Pentafluorobenzyl pentafluorophenyl sulfide is oxidised with moderate e.e. value and a low yield by the usually highly successful oxidation protocol based upon tert-butyl hydroperoxide (TBHP) in the presence of a titanium/hydrobenzoin complex. This disappointing result resisted until the present work, in which the switch of the oxidation agent (from TBHP to cumene hydroperoxide), suggested by our previous computations, yielded the enantiopure sulfoxide. This valuable chiral compound was obtained in good yields (76%) without resorting to a chromatographic separation. DFT computations uncovered that this favourable reactivity was originated by a stabilizing π-π-stacking between the phenyl group of the oxidant and the pentafluorophenyl moiety of the substrate.

Chiral nonracemic aminobenzylnaphthols were obtained by a Betti multi-component reaction between 2-naphthol, aryl aldehydes and enantiopure arylethylamine. Moreover, some new aminobenzylnaphthols were synthesized by a similar reaction between 2-naphthol, aryl aldehydes and prolinol. These aminobenzylnaphthols, synthesized from different components and thus having different structural features, were tested as anti-yeast agents inhibiting Candida albicans. The effect towards the test strain was studied with a microdilution approach and three different concentrations (150, 300 and 450 µg/mL) were tested. The best results were found for the aminobenzylnaphthols obtained from 1-naphthylethylamine and from natural prolinol. The use of the two-way ANOVA highlighted the better performances of the prolinol derivative among the differently structured aminobenzylnaphthols that were screened. The activity towards C. albicans of this prolinol derivative resulted to be interesting and could represent a promising alternative to overcome the problem of the strains resistant to the traditional antifungals.

A series of ten chiral aryl benzyl sulfoxides with perfluorinated aryl or benzyl rings, obtained by enantioselective oxidation of sulfides, has been investigated by means of electronic circular dichroism (ECD) spectroscopy and time-dependent DFT (TDDFT) calculations. The (per)fluorination of the aromatic rings has a large impact on the conformer population, the molecular orbitals shape, and the character of electronic transitions. In this series, the transition responsible for the "sulfoxide primary" CD band has a large charge transfer (CT) character, as demonstrated by the CT metric index ΓNTO. As a consequence, global DFT hybrids such as B3LYP are largely inaccurate in the prediction of excited states; nevertheless, a correct simulation of CD spectra may be achieved by using range-separated functionals such as CAM-B3LYP. The use of the empirical Mislow's rule for assigning the absolute configuration is strongly discouraged for this class of compounds. A series of ten chiral aryl benzyl sulfoxides with perfluorinated aromatic rings has been investigated by means of electronic circular dichroism and time-dependent DFT calculations. The perfluorination has a large impact on the molecular orbitals and electronic transitions. Range-separated functionals perform much better than global hybrids in the prediction of the ECD spectra.

The crystal structures of (S, S)-aminobenzylnaphthols, easily produced by a chromatography-free highly stereoselective Betti reaction, were investigated by means of single crystal X-ray diffraction analysis, and the main intra- and intermolecular interactions were described. The presence of a strong intramolecular hydrogen bond was confirmed, whereas the whole crystal building was found to be due mainly to other bondings, such as CH…O and CH…p interactions. As far as the last interactions were concerned, we observed many short distances from one hydrogen atom to an aryl plane, together with the appropriate geometric requirements for the assemblies. The observations suggest that these interactions can play a relevant role in the crystal building. The absence of similar short distance CH…p interactions in the crystal of a diastereomeric (R, S)-aminobenzylnaphthol could be a suggestion of the preferential crystallisation of the (S, S)-stereoisomer and, consequently, its prevalence as a product of the Betti reaction.

P-enantiomerically pure cyclic phosphonamides have been synthesized via a cyclisation reaction of (S, S)-aminobenzylnaphthols with chloromethylphosphonic dichloride. The reaction is highly stereoselective and gives almost exclusively (S, S, SP)-cyclic phosphonamides in good yields. Analysis of the X-ray crystal structures shows clearly that the cyclisation reaction forces the two naphthyl rings into a stable parallel displaced stacking assembly and indicates also the existence of intra-molecular CH…pi interactions and weak forms of inter-molecular hydrogen bondings, involving the oxygen and the chlorine atoms. QM computations and NMR spectra in solution confirm the stacked molecular assembly as the preferred arrangement of the two naphthyl groups.

The multi-component Betti reaction of 2-naphthol, benzaldehyde and (S)-amines, that usually provides highly valuable aminobenzylnaphthol bearing two stereogenic centers, yielded a completely racemic product, when (S)-valine methyl ester was employed as the amine in the usual reaction protocol. The cause of this drawback, that appears to be overlooked in the literature, was investigated. As a result, new reaction conditions were set up, that were able to yield the expected useful product, having two fully resolved stereogenic centers. Furthermore, when the effect of substituents on the phenyl ring was preliminarily studied, we found that 4-fluoro- and 4-chlorobenzaldeyde gave stereoisomerically pure compounds also in the original reaction protocol.

A series of 13 enantiopure aryl benzyl sulfoxides (1a-m) with different substituents on the two aromatic rings has been previously analyzed by means of electronic circular dichroism (CD) spectroscopy. Most of these compounds are crystalline and their X-ray structure is established. For almost one-half of the series, CD spectra measured in the solid state were quite different from those in acetonitrile solution. We demonstrate that the difference is due to strong exciton couplings between molecules packed closely together in the crystal. The computational approach consists of time-dependent density functional theory (TDDFT) calculations run on “dimers” composed of nearest neighbors found in the lattice. Solid-state CD spectra are well reproduced by the average of all possible pairwise terms. The relation between the crystal space group and conformation, and the appearance of solid-state CD spectra, is also discussed

Aminobenzylnaphthols are a class of compounds containing a large aromatic molecular surface which makes them suitable candidates to study the role of C—H⋅⋅⋅π interactions. We have investigated the effect of methyl or methoxy substituents on the assembling of aromatic units by preparing and determining the crystal structures of (S,S)-1-{(4-methylphenyl)[(1-phenylethyl)amino]methyl}naphthalen-2-ol, C 26 H 25 NO, and (S,S)-1-{(4-methoxyphenyl)[(1-phenylethyl)amino]methyl}naphthalen-2-ol, C 26 H 25 NO 2 . The methyl group influenced the overall crystal packing even if the H atoms of the methyl group did not participate directly either in hydrogen bonding or C—H π interactions. The introduction of the methoxy moiety caused the formation of new hydrogen bonds, in which the O atom of the methoxy group was directly involved. Moreover, the methoxy group promoted the formation of an interesting C—H⋅⋅⋅π interaction which altered the orientation of an aromatic unit.

A series of enantiopure crystalline aryl benzyl sulfoxides, bearing different substituents on both the aryl groups, were synthesized by an enantioselective oxidation of the corresponding sulfides. Structural investigations, achieved by means of single-crystal X-ray diffraction, allowed us to recognize the main assembling interactions. The same procedure was repeated for some corresponding fluorinated aryl benzyl sulfoxides. The synthesis of the enantiomers of a new fluorinated compound, which shows unusual structural patterns, prompted us to compare the structural motifs of the two families of sulfoxides (fluorinated and unfluorinated) and to investigate the changes due to the fluorine substitution. Some short contacts involving the fluorine atom were discussed in more details, taking into account the recent interest in these sometimes controversial interactions.

The synthesis of two new dye families of croconic acid derivatives, semicroconaine and non-symmetric croconaine dyes, is reported for the first time. These compounds show strong absorption in the UV-visible and NIR, respectively. Semicrocon-aine dyes were obtained by a scalable and efficient condensation of croconic acid with aromatic heterocyclic methylene-active compounds. The subsequent reaction of the semicroconaine dyes with aromatic heterocyclic compounds affords non-symmetric croconaines. The structure and electronic properties of the synthesized compounds have been investigated by preliminary theoretical calculations at DFT level of approximation.

The CD spectra of 13 crystalline aryl benzyl sulfoxides 1a-m with various substituents on the two aromatic rings were recorded in solution and in the solid state. Solution CD spectra were very homogeneous along the series, consisting in most cases of a couplet-like feature in the 200-300 nm region. The red-shifted component of the couplet, corresponding to the sulfoxide-centered n-π* transition, is always positive for (R) absolute configuration in accordance with Mislow’s rule. The presence of a strong electron-withdrawing substituent on the phenyl ring (nitro or ester group) alters the shape of the CD spectrum. CD calculations using the TDDFT method were run for eight representative compounds using DFT-optimized geometries. In all cases, calculated spectra were in very good agreement with experimental ones and allowed for rationalization of the diverse spectral behaviors. It is demonstrated thatTDDFT//DFTcalculations represent a reliable option for assigning the absolute configuration of this class of compounds whenever crystals suitable for X-ray are not available. Solid-state CD spectra recorded with the KCl pellet technique were in some cases in agreement with those in solution. However, in other cases new and strongCD signals appeared which were interpreted as being due to intermolecular couplings in the crystals.

Some aminophenyl benzyl sulfides or benzyl pyridyl sulfides were asymmetrically oxidized with tert-butyl hydroperoxide in the presence of a complex between titanium i-propoxide and (S, S)-hydrobenzoin, an oxidation system that works particularly well with a vast set of aryl benzyl sulfides. Notwithstanding the presence of nitrogen-containing moieties that, in principle, could interfere with the correct co-ordination of the sulfide to the metal center, satisfactory levels of enantioselectivity (up to 78%) were measured for this oxidation process.

The results of a combined computational-experimental study of the oxidation of various fluorinated aryl benzyl sulfides using tert-butyl hydroperoxide (TBHP) in the presence of a complex of titanium and (S,S)-hydrobenzoin are presented. As observed in previous studies for other aryl benzyl sulfides, the reaction leads to enantiopure sulfoxides (ee>98%) in good isolated yields (81–96%) except the case of pentafluorobenzyl pentafluorophenyl sulfide for which a lower ee (61%) is observed. DFT computations on a model-system formed by the substrate, the oxidant TBHP and the [(S,S)-hydrobenzoin]2-Ti complex satisfactorily explain this unexpected item. The enantioselectivity is governed by the relative energy of the two diastereomeric octahedral complexes that form if TBHP approaches the initial complex between substrate and [(S,S)-hydrobenzoin] 2-Ti before the oxygen transfer. For pentafluorobenzyl pentafluorophenyl sulfide, the two octahedral complexes are almost degenerate and, thus, they form in similar amounts. As the two corresponding diastereomeric transition states are similar in energy, the probability to follow one or the other diastereomeric reaction channel becomes comparable, which leads to the lower enantiomeric excess experimentally observed. Our computations indicate that the particular “folded conformation”, adopted by the substrate only if both phenyl rings are fluorinated, is the key factor that determines the near degeneracy of the two diastereomeric octahedral complexes.

After the discovery of a few cases of lower enantioselectivity in the oxidation of aryl benzyl sulfides with hydroperoxides in the presence of a complex between titanium isopropoxide and (S, S)-hydrobenzoin, a screening of the oxidation of new substrates that are related to the structures that gave low ee values, was performed. From this screening, we confirmed that only a few sulfides remain as exceptions within a framework of exceptionally high stereoselectivity of the oxidation reaction. Moreover, the exceptions are clearly identified and are connected to particular coordinating moieties present on the aryl groups.