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Some Brief Notes on Theoretical and Experimental Investigations of Intramolecular Hydrogen Bonding Lucjan Sobczyk 1 , Dorota Chudoba 2,3 , Peter M. Tolstoy 4 and Aleksander Filarowski 1,3, * 1 2 3 4

*

Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie Str., 50-383 Wrocław, Poland; [email protected] Faculty of Physics, A. Mickiewicz University, Umultowska 85, 61-614 Poznan, Poland; [email protected] Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, 141980 Dubna, Russia Center for Magnetic Resonance, St. Petersburg State University, St. Petersburg 198504, Russia; [email protected] Correspondence: [email protected]; Tel.: +48-71-3757229; Fax: +48-71-3282348

Academic Editor: Steve Scheiner Received: 22 October 2016; Accepted: 28 November 2016; Published: 2 December 2016

Abstract: A review of selected literature data related to intramolecular hydrogen bonding in ortho-hydroxyaryl Schiff bases, ortho-hydroxyaryl ketones, ortho-hydroxyaryl amides, proton sponges and ortho-hydroxyaryl Mannich bases is presented. The paper reports on the application of experimental spectroscopic measurements (IR and NMR) and quantum-mechanical calculations for investigations of the proton transfer processes, the potential energy curves, tautomeric equilibrium, aromaticity etc. Finally, the equilibrium between the intra- and inter-molecular hydrogen bonds in amides is discussed. Keywords: intramolecular hydrogen bond; Schiff base; Mannich base; proton sponge; acetophenone; salicylamide; pyridoxal

1. Introduction This paper reports on the studies of the systems with intramolecular hydrogen bonding by experimental (IR, NMR, UV-Vis, X-ray and IINS) and theoretical (DFT, ab initio, AIM) methods. As the primary objects for this short review we have selected Schiff bases, Mannich bases, ortho-hydroxyaryl ketones and amides, as well as some proton sponges. A majority of the presented studies covers the phenomena of proton transfer (PT), steric effect, quasi-aromatic hydrogen bonding, aromaticity, tautomeric and conformational equilibria. It should be stressed that the studies of the proton transfer process are of great importance in the description of some enzymatic reactions activated by the hydrogen bonding with a low barrier proton transfer [1–3]. The studies of the ortho-hydroxyaryl Schiff bases can greatly contribute to the understanding of mechanisms of activity of some drugs as well as support the design of new ones [4,5]. For instance, ortho-hydroxyaryl Schiff thiosemicarbazones intercalate between the nitrogen bases in double DNA helix blocking the replication. This feature enables these compounds to be used in the treatment of cancer diseases. There are also substances with ortho-hydroxyaldiminecarbazyne structure which coordinate the iron atoms [6,7]. Their presence in the organism regulates the amount of iron in cells, thus preventing the formation of cancer cells. It is important to note that the salicylamides are nonsteroidal anti-inflammatory medicaments. The modelling of the physicochemical features of salicylamides makes it possible to describe the mechanisms of their biological activity. The major types of compounds with intramolecular hydrogen bonds which are discussed in this review (compounds 1–5) are shown in Figure 1.

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2

ortho-hydroxyaryl Schiff bases

ortho-hydroxyaryl aldehydes and ketones

3 ortho-hydroxyaryl amides

4 N,N-dialkylaminonaphthalene (proton sponge)

5 ortho-hydroxyaryl Mannich bases

hydrogen, aryl and Figure 1. Schematic structures of discussed in in this this work. work. R R111 and of compounds compounds discussed and R R22 == hydrogen, alkyl substitutions. alkyl substitutions.

2. Study Quantum-Mechanical Methods Methods Study of Proton Transfer Process Process in in Hydrogen Hydrogen Bridge Bridge by by Quantum-Mechanical To study study the the energetic energetic and geometric properties of intramolecular hydrogen bonds a full spectrum of quantum-mechanical quantum-mechanicalmethods methodscould couldbebe applied. Concerning choice of method the method andbasis the applied. Concerning thethe choice of the and the basis set, usually the recommendations are the same as for other types of H-bonded systems. The level set, usually the recommendations are the same as for other types of H-bonded systems. The level of of theory is often limited of the molecule in question. Though MP2 performs admirably theory is often limited by by thethe sizesize of the molecule in question. Though MP2 performs admirably [8], [8], cost-effective DFT methods (usually withB3LYP B3LYPand andPBE PBEfunctionals) functionals)perform perform quite quite good the the cost-effective DFT methods (usually with good as well [9]. The basis set preferably should include diffuse functions. While basis sets such as aug-cc-pVTZ are desired, it seems that 6-311++G(d,p) 6-311++G(d,p) remains remains one one of of the the most most widely widely used usedbasis basissets setsup upto tonow. now. Bader’s Bader’s “Atoms “Atoms in in Molecules” Molecules” calculations calculations are are often often used used to to estimate estimate the the hydrogen hydrogen bond bond strength. strength. Calculations are usually performed for isolated molecules, while medium effects are treated by polarized continuum models (PCM) or including one or several solvent molecules explicitly in calculations [10]. [10]. Ortho-Hydroxyaryl Schiff Bases Bases 11 The thethe quantum-mechanical calculations of ortho-hydroxyaryl SchiffSchiff bases The papers papers[11–16] [11–16]present present quantum-mechanical calculations of ortho-hydroxyaryl 1 showing the influence of the proton transfer in quasi-aromatic hydrogen bonds on the shape of bases 1 showing the influence of the proton transfer in quasi-aromatic hydrogen bonds on the shape thethe potential energy curve and rings. rings. of potential energy curveasaswell wellasason onthe theelectron electrondensity densityin in critical critical points points of of bonds and elaborated the methodology calculations spectroscopic The authors of [11] of the of features and [11] elaborated the methodology calculations spectroscopic potentials for proton motion in hydrogen bonds. The adiabatic and the non-adiabatic potentials potentials for proton motion in hydrogen bonds. The adiabatic and the non-adiabatic potentials and and energy levels a number ortho-hydroxyaryl ketiminesand andtheir theirdeuterated deuteratedanalogues analogues were energy levels for for a number of of ortho-hydroxyaryl ketimines calculated. From the energy levels, the positions of ν(XH) bands and the H/D isotope on calculated. From the energy levels, the positions of ν(XH) bands and the H/D isotope effectseffects on them them estimated. were estimated. Estimation of the anharmonic ν(XH) stretching the were Estimation of the anharmonic ν(XH) stretching vibrationvibration frequencyfrequency for the XHfor bond XH bond in engaged in hydrogen bond formation is a valuable result because computational programs engaged hydrogen bond formation is a valuable result because computational programs with with standard methods usually not provide a sufficiently precise description of the ν(XH) band standard methods usually do notdo provide a sufficiently precise description of the ν(XH) band position. position. In [11,12,15] the calculations the non-adiabatic potential along bridgingproton proton transfer transfer In [11,12,15] the calculations of the ofnon-adiabatic potential along thethe bridging coordinate were based on the optimization optimization of all the parameters parameters of the molecule for the gradually coordinate elongated XH This approach approach serves serves for for the the description description of of the the changes changes of of structural structural parameters parameters elongated XH bond. bond. This during the transition from the molecular It was was shown shown that the during molecular form to the the proton proton transfer transfer form. form. It proton transfer process leads to the shortening and strengthening of the hydrogen bonding in the in first the proton transfer process leads to the shortening and strengthening of the hydrogen bonding phasephase of thisofphenomenon (going from thefrom molecular form to the transition and the lengthening first this phenomenon (going the molecular form to the state), transition state), and the in the secondinphase (goingphase from the transition state to the PT form) (Figure 2). (Figure 2). lengthening the second (going from the transition state to the PT form)

Molecular form

Transition state

Proton transfer (zwitterionic) form

Figure 2. 2. Transition Transitionfrom from molecular the proton (zwitterionic) form of the thethe molecular formform to thetoproton transfertransfer (zwitterionic) form of the hydrogenbonded complex. complex. hydrogen-bonded

The paper [11] presents the computational study of the influence of the environment polarity on the potential energy profile for the proton transfer process. The lowering of the energy minimum for the PT form upon increase of the environment polarity for non-adiabatic potential is shown. A similar

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The paper [11] presents the computational study of the influence of the environment polarity on the potential energypotential profile forfor thethe proton transfer form process. The lowering of the energy minimum for of trend of the adiabatic molecular is observed. However, untypical increase the PT form upon increase of the environment polarity for non-adiabatic potential is shown. A similar the local minimum of the adiabatic potential for the PT form with the increase of the solvent polarity trend of the adiabatic potential for the molecular form is observed. However, untypical increase of the was also presented. local minimum of the adiabatic potential for the PT form with the increase of the solvent polarity was To describe also presented.the changes in the electron densities taking place in a molecule during the proton transfer in bridge thein“Atoms in Molecules” (AIM) developed applied Tohydrogen describe the changes the electron densities taking placemethod in a molecule duringby theBader protonwas transfer [12,17–23]. The changes the electronic density in the bonddeveloped critical points (including hydrogen bonds in hydrogen bridge thein“Atoms in Molecules” (AIM) method by Bader was applied [12,17–23]. and The rings) in the non-adiabatic approach for 2-[(1E)-N-methyl-ethanimidoyl)]-phenol R1 in = R2 = changes in the electronic density in the bond critical points (including hydrogen bonds and (1, rings) non-adiabatic approachinfor 2-[(1E)-N-methyl-ethanimidoyl)]-phenol (1, R1the = Rdependencies = CH ; Figure 1) are Figure 1) are analysed [12]. New correlations were obtained and presented CH3;the 2 3 analysed in [12]. correlations and the in the literature [23]New were verified. were The obtained dependency of dependencies the electronicpresented density in inthe theliterature critical [23] point of were verified. The dependency of the electronic density in the critical point of the chelate chain the chelate chain (O–C=C–C=N) on the length of XH bonding is shown in Figure 3. The electron (O–C=C–C=N) on the bond lengthcritical of XH bonding is shown in Figure 3. The electron at the hydrogen density at the hydrogen point goes through a maximum for thedensity transition state (Figure 2), bond critical point goes through a maximum for the transition state (Figure 2), which corresponds which corresponds to the most linear and shortest hydrogen bridge [24]. It can be seen that the to the most linear and shortest hydrogen bridge [24]. It can be seen that the application of the third application of the third state is necessary for the description of the tautomeric equilibrium. According state is necessary for the description of the tautomeric equilibrium. According to the studies of the to the studies of the potentials this state corresponds to the transition state (Figure 2). potentials this state corresponds to the transition state (Figure 2).

Figure 3. The dependence of the electron densities in the critical point of the quasi-aromatic ring Figure 3. The dependence of the electron densities in the critical point of the quasi-aromatic ring (HO–C=C–C=N) on the length of hydroxyl bond of the ortho-hydroxyaryl Schiff base 1 (Figure 1, (HO–C=C–C=N) on the length of hydroxyl bond of the ortho-hydroxyaryl Schiff base 1 (Figure 1, R1 = R1 = R2 = CH3 ). Dark points correspond to: —molecular form, —transition state and N—PT form. R2 = CH3). Dark points correspond to: ■—molecular form, ♦—transition state and ▲—PT form. Reprinted with permission from [12]. Copyright 2008 American Chemical Society. Reprinted with permission from [12]. Copyright 2008 American Chemical Society.

3. Spectroscopic Studies of Tautomeric Equilibrium in Intramolecular Hydrogen Bonds

3. Spectroscopic Studies of Tautomeric Equilibrium in Intramolecular Hydrogen Bonds

According to a recent IUPAC recommendation, the NMR and IR signatures of a hydrogen bond

According a recent IUPAC recommendation, the NMR IR signatures of aproperties hydrogenofbond are the mainto spectroscopic criteria of its formation [25,26]. As aand result, in practice the are the main spectroscopic itsoften formation As a result, practice thevibrational properties of intramolecular H-bondedcriteria systemsofare studied[25,26]. experimentally usingin the values of frequencies, NMR chemical shifts and coupling constants. As for the majority of H-bonded complexes, intramolecular H-bonded systems are often studied experimentally using the values of vibrational in systems discussed hereshifts upon and formation of the intramolecular bondofthe ν(XH) frequency frequencies, NMR chemical coupling constants. As forhydrogen the majority H-bonded complexes, decreases, while the chemical shifts of the bridging proton increases. Interpretation of these in systems discussed here upon formation of the intramolecular hydrogen bond the ν(XH) frequency spectroscopic changes in terms of hydrogen bond geometry and energy might be done using previously decreases, while the chemical shifts of the bridging proton increases. Interpretation of these published correlational dependencies [27–36]. Despite the typical spectroscopic manifestations of the spectroscopic changes in terms of hydrogen bond geometry and energy might be done using previously intramolecular hydrogen bonds, the situation is often complicated by the presence of a tautomeric published correlational dependencies [27–36]. Despite the typical spectroscopic manifestations of the equilibrium between molecular of proton-transfer form of the complex (except for proton sponges, intramolecular hydrogen bonds, the situation often complicated bywell theaspresence of a tautomeric where both forms are positively charged). Theisequilibrium constant as the characteristics of equilibrium between molecular of proton-transfer of the complex (except for proton sponges, individual tautomers are temperature-, solvent- and form substituent-dependent. Disentangling the overall where both formspatterns are positively The equilibrium constant as well as the characteristics spectroscopic requires charged). a careful analysis and usage of other spectroscopic markers, such as, of individual tautomers are temperature-, solvent- and substituent-dependent. Disentangling the overall spectroscopic patterns requires a careful analysis and usage of other spectroscopic markers, such as, i.e., UV-Vis band positions and intensities, C=O stretching frequencies, 13C-, 15N-NMR chemical shifts, spin-spin coupling constants and H/D isotope effects on all of the abovementioned parameters.

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i.e., UV-Vis band positions and intensities, C=O stretching frequencies, 13 C-, 15 N-NMR chemical shifts, spin-spin coupling constants and H/D isotope effects on all of the abovementioned parameters. 3.1. Ortho-Hydroxyaryl Schiff Bases 1 Spectroscopic studies including IR and Raman spectroscopic data as well as incoherent inelastic 4 of 17 neutron scattering (IINS) data were presented in the literature [37–44]. These studies were based on seriesofofspectra spectrarecorded recordedunder underthe theargon argon matrix condition, phase solid state. aaseries matrix condition, in in thethe gasgas phase andand thethe solid state. A A detailed analysis of vibration spectra was also carried out by quantum-mechanical calculations. detailed analysis of vibration spectra was also carried out by quantum-mechanical calculations. The The effects of deuteration band positions and intensities were investigated cases of effects of deuteration on bandonpositions and intensities were investigated for the casesfor of the deuteration deuteration in the hydrogen andgroup in theofmethyl group of (N=C–CH imine fragments (N=C–CH3 ) in in the hydrogen bridges and in bridges the methyl imine fragments 3) in ortho-hydroxyaryl ortho-hydroxyaryl ketimines (1,1). R2The = CH position of turns the ν(C–O) turns out be 3 ; Figure ketimines (1, R2 = CH 3; Figure position of1). theThe ν(C–O) band out toband be sensitive totothe sensitive to in thethe deuteration the hydrogen bridge for form, the molecular while forthe the deuteration PT form the deuteration hydrogeninbridge for the molecular while forform, the PT form deuteration influences the ν(C=N) band. This effect makes it possible to estimate the proton influences the ν(C=N) band. This effect makes it possible to estimate the proton positionposition in the in the hydrogen hydrogen bridge.bridge. In[45–47] [45–47]various varioussolutions solutionsof ofpartially partiallydeuterated deuteratedand and1515N-labelled N-labelledortho-hydroxyaryl ortho-hydroxyarylSchiff Schiffbases bases66 In 1 15 1 15 (Figure 4) were studied by Hand N-NMR spectroscopy, revealing the presence of intramolecular (Figure 4) were studied by H- and N-NMR spectroscopy, revealing the presence of intramolecular proton tautomerism tautomerism between molecular proton molecular (enol-imine) (enol-imine)and andzwitterionic zwitterionic(keto-amine) (keto-amine)forms. forms. Molecules 2016, 21, 1657

6

Figure Figure4.4.Schematic Schematicstructure structureofofortho-hydroxyaryl ortho-hydroxyarylSchiff Schiffbases, bases,studied studiedby byNMR NMRin in[46]. [46]. 1 15 The Theanalysis analysisof of substituentsubstituent-and and temperaturetemperature- dependent dependent 1H Hand and 15NNchemical chemicalshifts shiftshas hasrevealed revealed that upon the increase of the solvent polarity two effects are present: (i) shift of the that upon the increase of the solvent polarity two effects are present: (i) shift of the tautomeric tautomeric equilibrium and (ii)(ii) changes in in thethe hydrogen bond geometry in equilibriumtowards towardsthe thezwitterionic zwitterionicstructures structures and changes hydrogen bond geometry each of the tautomers. Namely, thethe hydrogen bond in each of the tautomers. Namely, hydrogen bondininthe themolecular molecularform formbecomes becomes stronger stronger (symmetrization of the bridging proton position) while that in the zwitterionic tautomer (symmetrization of the bridging proton position) while that in the zwitterionic tautomer becomes becomes weaker weaker(asymmetrization). (asymmetrization).AAsimilar similareffect effectwas waslater laterobserved observedfor forother otherstrongly stronglyhydrogen hydrogenbonded bonded systems systemsand andititwas wasascribed ascribedto tothe thenon-specific non-specific[48,49] [48,49]or orin insome somecases casesto tospecific specific[50] [50]solvent-solute solvent-solute interactions. interactions.For Forortho-hydroxyaryl ortho-hydroxyarylSchiff Schiffbases bases66(Figure (Figure4)4)the theformation formationof of additional additional hydrogen hydrogen bonds to the phenol/phenolate oxygen atom by one or several alcohol molecules was shown to bonds to the phenol/phenolate oxygen atom by one or several alcohol molecules was shown to induce induce the proton and stabilization of the keto-amine form [45,46]. the proton transfertransfer and stabilization of the keto-amine form [45,46]. In [51] the effect of an additional covalently linked carboxylic In [51] the effect of an additional covalently linked carboxylicgroup groupon onthe theintramolecular intramolecularproton proton tautomerism in 2-carboxy-4-methyl-6-[(E)-(phenyliminio)methyl]phenolate (ortho-hydroxyaryl tautomerism in 2-carboxy-4-methyl-6-[(E)-(phenyliminio)methyl]phenolate (ortho-hydroxyarylSchiff Schiff base, Figure5)5)has hasbeen been studied. It was shown that in a /CDF CDF3/CDF 2Cl solution the additional base, 7, 7, Figure studied. It was shown that in a CDF Cl solution the additional COOH 3 2 COOH groupan forms OHO hydrogen bond the phenolic oxygen atom, which “pushes” the group forms OHOanhydrogen bond with thewith phenolic oxygen atom, which “pushes” the proton in proton in the neighboring OHN bonds nitrogen atom. 7Asexists a result, 7 exists almost the neighboring OHN bonds towards thetowards nitrogenthe atom. As a result, almost exclusively in exclusively in a proton transfer form OH···O−···HN+, in which two proton donors form coupled a proton transfer form OH···O− ···HN+ , in which two proton donors form coupled hydrogen bonds hydrogen bonds and compete for the central phenolate oxygen acceptor. and compete for the central phenolate oxygen acceptor.

7 Figure 5. Schematic structure of ortho-hydroxyaryl Schiff base 7, studied by NMR in [51].

An interesting case of proton tautomerism and hydrogen bond coupling is represented by pyridoxal 5′-phosphate (PLP), which forms ortho-hydroxyaryl Schiff bases 8 (Figure 6) as a cofactor of many enzymes and also during the course of its catalytic cycle (so called “internal” and “external” aldimines, respectively) [52].

tautomerism in 2-carboxy-4-methyl-6-[(E)-(phenyliminio)methyl]phenolate (ortho-hydroxyaryl Schiff base, 7, Figure 5) has been studied. It was shown that in a CDF3/CDF2Cl solution the additional COOH group forms an OHO hydrogen bond with the phenolic oxygen atom, which “pushes” the proton in the neighboring OHN bonds towards the nitrogen atom. As a result, 7 exists almost exclusively a proton transfer form OH···O−···HN+, in which two proton donors form coupled Molecules 2016, in 21, 1657 5 of 19 hydrogen bonds and compete for the central phenolate oxygen acceptor.

7 Figure 5. 5. Schematic Schematic structure structure of of ortho-hydroxyaryl ortho-hydroxyaryl Schiff Schiff base Figure base 7, 7, studied studied by by NMR NMR in in [51]. [51].

An interesting case of and hydrogen bond coupling coupling is is represented represented by by An interesting case of proton proton tautomerism tautomerism and hydrogen bond 0 -phosphate (PLP), which forms ortho-hydroxyaryl Schiff bases 8 (Figure 6) as a cofactor pyridoxal 5 pyridoxal 5′-phosphate (PLP), which forms ortho-hydroxyaryl Schiff bases 8 (Figure 6) as a cofactor of many many enzymes enzymes and and also also during during the the course course of of its its catalytic catalytic cycle cycle (so (so called called “internal” “internal” and and “external” “external” of aldimines, respectively) aldimines, respectively) [52]. [52]. Protonation states, hydrogen bond bond geometries geometries and and hydrogen hydrogen bond bond coupling coupling in in PLP PLP has Protonation states, hydrogen has been been studied2016, recently byNMR NMRininaqueous aqueoussolution solution [53,54], aprotic medium in solid [56,57] Molecules 21, 1657 5 ofand 17 studied recently by [53,54], in in aprotic medium [55],[55], in solid statestate [56,57] and also in hydrophobic pockets of proteins (alanine racemase, AlaR, and aspartate aminotransferase, also in hydrophobic pockets of proteins (alanine racemase, AlaR, and aspartate aminotransferase, AspAT) [58,59]. [58,59]. ItIt was was demonstrated demonstratedthat thatthe the proton proton position position in in the the intramolecular intramolecular OHN OHN bond bond isis AspAT) determinedtotoaa large large extent extent by by the the additional additional bonds bonds formed formed with with the the phenolic phenolic oxygen oxygen or or pyridine pyridine determined nitrogenatoms atomsof ofPLP. PLP. In In both both cases, cases, the the formation formation of of additional additional hydrogen hydrogen bonds bonds shifts shifts the the equilibrium equilibrium nitrogen towards the the catalytically catalytically active active zwitterionic zwitterionic ketoamine ketoamine form. form. For Forexample, example,in inAspAT AspAT the the pyridine pyridine towards nitrogenatom atomof ofPLP PLPisis fully fully protonated protonatedby by the the COOH COOH group group of of the the neighboring neighboring aspartic asparticacid acidside side nitrogen chain[58]. [58]. chain

8

Figure 6. Schematic structure of ortho-hydroxy Schiff bases 8, formed by PLP, studied by NMR ([59] Figure 6. Schematic structure of ortho-hydroxy Schiff bases 8, formed by PLP, studied by NMR ([59] and references cited therein). and references cited therein).

3.2. Ortho-Hydroxyaryl Aldehydes and Ketones 2 3.2. Ortho-Hydroxyaryl Aldehydes and Ketones 2 Ortho-hydroxyaryl aldehydes and ketones are structurally close to ortho-hydroxyaryl Schiff bases, Ortho-hydroxyaryl aldehydes and ketones are structurally close to ortho-hydroxyaryl Schiff but they do not display proton transfer in the ground state [60–62]. The studies of two derivatives bases, but they do not display proton transfer in the ground state [60–62]. The studies of two of ortho-hydroxyacetophenone (5-cyano-2-hydroxyacetophenone and 2-hydroxy-4-methoxy-5-nitroderivatives of ortho-hydroxyacetophenone (5-cyano-2-hydroxyacetophenone and 2-hydroxy-4-methoxyacetophenone) [62] which possess markedly strong acidity of the hydroxyl group failed to show the 5-nitro-acetophenone) [62] which possess markedly strong acidity of the hydroxyl group failed to show existence of the PT form in the ground state. Moreover, the investigation of fluorescent spectra the existence of the PT form in the ground state. Moreover, the investigation of fluorescent spectra recorded in solution and in the solid state show the prevailing of the PT form in the excited state for recorded in solution and in the solid state show the prevailing of the PT form in the excited state for the o-hydroxyacyl aromatic compounds [63–65]. the ortho-hydroxyacyl aromatic compounds [63–65]. 3.3. 3.3.Ortho-Hydroxyaryl Ortho-HydroxyarylMannich MannichBases Bases55 The The studies studies of of adiabatic adiabatic potentials potentials for for the the proton proton motion motion in in 3,5,6-trimethyl-2-(N,N3,5,6-trimethyl-2-(N,Ndimethylaminomethyl)phenol (5, R 1 = R2 = CH3; Figure 1) and the description of infrared spectra by dimethylaminomethyl)phenol (5, R1 = R2 = CH3 ; Figure 1) and the description of infrared spectra by means meansof ofCar-Parrinello Car-Parrinellomolecular moleculardynamics dynamics(CPMD) (CPMD)isispresented presentedin in[51]. [51]. The Thestrengthening strengtheningof ofthe the intramolecular hydrogen bond in this compound due to the steric effect of the methyl substituents in the intramolecular hydrogen bond in this compound due to the steric effect of the methyl substituents phenyl wasring earlier stated andstated proved experimentally [66]. The aim[66]. of paper the verification in the ring phenyl was earlier and proved experimentally The[67] aimwas of paper [67] was of the conformity of the applied computational methods with the description of the intramolecular the verification of the conformity of the applied computational methods with the description of hydrogen bonding. The presented calculations for solution and solid states of 3,5,6-trimethyl-2-(N,Nthe intramolecular hydrogen bonding. The presented calculations for solution and solid states of dimethylamine-methyl)phenol by CPMD has allowed the authors to describe both spectral and 3,5,6-trimethyl-2-(N,N-dimethylamine-methyl)phenol by CPMD has allowed the authors to describe structural parameters. The potential energy curves and corresponding vibrational energy levels estimated at B3LYP/cc-pVDZ and MP2/cc-pVDZ levels of theory for the adiabatic proton movement also made it possible to calculate the position of the ν(OH) stretching band. It was stated that the resulting calculated frequency is in a satisfactory agreement with experimental data. It should be underlined that CPMD method allows to study chemical reactions dynamically and to compute free

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both spectral and structural parameters. The potential energy curves and corresponding vibrational energy levels estimated at B3LYP/cc-pVDZ and MP2/cc-pVDZ levels of theory for the adiabatic proton movement also made it possible to calculate the position of the ν(OH) stretching band. It was stated that the resulting calculated frequency is in a satisfactory agreement with experimental data. It should be underlined that CPMD method allows to study chemical reactions dynamically and to compute free energy profiles via thermodynamic integration of fluctuations and, therefore, to calculate entropy [68]. In [69,70] the potential energy curves of proton transfer in intramolecular hydrogen bond in ortho-hydroxyaryl Schiff base [69] and acetic acid dimer [70] were studied, and the consistency of CPMD method was shown. In liquid-state NMR spectra of ortho-hydroxyaryl Mannich bases the intramolecular OHN hydrogen bond manifests itself by a low-field shift of the bridging proton signal [71–74] and in some cases by the inversion of the sign of H/D isotope effects on 13 C-NMR chemical shifts upon temperature decrease [75]. The latter is associated with the shift of the proton equilibrium from the molecular OH···N form to the zwitterionic O− ···HN+ form. In [74] compound 9 (Figure 7) was studied by a combination of NMR and UV/Vis spectroscopy showing that in a polar aprotic medium such as a mixture of Freon gases CDF3 /CDF2 Cl the molecule exists in a molecular OH···N form, which changes to the zwitterionic O− ···HN+ form upon the formation of cyclic dimers (shown in Figure 7, right). The Molecules 2016,existence 21, 1657 of the zwitterionic forms for monomers of compound 9 was not confirmed. 6 of 17 9

Figure 7. Schematic structure of ortho-hydroxyaryl Mannich base 9 (left) and its zwitterionic cyclic Figure 7. Schematic structure of ortho-hydroxyaryl Mannich base 9 (left) and its zwitterionic cyclic dimer (right), studied by NMR in [74]. dimer (right), studied by NMR in [74].

3.4. Dimethylaminonaphthalene (4) 3.4. Dimethylaminonaphthalene (4) Dimethylaminonaphthalene, so-called proton sponge, is the subject of intensive studies [76–89]. Dimethylaminonaphthalene, so-called proton sponge, is the subject of intensive studies [76–89]. In [76–80] the methods of synthesis, the analysis of the structural characteristics and the results of ab In [76–80] the methods of synthesis, the analysis of the structural characteristics and the results of ab initio initio (MP2/6-31+G(d,p)) calculations for a series of dimethylaminonaphthalene derivatives are (MP2/6-31+G(d,p)) calculations for a series of dimethylaminonaphthalene derivatives are presented. presented. It is noteworthy that the results of quantum-mechanical calculations and the interpretation It is noteworthy that the results of quantum-mechanical calculations and the interpretation of the NMR of the NMR spectra of proton sponges with a strong buttressing effect coincide. For example, the spectra of proton sponges with a strong buttressing effect coincide. For example, the calculated potential calculated potential for the proton transfer for 2,7-dibromo-1,8-bis(dimethylamino)naphthalene is for the proton transfer for 2,7-dibromo-1,8-bis(dimethylamino)naphthalene is symmetric and possesses symmetric and possesses a low energy barrier (Figure 8) [79]. This result points out the delocalization of a low energy barrier (Figure 8) [79]. This result points out the delocalization of the proton in the hydrogen the proton in the hydrogen bridge which is in accordance with the record 1H-NMR chemical shift δ(1H) = bridge which is in accordance with the record 1 H-NMR chemical shift δ(1 H) = 21–22 ppm [81,82] and 21–22 ppm [81,82] and a very high isotopic spectroscopic ratio, ISR = ν(NHN)/ν(NDN) = 1.8 [83]. a very high isotopic spectroscopic ratio, ISR = ν(NHN)/ν(NDN) = 1.8 [83].

Figure 8. The potential energy curve for protonated 2,7-dibromo-1,8-bis(dimethylamino)naphthalene obtained by MP2/6-31+G(d,p) level of theory. Reprinted with permission from [79]. Copyright 2008 AIP Publishing.

initio (MP2/6-31+G(d,p)) calculations for a series of dimethylaminonaphthalene derivatives are presented. It is noteworthy that the results of quantum-mechanical calculations and the interpretation presented. It is noteworthy that the results of quantum-mechanical calculations and the interpretation of the NMR spectra of proton sponges with a strong buttressing effect coincide. For example, the of the NMR spectra of proton sponges with a strong buttressing effect coincide. For example, the calculated potential for the proton transfer for 2,7-dibromo-1,8-bis(dimethylamino)naphthalene is calculated potential for the proton transfer for 2,7-dibromo-1,8-bis(dimethylamino)naphthalene is symmetric and possesses a low energy barrier (Figure 8) [79]. This result points out the delocalization of symmetric and possesses a low energy barrier (Figure 8) [79]. This result points out the delocalization of the proton in21, the1657 hydrogen bridge which is in accordance with the record 1H-NMR chemical shift δ(71H) = Molecules 2016, of 19 the proton in the hydrogen bridge which is in accordance with the record 1H-NMR chemical shift δ(1H) = 21–22 ppm [81,82] and a very high isotopic spectroscopic ratio, ISR = ν(NHN)/ν(NDN) = 1.8 [83]. 21–22 ppm [81,82] and a very high isotopic spectroscopic ratio, ISR = ν(NHN)/ν(NDN) = 1.8 [83].

Figure 8. The potential energy curve for protonated 2,7-dibromo-1,8-bis(dimethylamino)naphthalene Figure Figure8.8.The Thepotential potentialenergy energycurve curvefor forprotonated protonated2,7-dibromo-1,8-bis(dimethylamino)naphthalene 2,7-dibromo-1,8-bis(dimethylamino)naphthalene obtained by MP2/6-31+G(d,p) level of theory. Reprinted with permission from [79]. Copyright 2008 obtained obtainedby byMP2/6-31+G(d,p) MP2/6-31+G(d,p)level levelofoftheory. theory.Reprinted Reprintedwith withpermission permissionfrom from[79]. [79].Copyright Copyright2008 2008 AIP Publishing. AIPPublishing. Publishing. AIP

The NMR studies of hydrogen bonding in proton sponges of type 10 (Figure 9) are mostly based The NMR hydrogen bonding in in protonsponges spongesofoftype type 10(Figure (Figure 9)are are mostly based The NMRstudies studiesofof of1H-, hydrogen bonding mostly based on 15N-NMR 1JNH, 1h10 on the interpretation chemicalproton shifts, as well as JNH and2h2hJ9) NN spin-spin coupling 1 15 1 1h on the interpretation of H-, N-NMR chemical shifts, as well as J NH1h , J NH and 2hJNN spin-spin coupling 1 15 1 the interpretation of can H-,be N-NMR shifts, well as [68]) JNH , and JNH andisotope JNN effects spin-spin constants (the latter detectedchemical directly [84] or as indirectly H/D on coupling them. constants constants(the (thelatter lattercan canbe bedetected detecteddirectly directly[84] [84]or orindirectly indirectly[68]) [68])and andH/D H/Disotope isotopeeffects effectson onthem. them.

10 10

Figure 9. Schematic structure of protonated proton sponge 10, studied by NMR in [86]. Figure Figure9.9.Schematic Schematicstructure structureofofprotonated protonatedproton protonsponge sponge10, 10,studied studiedby byNMR NMRin in[86]. [86].

In [86] the (NHN)+ hydrogen bond geometry and symmetry was studied depending on the In [86] the (NHN)++hydrogen bond geometry and symmetry was studied depending on the solvent, counter-anion temperature used (solvents: CDsymmetry 3CN, CD2Cl 2, toluene-D and CDF3/CDF 2Cl In [86] the (NHN)andhydrogen bond geometry and was studied 8depending on the solvent, counter-anion and temperature used (solvents: CD3CN, CD2Cl2, toluene-D8 and CDF3/CDF2Cl − − mixture; counter-anions: 4 , trifluoroacetate (TFA ),CD tetrakis[3,5-bis(trifluoromethyl)phenyl]borate solvent, counter-anion andClO temperature used (solvents: 3 CN, CD2 Cl2 , toluene-D 8 and CDF3 /CDF2 Cl mixture; counter-anions: ClO4−,−trifluoroacetate (TFA−),− tetrakis[3,5-bis(trifluoromethyl)phenyl]borate −)). + bond is well localized, (BARF It was shown that the positive charge in the (NHN) indicating the mixture; counter-anions: ClO , trifluoroacetate (TFA ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate 4 (BARF−− )). It was shown that the positive charge in the (NHN)+ +bond is well localized, indicating the (BARF )). It was shown that the positive charge in the (NHN) bond is well localized, indicating the presence of a degenerate tautomeric equilibrium between NH+ ···N and N···+ NH forms (asymmetric proton position was also detected in some proton sponges by dipolar solid-state NMR [87]). Lowering the temperature increases the symmetry of the hydrogen bond, as evidenced by the changes in NMR parameters; this phenomenon was attributed to the increase of the polar solvent ordering around the charged hydrogen bridge. It was also noticed that small counter-anions tend to perturb the hydrogen bond symmetry (presumably, due to the asymmetrical placement). In contrast, usage of large counter-anions with strongly delocalized negative charge leads to hydrogen bond symmetrization. A similar effect was studied later for other NHN-bonded systems [88,89]. 4. Potential for Proton Transfer and Tautomeric Equilibrium The studies of the non-adiabatic potential for the proton transfer in ortho-hydroxyaryl Schiff bases [11,90], ortho-hydroxyaryl ketones [91], ortho-hydroxyaryl Mannich bases [66,92,93], dimethylaminonaphthalene [76–80] and ortho-hydroxyaryl amides [94] confirm the presence of the second local minimum on the potential curve for some ortho-hydroxyaryl Schiff bases and proton sponges (Figure 10), which allows one to observe tautomeric equilibrium. The potential energy curves do not exhibit a second a local minimum for ortho-hydroxyaryl amides, ortho-hydroxyaryl

The studies of the non-adiabatic potential for the proton transfer in ortho-hydroxyaryl Schiff bases [11,90], ortho-hydroxyaryl ketones [91], ortho-hydroxyaryl Mannich bases [66,92,93], dimethylaminonaphthalene [76–80] and ortho-hydroxyaryl amides [94] confirm the presence of the second local minimum on the potential curve for some ortho-hydroxyaryl Schiff bases and proton Molecules 2016, 21, 1657 8 of 19 sponges (Figure 10), which allows one to observe tautomeric equilibrium. The potential energy curves do not exhibit a second a local minimum for ortho-hydroxyaryl amides, ortho-hydroxyaryl ketones, ketones, ortho-hydroxyaryl ortho-hydroxyarylMannich Mannich bases basesand, and, therefore, therefore, the the experimental experimental observation observation of of the the stable stable PT PT tautomeric tautomeric form form is is not not possible. possible.

(A)

(B)

(D)

(E)

(C)

Figure R1 == R Figure 10. 10. The The non-adiabatic non-adiabatic potential potential curves curves for: for: ortho-hydroxyaryl ortho-hydroxyaryl Schiff Schiff base base (1; (1; R R22 == CH CH33, , 1 Figure Figure 1) 1) (A); (A); 1,8-bis(dimethylamino)-2,7-bis(trimethylsilyl)naphthalene 1,8-bis(dimethylamino)-2,7-bis(trimethylsilyl)naphthalene(derivative (derivativeofofproton protonsponge) sponge) 1 = R2 = CH3; Figure 1) (B); 2-hydroxy-N,N-diethylbenzamide (3; R1 = R2 = C2H5; Figure 1) (C); (4; R (4; R1 = R2 = CH3 ; Figure 1) (B); 2-hydroxy-N,N-diethylbenzamide (3; R1 = R2 = C2 H5 ; Figure 1) = CH 1) (D) and ortho-hydroxyaryl MannichMannich base (5; R 1 = ortho-hydroxyacetophenone (2; R1 (2; (C); ortho-hydroxyacetophenone R13;=Figure CH3 ; Figure 1) (D) and ortho-hydroxyaryl base 2 = CH3; Figure 1) (E). R(5; R = R = CH ; Figure 1) (E). 1

2

3

5. Proton Transfer Process and Aromaticity 5. Proton Transfer Process and Aromaticity Ortho-Hydroxyaryl Ortho-Hydroxyaryl Schiff Schiff Bases Bases 11 The formationof the of intramolecular the intramolecular quasi-aromatic bonding via delocalization π-electronic The formation quasi-aromatic hydrogenhydrogen bonding via π-electronic delocalization in the systems with the alternated double bonds (so-called chelate chain) stabilizes of a in the systems with the alternated double bonds (so-called chelate chain) stabilizes a flat conformation a molecule and enforces hydrogen bonding. This effect is known as Resonance Assisted Hydrogen Bond (RAHB) [95]. From the point of view of the acid-base interactions, such strengthening of hydrogen bonding is caused by the mutual increase of basicity and acidity due to the +M and −M mesomeric effects via the chelate chain [96,97]. Recently, some literature sources have put in question the abovementioned point of view [98]. Yanez et al. [98] demonstrate that π-electronic conjugation does not strengthen hydrogen bonding. Obviously, the studies of aromaticity are very important for answering the question about the strengthening of hydrogen bonding in quasi-aromatic systems. References [99–103] dwell on the description of the aromaticity changes in systems with intramolecular hydrogen bonding depending on the state of tautomeric equilibrium. The papers [104–108] demonstrate that the parameters of aromaticity HOMA and HOSE [104] are reliable indicators in the estimation of tautomeric equilibrium. Based on X-ray diffraction data the correlations between the HOMA and HOSE aromaticity indexes and the XH bond length were obtained [100]. The phenyl and naphthalene derivatives of Schiff bases show the existence of aromaticity equilibrium, which reflects the decrease of aromaticity of the A ring with a little increase of aromaticity of the B ring under the proton transfer process

intramolecular intramolecular hydrogen hydrogen bonding bonding depending depending on on the the state state of of tautomeric tautomeric equilibrium. equilibrium. The The papers papers [104–108] [104–108] demonstrate demonstrate that that the the parameters parameters of of aromaticity aromaticity HOMA HOMA and and HOSE HOSE [104] [104] are are reliable reliable indicators indicators in in the the estimation estimation of of tautomeric tautomeric equilibrium. equilibrium. Based Based on on X-ray X-ray diffraction diffraction data data the the correlations correlations between between the the HOMA HOMA and and HOSE HOSE aromaticity aromaticity indexes indexes and and the the XH XH bond bond length length were were obtained obtained [100]. [100]. The The phenyl phenyl and and naphthalene naphthalene derivatives derivatives of of Schiff Schiff bases bases show show the the existence existence of of aromaticity aromaticity equilibrium, equilibrium, Molecules 2016, 21, 1657 9 of 19 which which reflects reflects the the decrease decrease of of aromaticity aromaticity of of the the A A ring ring with with aa little little increase increase of of aromaticity aromaticity of of the the BB ring ring under under the the proton proton transfer transfer process process (HOMA(A,B) (HOMA(A,B) == f(HOSE(ch)), f(HOSE(ch)), Figure Figure 11). 11). ItIt was was stated stated that that the the change molecular to the state the increase of change from from the the molecular form form to11). theIttransition transition state triggers the from increase of aromaticity aromaticity of the (HOMA(A,B) = f (HOSE(ch)), Figure was stated thattriggers the change the molecular formof to the the chelate on the change the transition form the chelate chain, chain, and on the the contrary, the change from from the transition state to the PT form evokes evokes the transition stateand triggers thecontrary, increase of aromaticity of the chelate chain,state and to onthe the PT contrary, the change decrease of aromaticity (HOMA(ch) = f(d(OH)), Figure 11). It was also shown that the changes of decrease of aromaticity (HOMA(ch) = f(d(OH)), Figure 11). It was also shown that the changes of from the transition state to the PT form evokes the decrease of aromaticity (HOMA(ch) = f(d(OH)), aromaticity the chain (HOMA(ch)) depend in way the of aromaticity ofwas the chelate chelate chain (HOMA(ch)) depend in aa non-linear non-linear way on onchain the changes changes of aromaticity aromaticity Figure 11). Itof also shown that the changes of aromaticity of the chelate (HOMA(ch)) depend of phenyl naphthalene A) (HOMA(ph) == f(HOMA(ch)), of athe the phenyl ring ring (or naphthalene ring A) under under the proton transfer transfer (HOMA(ph)ring f(HOMA(ch)), in non-linear way (or on the changes ofring aromaticity ofthe the proton phenyl ring (or naphthalene A) under the Figure Figure 12). 12). proton transfer (HOMA(ph) = f (HOMA(ch)), Figure 12).

Figure 11. Left side: correlations between HOMA(A), HOMA(B) and (HOSE(ch)) aromaticity indexes Figure Figure 11. 11. Left Left side: side: correlations correlations between between HOMA(A), HOMA(A), HOMA(B) HOMA(B) and and (HOSE(ch)) (HOSE(ch)) aromaticity aromaticity indexes indexes calculated on the X-ray diffraction data. Reprinted with permission from [100]. Copyright 2008 John calculated calculated on on the the X-ray X-ray diffraction diffraction data. data. Reprinted Reprinted with with permission permission from from [100]. [100]. Copyright Copyright 2008 2008 John John Wiley side: dependency of the aromaticity of chelate chain (HOMA(ch)) depending Wiley & Sons, Ltd. Right Wiley& &Sons, Sons,Ltd. Ltd. Right Right side: side: dependency dependency of of the the aromaticity aromaticity of of chelate chelate chain chain (HOMA(ch)) (HOMA(ch)) depending depending data. R11 and R22 substitutions substitutions are hydrogen, on bond length calculated on MP2/6-31+(d,p) on the the OH OH bond bondlength lengthcalculated calculatedon onMP2/6-31+(d,p) MP2/6-31+(d,p) data. data. R and R substitutions are hydrogen, alkyl alkyl and and aryl aryl substitutions. substitutions.

Figure of the HOMA aromaticity index of ring (HOMA(ph)) (solid line) and Figure 12. 12. Dependencies ofof the HOMA aromaticity index of phenyl phenyl ringring (HOMA(ph)) (solid line)line) and Figure 12. Dependencies Dependencies the HOMA aromaticity index of phenyl (HOMA(ph)) (solid naphthalene (HOMA(A)) (dotted line) on the changes of aromaticity naphthalene (HOMA(A)) (dotted line) onon thethe changes ofof aromaticity ofofchelate chelate chain (HOMA(ch)) and naphthalene (HOMA(A)) (dotted line) changes aromaticityof chelatechain chain(HOMA(ch)) (HOMA(ch)) obtained obtained from from the the experimental experimental data data (A); (A); calculated calculated with non-adiabatic approach for 2-[(1E)-Nobtained from the experimental data (A); calculated with with non-adiabatic non-adiabatic approach approach for for 2-[(1E)-N2-[(1E)-Nmethylethanimidoyl]phenol (R 1 = R 2 = CH 3 ) and 2-[(1E)-1-(methyliminio)ethyl]-naphthalen-1-olate methylethanimidoyl]phenol (R (R11 == R R22 == CH methylethanimidoyl]phenol CH33)) and and 2-[(1E)-1-(methyliminio)ethyl]-naphthalen-1-olate 2-[(1E)-1-(methyliminio)ethyl]-naphthalen-1-olate (R tautomeric form (C). (R R222 ===CH CH33)3))molecules molecules(B) (B)and andfor for fully fully optimised (R111 == = RR CH molecules (B) and for fully optimised optimisedtautomeric tautomericform form(C). (C).

An interesting fact is that the calculated results obtained by the non-adiabatic approach give a precise description of the aromaticity changes. 6. Equilibrium between Different Intra-/Intra-Molecular Hydrogen Bonding and Intra-/InterMolecular Hydrogen Bonding 6.1. Ortho-Hydroxyaryl Aldehydes and Ketones 2 The phenomenon of competition between two hydrogen bonds within one molecule is an interesting point to consider [109,110]. The competitive equilibrium between the O–H···O2 N– and O–H···O=C hydrogen bonds in 5-methyl-3-nitro-2-hydroxyacetophenone (11) (Figure 13) by infrared spectroscopy and quantum-mechanical calculations is studied in [91,110].

6.1. 6.1. Ortho-Hydroxyaryl Ortho-Hydroxyaryl Aldehydes Aldehydes and and Ketones Ketones 22 The The phenomenon phenomenon of of competition competition between between two two hydrogen hydrogen bonds bonds within within one one molecule molecule is is an an interesting point to consider [109,110]. The competitive equilibrium between the O–H···O 2N– and interesting point to consider [109,110]. The competitive equilibrium between the O–H···O2N– and O–H···O=C bonds Molecules 2016,hydrogen 21, 1657 10 of 19 O–H···O=C hydrogen bonds in in 5-methyl-3-nitro-2-hydroxyacetophenone 5-methyl-3-nitro-2-hydroxyacetophenone (11) (11) (Figure (Figure 13) 13) by by infrared infrared spectroscopy and quantum-mechanical calculations is studied in [91,110]. spectroscopy and quantum-mechanical calculations is studied in [91,110].

11 11 Figure Figure13. 13.Scheme Schemeof ofthe thehydroxyl hydroxylgroup groupisomerization isomerizationin in5-methyl-3-nitro-2-hydroxyacetophenone 5-methyl-3-nitro-2-hydroxyacetophenone(11). (11). Figure 13. Scheme of the hydroxyl group isomerization in 5-methyl-3-nitro-2-hydroxyacetophenone (11).

The function of the the sublimation The infrared infrared spectra recorded recorded under under argon argon matrix matrix condition condition as as aa function The infrared spectra spectra recorded under argon matrix condition as function of the sublimation sublimation temperature revealed significant changes in the intensity of the ν(C=O) and ν(NO 2 ) stretching temperature revealed significant changes in the intensity vibration temperature intensity of of the the ν(C=O) ν(C=O) and and ν(NO ν(NO22) stretching vibration bands The result result was was used used to to attribute attributeparticular particularbands bandsto totwo twoisomers isomersof ofthe thecompound. compound. bands (Figure (Figure 14). 14). The The result was used to attribute particular bands to two isomers of the compound. ν(C=O) ν(C=O)

1700 1700

νas(NO2) νas(NO2)

1600 1600

1500 1500

1400 1400

1300 1300

1200 1200

wavenumbers, cm-1 wavenumbers, cm-1

1100 1100

Figure Figure 14. 14. Spectrum Spectrum of of 5-methyl-3-nitro-2-hydroxyacetophenone 5-methyl-3-nitro-2-hydroxyacetophenone (11) (11) in in argon argon matrix matrix condition condition in in the function of sublimation. Reprinted with permission from [91]. Copyright 2008 Elsevier. Figure 14. Spectrum of 5-methyl-3-nitro-2-hydroxyacetophenone (11) in argon matrix condition in the the function of sublimation. Reprinted with permission from [91]. Copyright 2008 Elsevier. function of sublimation. Reprinted with permission from [91]. Copyright 2008 Elsevier.

6.2. 6.2. Ortho-Hydroxyaryl Ortho-Hydroxyaryl Amides Amides (3) (3) 6.2. Ortho-Hydroxyaryl Amides (3) An An amide amide bond bond in in proteins proteins plays plays an an essential essential role role in in the the functioning functioning of of every every living living organism, organism, therefore, the description of the conformation of such systems is very important. Papers [94,111] An amide bond in proteins plays an essential role in the functioning of every living organism, therefore, the description of the conformation of such systems is very important. Papers [94,111] 1H and 13C-NMR spectra showed the importance of complex studies of ortho-hydroxyaryl amides. The 1 13 therefore, description of the conformation of such systemsamides. is veryThe important. Papers [94,111] showed thethe importance of complex studies of ortho-hydroxyaryl H and C-NMR spectra 13 C-NMR of ortho-hydroxyaryl amides studied as of demonstrate presence of showed the importance of complex of ortho-hydroxyaryl The 1the H and of ortho-hydroxyaryl amides studied studies as aa function function of temperature temperatureamides. demonstrate the presence of aa dynamic evoked non-equivalent orientation diethylamine, spectra ofeffect ortho-hydroxyaryl studied as a functionof temperature demonstrate themorpholine presence of dynamic effect evoked by by the theamides non-equivalent orientation ofofdimethylamine, dimethylamine, diethylamine, morpholine and pyrrolidine groups [94,111]. a dynamic effect evoked by the non-equivalent orientation of dimethylamine, diethylamine, and pyrrolidine groups [94,111]. The infrared spectra (Figure recorded morpholine and pyrrolidine groups 15) [94,111]. The infrared spectra (Figure 15) recorded as as aa function function of of temperature temperature in in weakly-polar, weakly-polar, proton-donating proton-accepting solvents existence The infrared and spectra (Figure 15) recorded as aindicate function the of temperature weakly-polar,between protonproton-donating and proton-accepting solvents indicate the existence of ofin equilibrium equilibrium between intramolecular and hydrogen bonds be that an donating and proton-accepting solvents indicate the [94]. existence of equilibrium between and intramolecular and intermolecular intermolecular hydrogen bonds [94]. It It should should be underlined underlined that intramolecular an easy easy disruption disruption of a rather strong intramolecular hydrogen bond observed in 2-hydroxy-N-methylbenzamide [112], intermolecular hydrogen bonds [94]. It should be underlined that an easy disruption of a rather strong of a rather strong intramolecular hydrogen bond observed in 2-hydroxy-N-methylbenzamide [112], salicylamide [113] and [114] Å) an of intramolecular hydrogen bond observed in 2-hydroxy-N-methylbenzamide [112], salicylamide salicylamide [113] and 4-chloro-2-hydroxybenzamide 4-chloro-2-hydroxybenzamide [114] (d(OO) (d(OO) == 2.53–2.47 2.53–2.47 Å) is is an outcome outcome[113] of aa steric effect of the ethyl groups in 2-hydroxy-N,N-dialkylbenzamides and a weakened conjugation and 4-chloro-2-hydroxybenzamide (d(OO) = 2.53–2.47 Å) is an outcome of a steric effect of the steric effect of the ethyl groups in [114] 2-hydroxy-N,N-dialkylbenzamides and a weakened conjugation between the phenyl and amide moieties due to competitive resonance [94,111]. Further investigations ethyl groups in 2-hydroxy-N,N-dialkylbenzamides and a weakened conjugation between the phenyl between the phenyl and amide moieties due to competitive resonance [94,111]. Further investigations of infrared revealed ν(C=O) depending the (Figure 15). and amidespectra moieties due to the competitive resonance [94,111]. Further on investigations of infrared spectra of infrared spectra revealed the shift shift of of the the ν(C=O) bands bands depending on the solvent solvent polarity polarity (Figure 15). In the case of proton-accepting solvent, we observe the disruption of intramolecular hydrogen revealed theof shift of the ν(C=O) bands depending on the polarity (Figure 15). In the case of In the case proton-accepting solvent, we observe thesolvent disruption of intramolecular hydrogen proton-accepting solvent, we observe the disruption of intramolecular hydrogen bonding and the formation of the complex with the solvent molecules, which shifts the ν(C=O) band towards higher wavenumbers with respect to that in weakly-polar solvent. This fact is explained by the disruption of hydrogen bonding (Figure 16) and the strengthening of the force constant of this bond. The shift of the ν(C=O) band in the case of the amphoteric solvent is drastically different (the shift towards lower wavenumbers) from the proton-acceptor solvent. Such effect is conditioned by the formation of intermolecular hydrogen bonding between the carbonyl group and the solvent molecules, which weakens the carbonyl bond and decreases force constant.

towards higher higher wavenumbers wavenumbers with with respect respect to to that that in in weakly-polar weakly-polar solvent. solvent. This This fact fact is is explained explained by by towards the disruption of hydrogen bonding (Figure 16) and the strengthening of the force constant of this the disruption of hydrogen bonding (Figure 16) and the strengthening of the force constant of this bond. The The shift shift of of the the ν(C=O) ν(C=O) band band in in the the case case of of the the amphoteric amphoteric solvent solvent is is drastically drastically different different (the (the bond. shift towards towards lower lower wavenumbers) wavenumbers) from from the the proton-acceptor proton-acceptor solvent. solvent. Such Such effect effect is is conditioned conditioned by by shift the formation of intermolecular hydrogen bonding between the carbonyl group and the solvent the formation intermolecular hydrogen bonding between the carbonyl group and the solvent Molecules 2016, 21,of 1657 11 of 19 molecules, which weakens the carbonyl bond and decreases force constant. molecules, which weakens the carbonyl bond and decreases force constant.

Figure 15. Infrared spectra spectra of of 2-hydroxy-N,N-diethylbenzamide 2-hydroxy-N,N-diethylbenzamide (3, (3, R R111 == =R R222 === C C H Figure 1) in the Figure 15. 15. Infrared Infrared spectra of (3, R R C222H H55;5; ;Figure Figure1) 1)in in the the Figure 2-hydroxy-N,N-diethylbenzamide region of the ν(OH) (left side) and ν(C=O) (right side) modes for 2-hydroxy-N,N-diethylbenzamide: region of the ν(OH) (left side) and ν(C=O) (right side) modes for 2-hydroxy-N,N-diethylbenzamide: region of the ν(OH) (left side) and ν(C=O) (right side) modes for 2-hydroxy-N,N-diethylbenzamide: (a,b) solid line—CCl 4, .. 3, bold line—C 4H8O; (c) line—C 4H9Cl, .. 2Cl2, -.-.- line (a,b)solid solidline—CCl line—CCl , ..line—CHCl line—CHCl line—C - - - line—C Hline—CH Cl2 , 3 , bold 4 H(c) 8 O; 9 Cl, .. line—CH (a,b) 4,4.. line—CHCl3, bold line—C 4H8O; -- --(c) -- line—C 4H9Cl, 4.. line—CH 2Cl2, -.-.- 2line 3CN; (d)3 CN; line—C 4line—C H 9Cl, ..4line—CH 2 Cl 2 , -.-.line—CH 3 CN, solid line—C 4 H 9 OH. Reprinted —CH -.-.line—CH (d) H Cl, .. line—CH Cl , -.-.line—CH CN, solid line—C H OH. 9 2 2 4 9 2Cl2, -.-.- line—CH 3CN, solid3line—C4H9OH. Reprinted —CH3CN; (d) - - - line—C4H9Cl, .. line—CH with permission from [94]. [94]. Copyright Copyright 2008 John John Wiley Wiley & Sons, Sons, Ltd. Reprinted with permission from [94]. 2008 Copyright 2008 John Wiley & Sons, Ltd. with permission from & Ltd.

R R

H H

O O

R R

O O N N

OII I I I O III

H H

I II IIII I

O O H H

H H

NII I I I N III

O O

O O

R1 R 1

N N

R2 R 2

(a) (a)

H H

O O

II I II I II

R R

R1 R 1

R2 R 2

(b) (b)

Figure 16. 16. Complexes Complexes of of 2-hydroxy-N,N-diethylbenzamide 2-hydroxy-N,N-diethylbenzamide (3, (3, R R11 == R R22 == C C22H H55;; Figure Figure 1) 1) with with pyridine pyridine Figure Figure 16. Complexes of= 2-hydroxy-N,N-diethylbenzamide (3, R1 = R2from = C2[94]. H5 ; Figure 1) with pyridine (a) and alcohol (b) (R alkyl group). Reprinted with permission Copyright 2008 John (a) and alcohol (b) (R = alkyl group). Reprinted with permission from [94]. Copyright 2008 John (a) and alcohol (b) (R = alkyl group). Reprinted with permission from [94]. Copyright 2008 John Wiley & & Sons, Sons, Ltd. Ltd. Wiley Wiley & Sons, Ltd.

The measurements measurements of of an an average average molecular molecular mass mass (Figure (Figure 17) 17) also also exhibit exhibit ambiguous ambiguous influence influence The The measurements of an average molecular mass (Figure 17) also exhibit ambiguous influence of amphoteric and proton-acceptor solvents. These results point out the presence of self-association of amphoteric and proton-acceptor solvents. These results point out the presence of self-association of amphoteric and proton-acceptor solvents. Thesebehaviour results point the presence self-association but only in in proton-accepting proton-accepting solvents. Different behaviour of out compound inofamphoteric amphoteric and but only solvents. Different of aa compound in and but only in proton-accepting solvents. Different behaviour of a compound in amphoteric proton-accepting solvents is due to the blocking of a basic center of the molecule, which prevents the proton-accepting solvents is due to the blocking of a basic center of the molecule, which prevents and the proton-accepting solvents is due to the blocking of a basic center of the molecule, which prevents the formation of the complex (Figure 16). This hypothesis is supported by the results obtained from the formation of the complex (Figure 16). This hypothesis is supported by the results obtained from the formation of the complex (Figure 16). This hypothesis is supported by the results obtained from the infrared measurements. infrared measurements. infrared measurements.

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Figure 17. Dependence of average molecular weight (Mav ) on concentration. Reprinted with permission from [94]. Copyright 2008 John Wiley & Sons, Ltd.

7. Short Summary Hydrogen bonding is one of the main concepts in contemporary chemistry [63,95,104,108,115–127] and its study is important for the development of the discipline. Intramolecular hydrogen bonds in ortho-hydroxyaryl Schiff and Mannich bases, in ortho-hydroxyaryl ketones and amides, in proton sponges and related compounds could be considered as classical objects for the investigation. Though the presented short review does not cover the topic in its entirety, we have tried to outline the main current research directions. On the one hand, the geometric and spectroscopic characteristics of the abovementioned intramolecular hydrogen bonds are typical for H-bonds of medium strength (for an XHY bond it is short XY contact, XH elongation, ordinary directionality pattern, ν(XH) frequency decrease, bridging proton deshielding etc.). On the other hand, there are enough specific properties, which make the study of such bonds a topic in its own right. Perhaps the most prominent feature is a possibility of proton delocalization due to the prototropic equilibrium between molecular and zwitterionic forms, possible in some systems. The tautomeric equilibrium is temperature-, solventand substituent dependent; it is also strongly influenced by additional intermolecular hydrogen bonds formed by the molecule (with or without breaking the intramolecular bond). Other sources of proton delocalization are the formation of stronger intramolecular hydrogen bonds with broader proton potentials and thermally fluctuating medium effect, which are influencing H-bond geometry. The equilibrium constant of the tautomeric equilibrium changes together with the intrinsic geometric and spectroscopic properties of individual tautomers, which complicates the analysis of the experimental data. Here, quantum-chemical computations are often providing the necessary insight via adiabatic and non-adiabatic PES calculations. Another interesting feature of intramolecular H-bond discussed in this short review is the stabilization provided by the π-electron delocalization in the chelate chain, which gives the name Resonance-Assisted Hydrogen Bonds (RAHB). Acknowledgments: This work was supported by KNOW-9 grant and project Nr 47 from 22.01.2016, p. 17. The authors gratefully acknowledge the Wroclaw Centre for Networking and Supercomputing (WCSS) for computational facilities. This work were prepared within the framework of RFBR grants: 14-03-00716 and 16-03-00405. Conflicts of Interest: The authors declare no conflict of interest.

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8. 9. 10. 11.

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