucleofuge.

Thermal motion of tert-butyl groups III. tert-Butyl substituents in aromatic hydrocarbons, the view from the bottom of the well.

The rigidity of the tert-butyl group (TBG) as a substituent in aromatic hydrocarbons is investigated, with a modified Hirshfeld test of anisotropic displacement parameters (ADPs) as a primary criterion. Four new structures are analyzed, along with low-temperature studies of a previously published crowded supermesityl dimer; three of the five structures meet the primary test. Most of the TBGs meet the Hirshfeld test at 100 K, and the ADPs are improved by omitting low-order data in the final refinement. The three most precise structures yield a wide variation in libration amplitudes (and in estimated rotation barriers) for 13 unique TBGs. A similar range of values is found in analyses of structures in the Cambridge Crystallographic Database. The libration amplitudes are calculated with the program THMA14C, with each TBG as an attached rigid group (ARG). Packing analysis suggests that large ADPs, especially for some individual TBG methyl groups, correspond to voids in the crystal. Published barriers to TBG reorientation, determined by solid-state NMR spin-lattice relaxation methods, for six related crystalline compounds are compared with barriers calculated from their crystal structure data.

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.

The first example of isomeric solid amide and its enol.

[Structure: see text] The first example of a crystalline amide and its tautomeric enol was obtained for the amide MeNHCSCH(CN)CONHMe (8) and its enol MeNHCSC(CN)=C(OH)NHMe (9). Their X-ray structures were determined, and their structural features resemble those of other related amides and enols. No other example of a similar pair was obtained. In solution, both 8 and 9 and a small percentage of the isomeric enol of thioamide MeNHCOC(CN)=C(SH)NHMe (10) were obtained in solvent-dependent compositions, which are rapidly established.

Bis(dimesitylmethylene)-1,3-dithietane, -1,2,4-trithiane, and -1,2,4,5-tetrathiane. Conformation and DNMR Study. Observable Dimesityl Thioketene.

The reaction of dimesityl ketene with P(2)S(5) and pyridine gives 2,4-bis(dimesitylmethylene)-1,3-dithietane (3), 3,6-bis(dimesitylmethylene)-1,2,4,5-tetrathiane (4), 3,5-bis(dimesitylmethylene)-1,2,4-trithiane (5), and dimesityl thioketene 2 as a transient. The structures of 3 and 4 were determined by X-ray crystallography. The dimesitylmethylene moieties in 3 and 4 have a propeller conformation, and the tetrathiane ring in 4 has a twist-boat conformation. Static NMR data are consistent with the presence of two enantiomers and one meso form for 3 and of three pairs of enantiomers for 4. The several aromatic signals observed for 3 and 4 at slow exchange at 160 K coalesce to a single signal at higher temperatures. The threshold barriers for these dynamic processes are 12.7 (3) and 13.3 (4) kcal mol(-)(1), and the dynamic behavior was analyzed in terms of flip processes. On standing, a solution of 3 develops a blue color which is attributed to formation of 2, by retro-dimerization of 3. Diphenylacetyl chloride gives with P(2)S(5) the analog of 5 and its one-double bond reduction product. Ditipylketene forms a product identified tentatively as the analog of 3.

Static and Dynamic Stereochemistry and Solvation of 2,2-Ditipylethenols(1).

The effect of increased bulk of the beta-aryl group in enols Ar(2)C=C(OH)R from Ar = mesityl = Mes (1) to Ar = 2,4,6-i-Pr(3)C(6)H(2) = Tip (2) was investigated. The solid-state structure when R = H (a) does not significantly differ for 1a and 2a. The dynamic behavior of 2a resembles that of 1a, but the rotational barriers for both the threshold one-ring flip process and the two-ring flip process are higher for 2a. The one-ring flip barrier for 2a is solvent-dependent. The threshold two-ring flip barriers when R = Me (2b) and t-Bu (2c) are higher than for the mesityl analogues, but that for 2c is higher than predicted. Solvations of 2a and 1a and their associations with DMSO are similar. The C=COH conformation is syn-planar with an OH.pi(Tip) association in non-hydrogen-bond-accepting solvents and is anti-clinal with OH.solvent association in hydrogen-bond-accepting solvents. In summary, the increased bulk associated with the change Mes --> Tip changes the structure and behavior in the expected direction but, except for the DeltaG(c)() values, not to a large extent.

Stereochemistry of the Vinylic S(RN)1 Reaction of Triarylvinyl Halides. The Structure of the Intermediate alpha-Arylvinyl Radical.

Evidence for the intermediacy of a vinyl radical in the vinylic S(RN)1 reaction (S(RN)1(V)) of 2-anisyl-1,2-diphenylvinyl bromide 2 is obtained. The photostimulated S(RN)1(V) reaction of pinacolone enolate ion with (E)-2 and (Z)-2, which are used as stereoindicators, gives complete loss of the original stereochemistry of the two precursors in the substituted and hydrodehalogenated products; i.e., stereoconvergence is found. It is concluded that in the reaction of 2 a beta-substituted alpha-phenylvinyl radical is a reactive intermediate and that it has either a linear structure or an average linear structure due to a rapidly interconverting E,Z mixture of bent radicals. This conclusion is supported by comparing the stereochemical course of the S(RN)1(V) reaction with those of other reactions of the same precursor, which unambiguously give rise to the same alpha-phenylvinyl radical intermediate by alternative mechanisms. Among the reactions investigated, the hydrodehalogenation of precursor 2 by LAH appears to take place by an ET mechanism.

Kinetics of the Reaction of beta-Methoxy-alpha-nitrostilbene with Cyanamide in 50 DMSO-50 Water. Failure to Detect the S(N)V Intermediate.

A kinetic study of the reaction of beta-methoxy-alpha-nitrostilbene (1-OMe) with cyanamide (CNA) over a pH range from 8.5 to 12.4 shows that it is the anion (CNA(-), pK(a) = 11.38) rather than the neutral amine that is the reactive species. Attempts at monitoring the reaction with the neutral CNA at low pH were unsuccessful because of competing hydrolysis. It is shown that the nucleophilic reactivity of CNA is abnormally low, probably because of a resonance effect, and that the reactivity of CNA(-) is high, higher than that of strongly basic oxyanion because of relatively weak solvation. The high reactivity of both 1-OMe and CNA(-) appeared to constitute favorable conditions conducive to the detection of the S(N)V intermediate, as has been the case in the reactions of 1-OMe with thiolate ions, alkoxide ions, and some amines. However, no intermediate was observed. Reasons for this failure are discussed.

Cyclobutene-1,2-diones. A Theoretical and Spectroscopic Study.

The properties of substituted cyclobutene-1,2-diones 1 are examined by the use of (17)O NMR spectroscopy and theoretical calculations and compared to those of cyclopropenones 2 and other models. Cyclobutene-1,2-diones have less negative charge per oxygen compared to cyclopropenones, and electron donation by substituents enhances the negative charge on oxygen. Calculated (17)O chemical shifts reproduce the measured trends. The dianions of squaric and deltic acids are highly stabilized by negative charge delocalization to the oxygens.

Conformations and Threshold Rotational Mechanisms of the (Z)-1,2-Diarylethene Moiety: A Structural Correlation Study.

The crystal structures of substituted (Z)-1,2-diarylethenes and (Z)-1,2-diarylcyclopropenes, -cyclobutenes, -cyclopentenes, and -cyclohexenes that were reported in the literature were retrieved from the Cambridge Structural Database, and the dihedral angles of the aryl rings with the double bond were plotted in a conformational map. Analysis of the data by the Structural Correlation method together with molecular mechanics calculations suggest that the conformation and the threshold rotational mechanism of the (Z)-1,2-diarylvinyl fragment strongly depend on its steric environment. In 1,2-diarylcyclopropenes the aryl rings are nearly coplanar with the double bond, whereas in 1,2-diarylcycloalkenes with larger rings a propeller conformation is adopted. The threshold rotational mechanism is the one-ring flip for (Z)-1,2-diphenylethene and 1,2-diphenylcyclobutene, and is the two-ring flip for 1,2-diarylcyclopentene and 1,2-diarylcyclohexene. The calculated rotational barriers of the aryl rings in the threshold mechanism for all systems were very low (0.2-2.4 kcal mol(-)(1)). The different conformations and rotational behaviors are dictated by an interplay of conjugation and steric effects.

Four Enantiomerization Routes of 1,2,2-Trimesitylvinyl Acetate. Enantioselective Liquid Chromatography of (E)- and (Z)-2-m-Methoxymesityl-1,2-dimesitylvinyl Acetates.

The vinyl propellers (E)- and (Z)-2-m-methoxymesityl-1,2-dimesitylvinyl acetates (3c and 3d) were prepared and their geometries assigned. The stereoisomerization barriers of the trimesityl vinyl acetate system were determined by DNMR and by enantioselective LC resolution and polarimetric monitoring of the behavior of the two diastereomeric racemates of 3c and 3d. Combined with data for trimesitylvinyl-OAc 3a and its 1-m-methoxymesityl analogue 3b, the following order of barriers DeltaG() is obtained: alphabeta-2-ring flip > alphabeta'-2-ring flip > betabeta'-2-ring flip > alphabetabeta'-3-ring flip (the threshold enantiomerization barrier). This order which differs from the previously found orders for trimesitylvinyl-X, X = H, OPr-i was rationalized and discussed.

Intramolecular Geminal and Vicinal Element Effects in Substitution of Simple Bromo(chloro)alkenes by Methoxide and Thiolate Ions. An Example of a Single Step Substitution?

Intramolecular element effects k(Br)/k(Cl) for substitution of geminal bromochloroalkenes BrC(Cl)=C(Br)Cl (1), BrC(Cl)=CCl(2) (2), Me(2)C=C(Br)Cl (3), and XCH=C(Br)Cl (X = Cl, 4; X = Br, 5), with MeO(-) and RS(-) nucleophiles were investigated. 3 did not give substitution, and 4 and 5 gave substitution with MeO(-) via an initial elimination (to acetylene)-addition route, followed by further reactions. In reactions of 4 with thiolates, geminal element effects of 2-10 were obtained. Formation of RSC(Cl)=C(Cl)Y, Y = SR, Br, is ascribed to an initial halophilic reaction, followed by addition of RSCl to the formed acetylene. Reaction of 2 with MeO(-) gave a high vicinal element effect, and RS(-) gave a high geminal element effect. Reaction of 1 with both MeO(-) and RS(-) ions gave high (2 orders of magnitude) geminal element effects, which were interpreted as indicating a rate-determining C-X bond cleavage. This is supported by the high k(Br)/k(Cl) intermolecular element effects (k(1)/k(Cl(2)C=CCl(2)) with MeO(-) and PhCH(2)S(-) ions. Mechanistic alternatives based on these observations are discussed.

Acid-Catalyzed Breakdown of Alkoxide and Thiolate Ion Adducts of Benzylidene Meldrum's Acid, Methoxybenzylidene Meldrum's Acid and Thiomethoxybenzylidene Meldrum's Acid.

A kinetic study of the acid-catalyzed loss of alkoxide and thiolate ions from alkoxide and thiolate ion adducts, respectively, of benzylidene Meldrum's acid (1-H), methoxybenzylidene Meldrum's acid (1-OMe), and thiomethoxybenzylidene Meldrum's acid (1-SMe) is reported. The reactions appear to be subject to general acid catalysis, although the catalytic effect of buffers is weak and the bulk of the reported data refers to H(+)-catalysis. alpha-Carbon protonation and, in some cases, protonation of one of the carbonyl oxygens to form an enol compete with alkoxide or thiolate ion expulsion. This rendered the kinetic analysis more complex but allowed the determination of pK(a) values and of proton-transfer rate constants at the alpha-carbon. In conjunction with previously reported data on the nucleophilic addition of alkoxide and thiolate ions to the same Meldrum's acid derivatives, rate constants for nucleophilic addition by the respective neutral alcohols and thiols could also be calculated. Various structure-reactivity relationships are discussed that help define transition-state structures. Comparisons with similar reactions of alkoxide ion adducts of beta-alkoxy-alpha-nitrostilbenes provide additional insights.

Oxa-ene reaction of enols of amides with 4-phenyl-1,2,4-triazoline-3,5-dione.

The reaction of 16 enols of amides with 4-phenyl-1,2,4-triazoline-1,3-dione gave open chain adducts rather than the [2 + 2] cycloadducts with a hemiaminal moiety, both in solid state and in solution. This assignment is based on X-ray crystallography, (1)H and (13)C NMR data, and IR spectra. The suggested mechanism involves hydroxyl proton loss in a formal oxa-ene reaction. Mechanistic details and a possible alternative are discussed.

A rich array of reactions of Cyanomonothiocarbonylmalonamides RNHCSCH(CN)CONHR' and their Thioenols RNHC(SH)=C(CN)CONHR'1.

The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide were found to be very reactive species. They react under a variety of conditions such as crystallization, reaction with several carbonyl compounds, and reactions with another thioenol molecule to give a variety of products, mostly heterocycles, including substituted 2,3-dihydroisothiazole-3-ones and 3-thione, 2-substituted methylenethiazoles, 3,4-dihydro-1,3-thiazine-4-ones and 4-thiones, divinyl sulfides, a 1,2-dithiolane radical, and a 3,7-diaza[3.3.0]bicyclooctane derivative. Mechanisms suggested for these reactions include radical mechanisms, nucleophilic substitutions, and condensations.

Enols and thioenols of substituted cyanomonothiocarbonylmalonamides: structures, enolization vs. thioenolization, equilibria and conformations.

Condensation of organic isothiocyanates with cyanoacetamides gave 24 N- and N'-substituted cyanomonothiocarbonylmalonamides in different tautomeric ratios i.e., amide-thioamides (TMA)R3NHCSCH(CN)CONR1R2 (12), thioamide-enols of amides (E) R3NHCSC(CN)=C(OH)NR1R2 (11)or amide-thioenols (TE) R3NHC(SH)=C(CN)CONR1R2 (13). The equilibrium constants (K(thioenol) =[TE]/[TMA] and K(enol) = [E]/[TMA]) in solution depend on R1, R2, R3 and the solvent. The %(E + TE)for NR1R2 increases in the order NMe2 < NHMe < NH2. The (K(thioenol) + K(enol)) in various solvents follows the order CCl4 > CDCl3 > C6D6 > THF-d8 > (CD3)2CO > CD3CN > DMF-d7 > DMSO-d6. The delta(OH) values are 16.46-17.43 and the delta(SH) values are 3.87-5.26 ppm in non polar solvents, e.g.,CDCl3 and 6.34-6.97 ppm in THF-d8 and CD3CN. An intramolecular O-H...O hydrogen bond leads to the preferred Z-configuration of the enols, and an N-H...O bond stabilizes the thioenols' preferred E-configuration with a non-bonded SH in solution. X-Ray crystallography revealed that systems with high %(E + TE) in solution mostly display the enols 11 in the solid state and systems with lower %(E +TE) in solution display structure 12. The differences in delta(OH), delta(NH), K(enol) and crystallographic data for analogous enol and thioenol systems are compared.

Role of negative hyperconjugation and anomeric effects in the stabilization of the intermediate in SNV reactions.

The role of negative hyperconjugation and anomeric and polar effects in stabilizing the XZHCbetaCalphaYY'- intermediates in SNV reactions was studied computationally by DFT methods. Destabilizing steric effects are also discussed. The following ions were studied: X = CH3O, CH3S, CF3CH2O and Y = Y' = Z = H (7b-7d), Y = Y' = H, Z = CH3O, CH3S, CF3CH2O (7e-7i), YY' = Meldrum's acid-like moiety (Mu), Z = H, (8b-8d), and YY' = Mu, Z = CH3O, CH3S, CF3CH2O (8e-8i). The electron-withdrawing Mu substituent at Calpha stabilizes considerably the intermediates and allows their accumulation. The hyperconjugation ability (HCA) (i.e., the stabilization due to 2p(Calpha) --> sigma*(Cbeta-X) interaction) in 8b-8d follows the order (for X, kcal/mol) CH3S (8.5) > CF3CH2O (7.6) approximately CH3O (7.5). The HCA in 8b-8d is significantly smaller than that in 7b-7d due to charge delocalization in Mu in the former. The calculated solvent (1:1 DMSO/H2O) effect is small. The stability of disubstituted ions (7e-7i and 8e-8i) is larger than that of monosubstituted ions due to additional stabilization by negative hyperconjugation and an anomeric effect. However, steric repulsion between the geminal Cbeta substituents destabilizes these ions. The steric effects are larger when one or both substituents are CH3S. The anomeric stabilization (the energy difference between the anti,anti and gauche,gauche conformers) in the disubstituted anions contributes only a small fraction to their total stabilization. Its order (for the following X/Z pairs, kcal/mol) is CF3CH2O/CH3S (8i, 4.9) > CF3CH2O/CH3O (8h, 3.9) > CH3O/CH3S (8g, 3.3) > CH3S/CH3S (8f, 2.9) > CH3O/CH3O (8e, 2.4). Significantly larger anomeric effects of ca. 8-9 kcal/mol are calculated for the corresponding conjugate acids.

Dialkoxyphosphinyl-substituted enols of carboxamides.

Reactions of isocyanates XNCO (e.g., X = p-An, Ph, i-Pr) with (MeO)2P(=O)CH2CO2R [R = Me, CF3CH2, (CF3)2CH] gave 15 formal "amides" (MeO)2P(=O)CH(CO2R)CONHX (6/7), and with (CF3CH2O)2P(=O)CH2CO2R [R = Me, CF3CH2] they gave eight analogous amide/enols 17/18. X-ray crystallography of two 6/7, R = (CF3)2CH systems revealed Z-enols of amides structures (MeO)2P(=O)C(CO2CH(CF3)2)=C(OH)NHX 7 where the OH is cis and hydrogen bonded to the O=P(OMe)2 group. The solid phosphonates with R = Me, CF3CH2 have the amide 6 structure. The structures in solution were investigated by 1H, 13C, 19F, and 31P NMR spectra. They depend strongly on the substituent R and the solvent and slightly on the N-substituent X. All systems displayed signals for the amide and the E- and Z-isomers. The low-field two delta(OH) and two delta(NH) values served as a probe for the stereochemistry of the enols. The lower field delta(OH) is not always that for the more abundant enol. The % enol, presented as K(enol), was determined by 1H, 19F, and 31P NMR spectra, increases according to the order for R, Me < CF3CH2 < (CF3)2CH, and decreases according to the order of solvents, CCl4 > CDCl3 approximately THF-d8 > CD3CN >DMSO-d6. In DMSO-d6, the product is mostly only the amide, but a few enols with fluorinated ester groups were observed. The Z-isomers are more stable for all the enols 7 with E/Z ratios of 0.31-0.75, 0.15-0.33, and 0.047-0.16 when R = Me, CF3CH2, and (CF3)2CH, respectively, and for compounds 18, R = Me, whereas the E-isomers are more stable than the Z-isomers. Comparison with systems where the O=P(OMe)2 is replaced by a CO2R shows mostly higher K(enol) values for the O=P(OMe)2-substituted systems. A linear correlation exists between delta(OH)[Z-enols] activated by two ester groups and delta(OH)[E-enols] activated by phosphonate and ester groups. Compounds (MeO)2P(=O)CH(CN)CONHX show

The first solid enols of anhydrides. Structure, properties, and enol/anhydride equilibria(1).

Reaction of beta-methylglutaconic anhydride with NaOMe followed by reaction with methyl or phenyl chloroformate gave the corresponding O-methoxy (and O-phenoxy) carbonylation derivatives. Reaction of the anhydride with MgCl2/pyridine, followed by methyl chloroformate gave C-methoxycarbonylation at C3 of the anhydride. The product (4) was previously suggested by calculation to be the enol of the anhydride 5 and this is confirmed by X-ray crystallography (bond lengths: C-OH, 1.297 A; C1C2 1.388 A; HO...O=C(OMe) distance 2.479 A) making it the first solid enol of an anhydride. In CDCl3, CD3CN, or C6D6 solution it displays the OH as a broad signal at ca. 15 ppm, suggesting a hydrogen bond with the CO2Me group. NICS calculations indicate that 4 is nonaromatic. With D2O in CDCl3 both the OH and the C5H protons exchange rapidly the H for D. An isomeric anhydride 5a of 5 is formed in equilibrium with 4 in polar solvents. In solution, anhydride(s)/enol equilibria are rapidly established with Kenol of 6.40 (C6D6, 298 K), 0.52 (CD3CN, 298 K), 9.8 (CDCl3, 298 K), 22.8 (CDCl3, 240 K), and decreasing Kenol in CDCl3:CD3CN mixtures with the increase in percent of CD3CN. The percentage of the rearranged anhydride in CDCl3:(CD3)2CO increases with the increased percent of (CD3)2CO. In DMSO-d6 and DMF-d7 the observed species are mainly the conjugated base 4- and 5a. Deuterium effects on the delta(13C) values were determined. An analogous C2-OH enol of anhydride 15 substituted by 3-CO2Me and 4-OCO2Me groups was prepared. Its structure was confirmed by X-ray crystallography (CO bond length 1.298 A, O...O distance 2.513 A); delta(OH) = 12.04-13.22 ppm in CDCl3, THF-d8, and CD3CN, and Kenol = > or = 100, 7.7, and 3.4 respectively. In DMSO-d6 enol 15 ionizes to its conjugate base. Substantial upfield shifts of the apparent delta("OH") proton on diluting the enol solutions are ascribed to the interaction of the H+ formed with the traces of water in the solvent to give H3O+, which gives the alleged "OH proton" signal.

Enols of substituted cyanomalonamides.

Twenty open-chain mono-, di-, and trialkyl and aryl-N-substituted cyanomalonamides R2R1NCOCH(CN)CONHR3 were prepared. In solution, signals for both amide and a single enol are mostly observed, despite the potential for E and Z isomeric enols. The equilibrium (KEnol) values between the amides and the enols were determined in different solvents by NMR spectra. They decrease on increasing the polarity of the solvent in the order CDCl3 approximately C6D6>THF-d8>(CD3)2CO>CD3CN>DMF-d7>DMSO-d6. For the R1R2NCOCH(CN)CONHR3 system when R1=R2=H, Me or R1=H, R2=Me, KEnol for R3 follows the order: C6F5>Ph>or=An>or= i-Pr>or= t-Bu, and for R1, R2:H, H>Me, H>Me, Me in all solvents. A unique feature is the appreciable % enol in DMSO-d6 when R1=R2=H, in contrast with enol systems with other electron-withdrawing groups (EWGs). Calculations (B3LYP/6-31G**) corroborate the higher KEnol values for less alkyl-substituted systems, showing that in the most stable conformer when R1=H, R2=R3=Me the N-hydrogens are closer to the CN group. The order of promoting substituents for enol of amide formation is CONH2>CO2CH2CF3>CO2Me>CONHMe. The solid-state structures of the isolated species, determined by X-ray crystallography, were either amides or enols, and a higher KEnol(CDCl3) value does not ensure a solid enol structure. In no system were both solid species isolated. The X-ray structures of the enols were temperature-dependent. In most cases, the difference between the O-H and O...H bond lengths at low temperature were appreciable, but they become closer at the higher temperature. Similar tendency for either the C=C/C-C or the C-O/C=O bonds was observed. This is ascribed to a hydrogen shift between two regioisomeric enols in an asymmetric double-well potential, which becomes faster at a higher temperature. Calculations show that the enol structures are nonsymmetrical, resembling the lower temperature structures, even when they are chemically symmetrical, but the energy differences between the two regioisomers are <1 kcal. The hydrogen bonds in the enol moiety are strong, with O...O distances <2.45 A, and are resonance-assisted hydrogen bonds. IR spectra in solution and the solid state qualitatively corroborate the NMR and X-ray structure determination.