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.

The complete mechanism of an aldol condensation in water.

The base-catalyzed aldol condensation between benzaldehyde and -acetylbenzoic acid in water shows an inverse solvent kinetic isotope effect, /, of 1.33 ± 0.03.

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.

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 and a Raman band at 1947 cm. Malonic anhydrides are unstable, decomposing below room temperature to a ketene plus carbon dioxide.

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, , 2021, , 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.

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 -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.

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 O ( n = 0, 1, 2) isotopologues. The symmetries of their hydrogen bonds were probed by isotopic perturbation of their CO NMR signals. The former mixture shows a total of four signals, due to both intrinsic and perturbation isotope shifts.

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.

Approach control. Stereoelectronic origin of geometric constraints on N-to-S and N-to-O acyl shifts in peptides.

Intramolecular N-to-S or N-to-O acyl shifts in peptides are of fundamental and practical importance, as they constitute the first step in protein splicing and can be used for the synthesis of thioester-modified peptides required for native chemical ligation. It has been stated that the nucleophile must be positioned to the carbonyl oxygen, as in a amide. Despite the importance of such reactions, an understanding of this geometric restriction remains obscure.

pH-Free Measurement of Relative Acidities, Including Isotope Effects.

A powerful pH-free multicomponent NMR titration method can measure relative acidities, even of closely related compounds, with excellent accuracy. The history of the method is presented, along with details of its implementation and a comparison with earlier NMR titrations using a pH electrode. Many of its areas of applicability are described, especially equilibrium isotope effects.

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.

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.

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.

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.

Direct observation of β-chloride elimination from an isolable β-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 β-chloroalkyl in a system relevant to coordination-insertion polymerization of polar olefins. Kinetic analysis of NiCl(CCl2CCl3)(CNAr(Mes2))2 decomposition indicates that β-chloride (β-Cl) elimination proceeds by a unimolecular mechanism that does not require initial dissociation of a CNAr(Mes2) ligand.

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.

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.

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.

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.

On the Intramolecular Hydrogen Bond in Solution: Car-Parrinello and Path Integral Molecular Dynamics Perspective.

The issue of the symmetry of short, low-barrier hydrogen bonds in solution is addressed here with advanced ab initio simulations of a hydrogen maleate anion in different environments, starting with the isolated anion, going through two crystal structures (sodium and potassium salts), then to an aqueous solution, and finally in the presence of counterions. By Car-Parrinello and path integral molecular dynamics simulations, it is demonstrated that the position of the proton in the intramolecular hydrogen bond of an aqueous hydrogen maleate anion is entirely related to the solvation pattern around the oxygen atoms of the intramolecular hydrogen bond. In particular, this anion has an asymmetric hydrogen bond, with the proton always located on the oxygen atom that is less solvated, owing to the instantaneous solvation environment.

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.