3.3.4. Cyclic Enols
Due to the electron withdrawing effect of the oxygen atom in a C=O double bond, the hydrogen(s) on the neighboring carbon atom become(s) more acidic. As a consequence, an equilibrium emerges between the –CHx–C(R)=O and the –CH(x−1)=C(R)–OH structural forms. The equilibrium is called keto-enol tautomerism. If there are no additional polar groups in the molecule, at least not close to the carbonyl group, the equilibrium is generally shifted toward the –C=O containing structure. A more complicated situation comes into existence if two carbonyl groups are separated by a CHx (x = 1,2) unit. Typical examples are β-diketones and dialdehydes, β-keto carboxylic acids and esters, the dicarboxylic malonic acid and its esters. For such species, the keto-enol tautomerism was demonstrated experimentally by Moriyasu et al., in different polarity solvents [225]. The determined equilibrium compositions indicate that the preference of the enol structure increases in more dilute solutions but decreases with the increasing polarity of the solvent. For ethyl acetoacetate (for the gas-phase molecular structure of the methyl acetoacetate, see [226]), which is favorably used for syntheses of ketones and carboxylic acid esters, the keto form predominates in chloroform and more polar solvents. In contrast, the enol form is much more favored in all studied solvents but water for acetylacetone. With aromatic rings connected to the β-diketo moiety, the enol form is overwhelming in any studied organic solvents.
Grabowski [2] referring to some former papers emphasized the importance of the interrelation between π-electron delocalization and H-bonding. For molecules possessing a β-diketo moiety, a favorable and coplanar six-member intramolecular H-bond can occur. The situation is similar to the case when the phenolic OH forms a H-bond to the carbonyl oxygen in 2-COOH phenol (salicylic acid). Whereas the formation of the intramolecular H-bond within a six-member ring does not need a solvent-affected keto-enol tautomeric shift for salicylic acid, formation of a H-bond donor hydroxy group is solvent dependent for a β-diketo moiety.
Malondialdehyde. This molecule is the simplest 1,3-dicarbonyl species, actually a dialdehyde. The gas-phase microwave spectrum was recorded by Baughcum et al., [227] and the IR spectrum by Seliskar and Hoffmann [228]. The string “malonaldehyde (3-hydroxy-2-propenal)” in the title of the Buaghcum paper is noteworthy. The authors want to emphasize in the title that the system is subject to keto-enol tautomerism.
For β-dicarbonyl systems, a conjugated double-bond moiety comes into existence in the form of HO–CH=CHx–C=O (x = 0, 1) when the enol structure is created. Such molecules are subject to s-cis/s-trans conformational equilibrium about the formal single CHx–C bond. This type of conformational equilibrium was recently studied by Nagy and Sarver [117], who also investigated the effect of the non-polar solvents and water on the in-solution conformer composition. Structures 13 and 14 are examples for the s-cis and s-trans conformations, respectively.
An intramolecular H-bond can be formed only in the s-cis conformation of the enolic malondialdehyde. If the heavy atom skeleton is not entirely coplanar, the structure is called gauche, as found for the second stable form of 1,3-butadiene. The above experimental studies found fully planar molecular structure for 3-hydroxy-2-propenal, as the enol form was called in [227]. Earlier theoretical studies have been summarized by Grabowki [2] on the keto-enol tautomerism and the geometric consequences of the process.
If the molecule has a C2v symmetry for the planar malondialdehyde in the dicarbonyl form or C2 for acetylacetone, then two equivalent enol forms can be derived from the structure. Since the molecules are undistinguishable except, e.g., if there are different isotopes for the oxygens, the proton relocation to one or to the other oxygen cannot be noticed macroscopically. A possible reaction route is that the two OH groups are formed via the intermediate formation of the dicarbonyl structure.
The authors of the experimental studies [227,228] argue, however, in favor of a tunneling mechanism. The two, undistinguishable enol forms, which are now unsymmetrical, could transform into each other through a structure of C2v symmentry, where the electrons of the two double bonds are delocalized. The quantum chemical explanation for the intramolecular proton relocation rests on the acceptance of a double-well potential for the process, where the isoenergetic enol forms correspond to local energy minima, and the symmetrical intermediate structure with four delocalized electrons in a six-member ring correspond to a transition state.
In-solution NMR investigations were performed in chlorofom by Bothner-By and Harris [229] and by Bertz and Dabbagh [230]. Bothner-By and Harris compared a number of s-cis and s-trans conformational/tautomeric isomers, Bertz and Dabbagh listed former publications in different solvents. These studies reveal that the trans enol form of malondialdehyde (called simply trans) exists in water, protic and polar solvents, whereas the enol adopts the cis form in non-polar solvents. Bertz and Dabbagh found, however, that polar impurities like methanol affect the conformer ratio in CHCl3. The methoxy oxygen of methanol competes with the carbonyl oxygen in forming an intermolecular vs. intramolecular H-bond with the OH group. This is exactly the problem addressed in the title of this review. Bertz and Dabbagh did not consider an O–H…O intramolcular H-bond as a decisive factor in stabilizing the cis conformation.
George et al., [231] optimized six planar conformers for β-hydroxyacrolein (malondialdehyde enol) and compared the energies of the most stable cis and trans forms at the 4–31G level. They concluded that the most stable cCc conformation can create an intramolecular H-bond. In the opinion of Bertz and Dabbagh, the result in favor of the intramolecularly bound structure is not convincing enough, because possible intermolecular H-bonds with proton acceptor molecules, like methanol, have not been considered. Indeed, pointing out the disruption of the intramolecular bond in solution, consideration of gas phase hydrates/solvates would still not be enough; explicit solvent or at least supermolecule studies in continuum solvents should be performed.
The structures presented by Bothner-By and Harris show a number of various conformers/tautomers, which could be in equilibrium in chloroform. By considering a series of solvents listed by Bertz and Dabbagh, chloroform represents a borderline solvent between very low dielectric constant solvents like hexane and carbon tetrachloride vs. protic, highly polar solvents like methanol and water. Although Bothner-By and Harris predicted a prevalent s-trans conformation, other researcher argue in favor of the s-cis form (see for references in [230]). The conformational problem becomes even more complicated if considering that not only s-cis/s-trans conformers have to be compared, but there are two different arrangements of the OH group relative to the –CH=CH–CH=O moiety.
In summary, prediction of the enolic malondialdehyde conformational/tautomeric equilibrium presents a very complicated structural problem, as revealed from experiments for solutions in moderately polar solvents. Satisfactory high-level theoretical calculations for any in-solution equilibrium, which could make at least initial suggestions about the structural preference have not been found through the literature search.
Acetylacetone. This molecule is the classical target for theoretical considerations of the keto-enol tautomerism. Belova et al., [31] found from gas-phase electron diffraction investigation 100% of the enol form at 300 K and 64% at 671 K. The enol form with CS symmetry possesses a strongly asymmetric intramolecular H-bond in the gas-phase. For aqueous solution, the CS symmetry, involving coplanar heavy atoms, has been called in question by Bothner-By and Harris [229], who mentioned that the NMR spectrum reflects the average of two, isoenergtic, non-planar molecular structures in water. The keto form is of C2 symmetry. Most of the molecular structural parameters, including the H-bond parameters and the critical O=C–C–C torsion angle for the keto form were reproduced well by B3LYP/aug-cc-pvtz and MP2/cc-pvtz calculations.
Moriyasu et al., [225] found an enol/keto ratio of 0.34 in 0.1 and 0.01 molar aqueous solutions at T = 298 K. Other experiments (for references, see Alagona et al. [232]) predict 0.14 as the lower limit. This suggests that although the enol form exists in aqueous solution, its fraction is much reduced even compared with its population at T = 671 K in the gas phase. On the basis of the experimental equilibrium compositions, the standard state free energy difference for the enol and keto forms is 2.7–4.9 kJ/mol. A number of recent theoretical in-solution studies have been performed for acetylacetone in order to reproduce this experimental value. Although any calculation predicted both stable enol and keto structures, their predicted ratio scattered considerably.
Ishida et al., [233] succeeded to closely reproduce the lower limit of the experimental data by performing RISM-SCF calculations in water. The general reliability of the method is questionable, however, if considering that the predominant gas-phase structure was not correctly predicted and the prevailing tautomer was strongly overestimated in carbon tetrachloride. Schlund et al., [234] calculated enol preference in aqueous solution and concluded that if the PCM model is used, the majority of the diketo form cannot be reproduced. Accordingly, Alagona et al., [232] used the IEF-PCM method at different theoretical levels only for estimating the relative internal free energy. The relative solvation free energy was predicted by means of the MC/FEP method. The calculated best in-water total free energy difference was 0.7 kJ/mol, corresponding to enol/keto ratio of 0.75.
Related systems. Six-member rings with an intramolecular H-bond have been found for a number of systems such as 2-phenyliminomethyl-naphthalen-l-ol [235,236], its isomer, 1-phenyliminomethyl-naphthalen-2-ol, and substituted 3-hydroxy-4-pyridaldehyde deivatives [237]. For these molecules, the covalent structure assures the possibility of the intramolecular hydrogen bond in some preferable conformation. The authors concentrated, however, on the tautomeric issue, thus whether an N–H…O= or an =N…H–O hydrogen bond is more stable under the conditions in solution. These studies are mentioned here only as related systems, because the authors did not investigate the possible disruption of the intramolecular H-bond.