Substituent effects on keto–enol tautomerization of β-diketones from X-ray structural data and DFT calculations

Abstract

Single crystal X-ray structure determinations of six crystals 1-6 of b-diketones, the related DFT calculations as well as a systematic investigation, on the CSD (Cambridge Structural Database) files, of all acyclic b-diketones having at least one a-hydrogen, in both b-diketo and b-keto-enol tautomeric forms, are reported. In spite of the stabilization energy gained by the formation of strong intramolecular O-HÁ Á ÁO resonace assisted hydrogen bonds (RAHB) a certain number of non-enolized structures were retrieved. The structural data show that the steric and electronic properties of the substituents play a definite role in tuning the hydrogen bond strength and determining the enolic site but the driving force able to shift from the more common b-keto-enol tautomer to the b-diketo one can be only the steric hindrance of bulky groups. In this context the substituents in position 2 play a crucial role in establishing the tautomeric form. In fact, while the 2-unsubstituted b-diketones (or 2-substitued by a group linked by a sp 2 carbon) assume almost exclusively the b-keto-enol form with some exceptions for very bulky substituents, b-diketones carrying 2-alkyl substituents, in general, display the b-diketo tautomeric form. The only exceptions are the 2-alkyl curcumin derivatives where the planar b-keto-enol group is stabilized by extended p-conjugation within the whole molecule and by the absence of short contacts between the alkyl R 2 groups and R 1 or R 3 substituents. DFT calculations on the six compounds, 1-6, show that in the four more overcrowded structures, 3-6, the trans-b-diketo tautomer is more stable than the Z-b-keto-enol isomer unlike what happens for 1 and 2 where the Z-b-keto-enol isomer is the most stable by a few kcal mol À1 . Thereby, the occurrence of the trans-b-diketo tautomer for all compounds, in the crystal, can be interpreted in terms of the existence of a large activation energy in the mechanism to attain the Z-b-keto-enol isomer containing an intramolecular O-HÁ Á ÁO hydrogen bond.

Curcumin and its Derivatives: Their Application in Neuropharmacology and Neuroscience in the 21st Century

“…1 ). In addition, these keto-enol tautomers also exist in several cis and trans forms whereby their relative concentrations vary according to temperature, polarity of solvent, pH and substitution of the aromatic rings [56-58]. The amount of keto-enol-enolate of the heptadienone moiety in equilibrium plays a crucial role in the physicochemical properties and anti-oxidant activities of curcumin [59].…”

Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

“…The discovery that the six-membered pseudoaromatic ring of the enol of curcumin [16] [(1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-triene- 3-one] can be replaced by the five-membered ring of the heteroaromatic 1H-pyrazole [17] maintaining but also modifying the biological properties of curcumin, has resulted in many works [18,19,20,21,22] including two by our group [23,24] (Fig. 1).…”

Resonance‐Assisted Hydrogen Bonding as a Driving Force in Synthesis and a Synthon in the Design of Materials

“…However,t he number of structures incorporating the latter form is far greater than that in the former form, owing to the stabilization energy gained by the formation of strong OÀH···O RAHB. [7,13,14,139,140] H-bond energies in the OÀH···O synthon have been calculatedt ob ea bout 10 kcal mol À1 in malondialdehyde, [18,121] 14 kcal mol À1 in acetylacetone, [18,141] 16 kcal mol À1 in benzoylacetone [142] and 19 kcal mol À1 in dibenzoylmethane, [19] much highert han the usual H-bond energies of 4-6 kcal mol À1 (Scheme 7b,c). [135,136] Owingt ot he strongR AHB system, the chemical shifts of the enolic hydrogen in the 1 HNMR spectra of heterodienic O=C(R 1 )ÀCH=C(R 2 )ÀOH (b-diketones or b-diketoesters) chains are at al ower field (d > 12.0 ppm; Scheme7b) [29,115,137,138] than the intramolecular H-bond in O= C(R 1 )ÀCH 2 -C(R 2 )ÀOH (aldols) at d % 8.6-10.1 ppm (Scheme 7c).…”

“…[7,13,14,139,140] H-bond energies in the OÀH···O synthon have been calculatedt ob ea bout 10 kcal mol À1 in malondialdehyde, [18,121] 14 kcal mol À1 in acetylacetone, [18,141] 16 kcal mol À1 in benzoylacetone [142] and 19 kcal mol À1 in dibenzoylmethane, [19] much highert han the usual H-bond energies of 4-6 kcal mol À1 (Scheme 7b,c). [140] The O···O distance shortening is concomitantw ith an increasei nt he p-delocalization along the heterodienic O=CÀC= CÀOH chain, and with ad ecrease of the IR n(OH) stretching frequencies of up to about 2560cm À1 . [136] For instance, the steric and electronic properties of the substituents plays ad efinite role in tuning the hydrogen bond strength and the choice between the bketo-enol or b-enol-keto tautomers, but the driving force able to shift from the b-keto-enol (or b-enol-keto) form to the bdiketo one can only be the steric hindrance of particular substituents.…”