Symmetry of Hydrogen Bonds: Application of NMR Method of Isotopic Perturbation and Relevance of Solvatomers.

Short, strong, symmetric, low-barrier hydrogen bonds (H-bonds) are thought to be of special significance. We have been searching for symmetric H-bonds by using the NMR technique of isotopic perturbation. Various dicarboxylate monoanions, aldehyde enols, diamines, enamines, acid-base complexes, and two sterically encumbered enols have been investigated. Among all of these, we have found only one example of a symmetric H-bond, in nitromalonamide enol, and all of the others are equilibrating mixtures of tautomers. The nearly universal lack of symmetry is attributed to the presence of these H-bonded species as a mixture of solvatomers, meaning isomers (or stereoisomers or tautomers) that differ in their solvation environment. The disorder of solvation renders the two donor atoms instantaneously inequivalent, whereupon the hydrogen attaches to the less well solvated donor. We therefore conclude that there is no special significance to short, strong, symmetric, low-barrier H-bonds. Moreover, they have no heightened stability or else they would have been more prevalent.

Malonic Anhydrides, Challenges from a Simple Structure.

After many years of unsuccessful attempts, monomeric malonic anhydrides were prepared by ozonolysis of ketene dimers, a procedure validated by model studies. The structure proof relied most heavily on IR absorption at 1820 cm-1 and a Raman band at 1947 cm-1. Malonic anhydrides are unstable, decomposing below room temperature to a ketene plus carbon dioxide. Surprisingly, according to kinetic studies, the dimethyl derivative is slightly less unstable than the parent, and the monomethyl is the fastest to decompose, with an enthalpy of activation of only 12.6 kcal/mol. Computations rationalize this behavior in terms of a concerted [2s + 2a] cycloreversion that requires a more highly organized transition state, as also manifested by a negative entropy of activation.

The complete mechanism of an aldol condensation in water.

The base-catalyzed aldol condensation between benzaldehyde and p-acetylbenzoic acid in water shows an inverse solvent kinetic isotope effect, k3,D2O/k3,H2O, of 1.33 ± 0.03. The reaction is definitely faster in D2O. This is interpreted to mean that the rate-limiting step in a five-step mechanism is Step 5, the final elimination of hydroxide from the enolate intermediate, not the formation of that intermediate. This is the same result and the same conclusion as from earlier studies in aqueous acetonitrile and refutes a suggestion, based on computations, that the rate-limiting step would change in water. Those computations are criticized as implying impossibly large isotope effects.

ipso.

On a substituted benzene ring the position that bears the substituent is designated as the ipso position. This Perspective presents the history behind that designation.

Comment on "Topography of the free energy landscape of Claisen-Schmidt condensation: solvent and temperature effects on the rate-controlling step" by N. D. Coutinho, H. G. Machado, V. H. Carvalho-Silva and W. A. da Silva, Phys. Chem. Chem. Phys., 2021, 23, 6738.

The referenced article in PCCP presents calculations of solvent kinetic isotope effects that indicate that the rate-limiting step in base-catalyzed chalcone formation in aqueous solution becomes the second enolization. This disputes our previous conclusion, based on experimental isotope effects in aqueous acetonitrile, that the rate-limiting step is the final loss of hydroxide and formation of the C-C double bond. That conclusion is here affirmed as general for any protic solvent, and it is further concluded that those calculations are flawed.

Symmetry of Hydrogen Bonds in Two Enols in Solution.

The enols of 4-cyano-2,2,6,6-tetramethyl-3,5-heptanedione and of nitromalonamide were prepared as statistical mixtures of 18O n ( n = 0, 1, 2) isotopologues. The symmetries of their hydrogen bonds were probed by isotopic perturbation of their 13CO NMR signals. The former mixture shows a total of four signals, due to both intrinsic and perturbation isotope shifts. Therefore, that enol is a mixture of tautomers with an asymmetric hydrogen bond. In contrast, the mixture of isotopologues of nitromalonamide enol shows only two signals, due to an intrinsic isotope shift. Therefore, this is the first case, to be compared with the FHF- anion, of a neutral species with a single symmetric structure in solution and with a centered hydrogen.

Isotopic-Perturbation NMR Study of Hydrogen-Bond Symmetry in Solution: Temperature Dependence and Comparison of OHO and ODO Hydrogen Bonds.

Is a hydrogen bond symmetric, with the hydrogen centered between two donor atoms, or is it asymmetric, with the hydrogen closer to one but jumping to the other? The NMR method of isotopic perturbation has been used to distinguish these. Previous evidence from isotope shifts implies that a wide variety of dicarboxylate monanions are asymmetric, present as a rapidly equilibrating mixture of tautomers. However, calculations of hydrogen trajectories across an anharmonic potential-energy surface could reproduce the observed isotope shifts in a phthalate monoanion. Therefore, it was concluded that those isotope shifts are instead consistent with isotope-induced desymmetrization on a symmetric potential-energy surface. To distinguish between these two interpretations, the 18O-induced isotope effects on the 13C NMR chemical shifts of cyclohexene-1,2-dicarboxylate monoanion in chloroform-d and on the 19F NMR chemical shifts of difluoromaleate monoanion in D2O have been investigated. In both cases the isotope effects are larger at lower temperature and also with deuterium in the hydrogen bond. It is concluded that these behaviors are consistent with the perturbation of an equilibrium between asymmetric tautomers and inconsistent with isotope-induced desymmetrization on a symmetric potential-energy surface.

Protein-like proton exchange in a synthetic host cavity.

The mechanism of proton exchange in a metal-ligand enzyme active site mimic (compound 1) is described through amide hydrogen-deuterium exchange kinetics. The type and ratio of cationic guest to host in solution affect the rate of isotope exchange, suggesting that the rate of exchange is driven by a host whose cavity is occupied by water. Rate constants for acid-, base-, and water-mediated proton exchange vary by orders of magnitude depending on the guest, and differ by up to 200 million-fold relative to an alanine polypeptide. These results suggest that the unusual microenvironment of the cavity of 1 can dramatically alter the reactivity of associated water by magnitudes comparable to that of enzymes.

Polynomial coefficients. Application to spin-spin splitting by N equivalent nuclei of spin I > 1/2.

The NMR intensity pattern of a nucleus split by N identical nuclei of spin 1/2 is given by the binomial coefficients. These are conveniently obtained from Pascal's triangle, equivalent to the chemist's branching diagram. Much less well-known is the pattern from splitting by N identical nuclei of spin I > 1/2. This was originally presented in terms of multinomial coefficients, but polynomial coefficients are more convenient. These describe the number of ways that N objects can be distributed to 2I + 1 numbered boxes. They arise in the polynomial expansion and are conveniently obtained from generalizations of Pascal's triangle. Examples and predictions are given.

The Logic behind a Physical-Organic Chemist's Research Topics.

Although my research has no common theme or defining area, a coherence connects the diverse topics insofar as one project leads logically to another. Thus, studies on mechanisms of hydrogen exchange in amides and amidines led to the influence of hydrogen bonding and to NMR methods for chemical kinetics, including 2D-EXSY spectroscopy. Another connection was the OH--catalyzed NH exchange in amines that had supported the hypothesis of stereoelectronic control. We therefore analyzed that hypothesis critically, tested it, found counterexamples, and proposed an alternative hypothesis. We next addressed one-bond NMR coupling constants in ethers and the reverse anomeric effect. The latter studies required a highly accurate NMR titration method that we developed to measure the additional steric bulk resulting from protonation of a substituent. This method is also applicable to measuring secondary isotope effects on acidity, and we could demonstrate that they arise from n-σ* delocalization, not from an inductive effect. Other studies included kinetic isotope effects for both dissociation and H exchange of aqueous NH4+, for C-N rotation in amides, and for a hydride transfer. The role of hydrogen bonding led us to the rotation of NH4+ within its solvent cage and then to the symmetry of hydrogen bonds.

The Complete Mechanism of an Aldol Condensation.

Although aldol condensation is one of the most important organic reactions, capable of forming new C-C bonds, its mechanism has never been fully established. We now conclude that the rate-limiting step in the base-catalyzed aldol condensation of benzaldehydes with acetophenones, to produce chalcones, is the final loss of hydroxide and formation of the C═C bond. This conclusion is based on a study of the partitioning ratios of the intermediate ketols and on the solvent kinetic isotope effects, whereby the condensations are faster in D2O than in H2O, regardless of substitution.

Can a secondary isotope effect be larger than a primary?

Primary and secondary (18)O equilibrium isotope effects on the acidities of a variety of Brønsted and Lewis acids centered on carbon, boron, nitrogen, and phosphorus were computed by density-functional theory. For many of these acids, the secondary isotope effect was found to be larger than the primary isotope effect. This is a counterintuitive result, because the H atom that is lost is closer to the (18)O atom that is responsible for the primary isotope effect. The relative magnitudes of the isotope effects can be associated with the vibrational frequency and zero-point energy of the X═O vibrations, which are greater than those of the X-O vibrations. However, the difference between these contributions is small, and the major responsibility for the larger secondary isotope effect comes from the moment-of-inertia factor, which depends on the position of the (18)O atom relative to the principal axes of rotation.

Variable-temperature study of hydrogen-bond symmetry in cyclohexene-1,2-dicarboxylate monoanion in chloroform-d.

The symmetry of the hydrogen bond in hydrogen cyclohexene-1,2-dicarboxylate monoanion was determined in chloroform using the NMR method of isotopic perturbation. As the temperature decreases, the (18)O-induced (13)C chemical-shift separations increase not only at carboxyl carbons but also at ipso (alkene) carbons. The magnitude of the ipso increase is consistent with an (18)O isotope effect on carboxylic acid acidity. Therefore it is concluded that this monoanion is a mixture of tautomers in rapid equilibrium, rather than a single symmetric structure in which a chemical-shift separation arises from coupling between a desymmetrizing vibration and anharmonic isotope-dependent vibrations, which is expected to show the opposite temperature dependence.

Selectivity and isotope effects in hydronation of a naked aryl anion.

An aryl anion is produced by rapid addition of iodide to the p-benzyne diradical formed by cycloaromatization of an enediyne. The aryl anion is then hydronated (protonated or deuteronated) to form 1-iodotetrahydronaphthalene. Hydrons can be incorporated not only from water but also from such weak acids as dimethyl sulfoxide and acetonitrile. The relative reactivity of each pair of hydron donors is evaluated from competition experiments. A low selectivity is observed and taken as evidence for a high basicity of the aryl anion. Moreover, the same relative reactivities are obtained with Bu4NI as with LiI; therefore the species that undergoes hydronation is not an aryllithium but a naked aryl anion. These studies thus characterize the reactivity of a naked aryl anion in solution and contrast it with the reactivity of an aryllithium or an aryl Grignard.

Direct observation of ß-chloride elimination from an isolable ß-chloroalkyl complex of square-planar nickel.

Reported here are the isolation, structural characterization, and decomposition kinetics of the four-coordinate pentachloroethyl nickel complex, NiCl(CCl2CCl3)(CNAr(Mes2))2 (Ar(Mes2) = 2,6-(2,4,6-Me3C6H2)2C6H3). This complex is a unique example of a kinetically persistent ß-chloroalkyl in a system relevant to coordination-insertion polymerization of polar olefins. Kinetic analysis of NiCl(CCl2CCl3)(CNAr(Mes2))2 decomposition indicates that ß-chloride (ß-Cl) elimination proceeds by a unimolecular mechanism that does not require initial dissociation of a CNAr(Mes2) ligand. The results suggest that a direct ß-Cl elimination pathway is available to four-coordinate, Group 10 metal vinyl chloride polymerization systems.

Decomposition of malonic anhydrides.

Malonic anhydrides decompose at or below room temperature, to form a ketene and carbon dioxide. Rate constants for the thermal decomposition of malonic, methylmalonic, and dimethylmalonic anhydrides were measured by NMR spectroscopy at various temperatures, and activation parameters were evaluated from the temperature dependence of the rate constants. Methylmalonic anhydride is the fastest, with the lowest ΔH(‡), and dimethylmalonic anhydride is the slowest. The nonlinear dependence on the number of methyl groups is discussed in terms of a concerted [2(s) + (2(s) + 2(s))] or [2(s) + 2(a)] cycloreversion that proceeds via a twisted transition-state structure, supported by computations.

Hydrogen-bond symmetry in difluoromaleate monoanion.

The symmetry of the hydrogen bond in hydrogen difluoromaleate monoanion is probed by X-ray crystallography and by the NMR method of isotopic perturbation in water, in two aprotic organic solvents, and in an isotropic liquid crystal. The X-ray crystal structure of potassium hydrogen difluoromaleate shows a remarkably short O-O distance of 2.41 Å and equal O-H distances of 1.206 Å, consistent with a strong and symmetric hydrogen bond. Incorporation of (18)O into one carboxyl group allows investigation of the symmetry of the H-bond in solution by the method of isotopic perturbation. The (19)F NMR spectra of the mono-(18)O-substituted monoanion in water, CD(2)Cl(2), and CD(3)CN show an AB spin system, corresponding to fluorines in different environments. The difference is attributed to the perturbation of the acidity of a carboxylic acid by (18)O, not to the mere presence of the (18)O, because the mono-(18)O dianion shows equivalent fluorines. Therefore, it is concluded that the monoanion exists as an equilibrating pair of interconverting tautomers and not as a single symmetric structure not only in water but also in organic solvents. However, in the isotropic liquid crystal phase of 4-cyanophenyl 4-heptylbenzoate, tetrabutylammonium hydrogen difluoromaleate-(18)O shows equivalent fluorines, consistent with a single symmetric structure. These results support earlier studies, which suggested that the symmetry of hydrogen bonds can be determined by the local environment.

Nucleophilic Addition of Enolates to 1,4-Dehydrobenzene Diradicals Derived from Enediynes: Synthesis of Functionalized Aromatics.

Alkylation of aromatics and formation of a new C-C bond is usually achieved by the electrophilic attack of an activated carbon species on an electron-rich aromatic ring. Herein, we report an alternative method for alkylation of aromatics via nucleophilic addition of enolates of active methylene compounds to 1,4-dehydrobenzene diradicals derived from enediynes cyclodec-1,5-diyne-3-ene, benzo[3,4]-cyclodec-1,5-diyne-3-ene, and cyclohexeno[3,4]-cyclodec-1,5-diyne-3-ene. The benzo-substituted enediyne produces slightly higher yields of alkylation products than do the other two enediynes, but the differences are not substantial. The reaction produces a new C-C bonded aromatic alkylation product, which allows the construction of complex polyfunctional structures in a few steps. Moreover, this reaction provides solely C-arylated products, and no O-arylation products were observed.

Are short, low-barrier hydrogen bonds unusually strong?

In a symmetric hydrogen bond (H-bond), the hydrogen atom is perfectly centered between the two donor atoms. The energy diagram for hydrogen motion is thus a single-well potential, rather than the double-well potential of a more typical H-bond, in which the hydrogen is covalently bonded to one atom and H-bonded to the other. Examples of symmetric H-bonds are often found in crystal structures, and they exhibit the distinctive feature of unusually short length: for example, the O-O distance in symmetric OHO H-bonds is found to be less than 2.5 Å. In comparison, the O-O distance in a typical asymmetric H-bond, such as ROH···OR(2), ranges from about 2.7 to 3.0 Å. In this Account, we briefly review and update our use of the method of isotopic perturbation to search for a symmetric, centered, or single-well-potential H-bond in solution. Such low-barrier H-bonds are thought to be unusually strong, owing perhaps to the resonance stabilization of two identical resonance forms [A-H···B ↔ A···H-B]. This presumptive bond strength has been invoked to explain some enzyme-catalyzed reactions. Yet in solution, a wide variety of OHO, OHN, and NHN H-bonds have all been found to be asymmetric, in double-well potentials. Examples include the monoanion of (±)-2,3-di-tert-butylsuccinic acid and a protonated tetramethylnaphthalenediamine, even though these two ions are often considered prototypes of species with strong H-bonds. In fact, all of the purported examples of strong, symmetric H-bonds have been found to exist in solution as pairs of asymmetric tautomers, in contrast to their symmetry in some crystals. The asymmetry can be attributed to the disorder of the local solvation environment, which leads to an equilibrium among solvatomers (that is, isomers that differ in solvation). If the disorder of the local environment is sufficient to break symmetry, then symmetry itself is not sufficient to stabilize the H-bond, and symmetric H-bonds do not have an enhanced stability or an unusual strength. Nor are short H-bonds unusually strong. We discuss previous evidence for "short, strong, low-barrier" H-bonds and show it to be based on ambiguous comparisons. The role of such H-bonds in enzyme-catalyzed reactions is then ascribed not to any unusual strength of the H-bond itself but to relief of "strain."

Cyclohexeno[3,4]cyclodec-1,5-diyne-3-ene: A Convenient Enediyne.

Enediynes are widely studied to understand their cycloaromatization and the trapping of the resulting p-dehydrobenzene diradical. However, few model substrates are known, and they are hard to synthesize and difficult to handle. Herein we report cyclohexeno[3,4]cyclodec-1,5-diyne-3-ene as a convenient model for studying the reactivity of enediynes. It can be easily synthesized from 1,2-diethynylcyclohexene and 1,4-diiodobutane. It is a solid that is stable at room temperature. In solution the p-dehydrobenzene diradical derived from its cycloaromatization can be trapped by nucleophiles. The rate-limiting step is the cyclization, which is slightly slower than that of the parent cyclodec-1,5-diyne-3-ene but faster than that of its benzo analogue, consistent with the distances between the reacting carbon atoms.