Simon Bolvig

Deuterium-Induced Isotope Effects on13C Chemical Shifts as a Probe for Tautomerism in Enolic β-Diketones

Deuterium isotope effects on 13C nuclear shielding, nΔC(OD), were investigated for a series of enolic β‐diketones at different temperatures. The investigated enolic β‐diketones cover a broad range of tautomeric equilibrium constants (K). The equilibrium constants were estimated from 17O and 13C chemical shifts. 13C chemical shifts and the deuterium isotope effects show changes with temperature, which are due to a change in the tautomeric equilibrium. It is shown that the variation of K with deuterium substitution depends on K. This has the important consequence that the equlibrium isotope effects for a series with different K may go through a maximum. If the sum of the deuterium isotope effects on 13C chemical shifts for the carbonyl and enolic carbons is above 0.8 ppm for five‐membered and 1.2 ppm for six‐membered ring compounds, the system is tautomeric. This statement holds for sterically non‐hindered compounds. The intrinsic two‐bond deuterium isotope effects for an intramolecular hydrogen bonded system with a chelate six‐membered ring with optimal geometry and a localized double bond are estimated to be 1.2 ppm. Knowing the intrinsic contribution, deuterium isotope effects can be used to estimate the position of tautomeric equilibria for β‐diketones. 1H chemical shifts of OH groups display a linear relation with the molar fraction X.

Tautomerism of enolic triacetylmethane, 2‐acyl‐1,3‐cycloalkanediones, 5‐acyl Meldrum’s acids and 5‐acyl‐1,3‐dimethylbarbituric acids studied by means of deuterium isotope effects on 13C chemical shifts

Deuterium isotope effects on 13C nuclear shielding, nΔC(OD), were investigated for a series of enolic triacetylmethane, 2‐acyl‐1,3‐cycloalkanediones, 5‐acyl Meldrum’s acids and 5‐acyl‐1,3‐dimethylbarbituric acids at different temperatures. The enolic 2‐acyl‐1,3‐cycloalkanediones, 5‐acyl Meldrum’s acids and 5‐acyl‐1,3‐dimethylbarbituric acids all exhibit intramolecular enol–enol tautomerism. For the first two the equilibrium constants were estimated from the deuterium isotope effects on the enolic and carbonylic carbons. The equilibrium constants were estimated to be 1.5 for the enolic 2‐acyl‐1,3‐cyclohexanediones and 2‐acetyl‐1,3‐cyclopentanedione, favouring the form having an endocyclic enolic double bond, and 0.8 for 5‐acyl‐1,3‐dimethylbarbituric acids, favouring the form having an exocyclic enolic double bond. Apparently, the equilibrium position is unaffected by increasing the size of the acyl group, and therefore no distinct effects caused by steric hindrance were observed. The non‐hydrogen‐bonded α‐carbonyl group of enolic triacetylmethane, the 2‐acyl‐1,3‐cycloalkanediones, 5‐acyl Meldrum’s acids and 5‐acyl‐1,3‐dimethylbarbituric acids cause a high frequency shift of the OH 1H chemical shifts. A plot of the latter against the sum of 2ΔC(OD)+4ΔC(OD) shows a larger sum for the compounds apparently exhibiting intramolecular enol–enol tautomerism than for compounds apparently not exhibiting such tautomerism.

Variable temperature 1H and 13C NMR spectroscopic investigation of the enol–enethiol tautomerism of β-thioxoketones. Isotope effects due to deuteron chelation

Abstract A chemical shift vs. temperature analysis of β-thioxoketones has been performed for the four β-thioxoketones, thioacetylacetone ( 1 ), benzoylthioacetone ( 2 ), thiobenzoylacetone ( 3 ) and monothiodibenzoylmethane ( 4 ), to test this method as a general way of obtaining the individual chemical shifts of tautomers involved in tautomeric equilibria. Both 13 C and chelate 1 H resonances for 1 and 2 showed a coalescence point subsequently followed by observation of two sets of resonances when lowering the temperature. Analysis of chemical shifts and isotope effects on these reveals that a three component system is involved in the tautomeric equilibria for 1 and 2 . The three components are the intramolecularly hydrogen-bonded ( Z )-enol form (A), the intramolecularly hydrogen-bonded ( Z )-enethiol form (B) (which are interconverting rapidly by intramolecular proton transfer/electron redistribution) and the non-proton chelated ( Z )-enethiol form (C). This third species is observable at low temperature in CD 2 Cl 2 as well as in mixtures of freons. The hydrogen-bonded ( Z )-enol and ( Z )-enethiol forms A and B appear to be in equilibrium at all obtainable temperatures. The analysis of the data for 3 and 4 leads to Δ H ° and Δ S ° values as well as chemical shifts for the individual tautomers. It is demonstrated how deuteriation of the chelate proton may lead to analysis of a complex three species equilibrium system of which only one component can be observed directly. The large negative isotope effects observed are due to large equilibrium isotope effect contributions. A very large shift in the equilibrium is observed upon deuteriation. The negative primary isotope effects found for the chelate protons are resolved into intrinsic and equilibrium parts. The large positive intrinsic effects clearly point to a two-potential well in agreement with results from UV and IR measurements and indicate strong hydrogen bonds.

Intramolecular hydrogen bonding of the enol forms of β-ketoamides and β-ketothioamides. Deuterium isotope effects on 13C chemical shifts☆

Abstract Deuterium isotope effects of 13 C chemical shifts are studied in a series of enol and keto forms of β-ketoamides and the corresponding thioamides. In addition, the 2,6-cyclohexanediketo-1-amides and thioamides are studied. The effects of ring size (five- and six-membered rings) on the isotope effects and the tautomeric nature of the systems are also looked into. Rather unusual isotope effects are found for the amides, indicating a tautomeric system of the CONHRCOHNHR type. This is supported by the 17 O chemical shift studies. The isotope effects of the simple amides are compared with those of the tetracyclines and piroxicams. The study of N -phenyl-3-phenyl-3-oxo-propiothioamide at low temperature reveals that this thioamide exists as a mixture of s-cis and s-trans species. The isotope effects and the influence of intramolecular hydrogen bonding in the two species can thus be studied. Thioamides of indan-1,3-diones show tautomeric behaviour, as revealed by very large deuterium isotope effects of both signs. Deuteriation shifts the equilibrium in the direction of the thioamide. Finally, the tendency of a series of β-hydroxy esters, thioesters, anhydrides, amides, thioamides, aldehydes and ketones to become tautomeric is discussed in terms of hydrogen bonding, isotope effects, 2 Δ C(OD), and the nature of the acceptor.

Deuterium Isotope Effects on 13C Chemical Shifts of o‐Hydroxyacyl Aromatics. Intramolecular Hydrogen Bonding

The interesting deuterium isotope effects of gossypols have been reinvestigated and the very large two‐bond isotope effect, 2ΔC‐6(OD), is ascribed to electric field effects. Common to the investigated compounds is the presence of intramolecular hydrogen bonds. A feature strongly related to the strength of the intramolecular hydrogen bond is intermolecular OH exchange. Electron‐attracting substituents at the 3‐ and 5‐positions of 2‐hydroxyacyl aromatics increase the acidity of the 2‐OH proton and therefore the intermolecular exchange, but not the hydrogen bond strength, whereas alkyl groups ortho to the intramolecularly hydrogen bonded OH prevent the OH group from swinging out and therefore prevent intermolecular exchange. Conformational equilibria were studied in 2‐hydroxy‐3‐nitro‐6‐methoxyacetophenone. Surprisingly, the form with the weaker intramolecular hydrogen bond to the nitro group is dominant at ambient temperature, whereas it is the opposite at 160 K. For 2‐hydroxy‐5‐methyl‐3‐nitroacetophenone a similar pattern is seen, but with much less of the form having hydrogen bonding to the nitro group at ambient temperature. 2‐Acetyl‐1, 8‐dihydroxy‐3,6‐dimethylnaphthalene is involved in tautomerism of the enolic β‐diketone type and large deuterium isotope effects on the 13C and OH chemical shifts are observed.

Primary tritium and deuterium isotope effects on chemical shifts of compounds having an intramolecular hydrogen bond

The primary deuterium and tritium isotope effects, δ(XH) − δ(XD/T), were measured for 55 compounds having one or more intramolecular hydrogen bonds. The primary isotope effects were measured at various temperatures. For compounds displaying tautomerism the primary isotope effects are found to have contributions from both intrinsic and equilibrium isotope effects. The primary tritium isotope effect, PΔ(1H,3H), and the primary deuterium isotope effect, PΔ (1H,2H), are shown to be related by

NJ(13C, O1H) COUPLING CONSTANTS OF INTRAMOLECULARLY HYDROGEN-BONDED COMPOUNDS

^{\rm P}\Delta (^{1}\hbox{H},^{3}\hbox{H}) =1.4 ^{\rm P}\Delta (^{1}\hbox{H},^{2}\hbox{H})

Intramolecular hydrogen bonding and tautomerism of acylpyran-2,4-diones, -2,4,6-triones and acylpyridinediones and benzannelated derivatives. Deuterium isotope effects on 13C NMR chemical shifts

This finding is valid for both tautomeric compounds and compounds with localized hydrogen bonds. Large negative primary tritium and deuterium isotope effects were observed for compounds displaying tautomerism and having sulfur as donor or acceptor. These isotope effects show a strong temperature dependence, which is related to the change in equilibrium due to isotope substitution. For the compounds with localized hydrogen bonds, the primary deuterium and tritium isotope effects correlated with the two bond deuterium isotope effect on 13C chemical shifts. The primary deuterium and tritium isotope effects are therefore a measure of the hydrogen bond strength for compounds with localized hydrogen bonds. Copyright