Push–Pull Effect on the Gas-Phase Basicity of Nitriles

S S symmetry

Article Push–Pull Effect on the Gas-Phase Basicity of Nitriles: Transmission of the Resonance Effects by Methylenecyclopropene and Cyclopropenimine π-Systems Substituted by Two Identical Strong Electron Donors

Ewa D. Raczy ´nska 1,*, Jean-François Gal 2,* , Pierre-Charles Maria 2 and Hamid Saeidian 3,*

1 Department of Chemistry, Warsaw University of Life Sciences (SGGW), ul. Nowoursynowska 159c, 02-776 Warszawa, Poland 2 Institut de Chimie de Nice, UMR 7272, Université Côte d’Azur, Parc Valrose, 06108 Nice, France; [email protected] 3 Department of Science, Payame Noor University (PNU), Teheran P.O. Box 19395-4697, Iran * Correspondence: [email protected] (E.D.R.); [email protected] (J.-F.G.); [email protected] (H.S.)

Abstract: The gas-phase basicity of nitriles can be enhanced by a push–pull effect. The role of the intercalated scaffold between the pushing group (electron-donor) and the pulling (electron-acceptor) nitrile group is crucial in the basicity enhancement, simultaneously having a transmission function Citation: Raczyńska,E.D.; Gal, J.-F.; and an intrinsic contribution to the basicity. In this study, we examine the methylenecyclopropene Maria, P.-C.; Saeidian, H. Push–Pull and the N-analog, cyclopropenimine, as the smallest cyclic π systems that can be considered for Effect on the Gas-Phase Basicity of resonance propagation in a push–pull system, as well as their derivatives possessing two strong Nitriles: Transmission of the pushing groups (X) attached symmetrically to the cyclopropene scaffold. For basicity and push–pull Resonance Effects by effect investigations, we apply theoretical methods (DFT and G2). The effects of geometrical and Methylenecyclopropene and rotational isomerism on the basicity are explored. We establish that the protonation of the cyano Cyclopropenimine π-Systems Substituted by Two Identical Strong group is always favored. The push–pull effect of strong electron donor X substituents is very similar Electron Donors. Symmetry 2021, 13, and the two π-systems appear to be good relays for this effect. The effects of groups in the two 1554. https://doi.org/10.3390/ cyclopropene series are found to be proportional to the effects in the directly substituted nitrile series sym13091554 X–C≡N. In parallel to the basicity, changes in electron delocalization caused by protonation are also assessed on the basis of aromaticity indices. The calculated proton affinities of the nitrile series Academic Editor: reported in this study enrich the gas-phase basicity scale of nitriles to around 1000 kJ mol−1. Anastasios Keramidas Keywords: gas-phase basicity; nitriles; push–pull effect; cyanoimines; aromaticity Received: 28 June 2021 Accepted: 18 August 2021 Published: 24 August 2021 1. Introduction Publisher’s Note: MDPI stays neutral Nitriles are usually considered weak bases because of the unfavorable sp hybridization with regard to jurisdictional claims in of the nitrogen atom and the high s character, being adverse to electron pair sharing with published maps and institutional affil- iations. acids. Nevertheless, their gas-phase basicity, as experimentally measured or calculated, may be increased by the push–pull effect. This effect occurs when a strong electron- donating group pushes its electron density toward the electron-accepting cyano group through a conjugated system [1]. Several examples can be found in a review reporting on the gas-phase basicity values of nitriles [2]. For example, 3-(dimethylamino)acrylonitrile Copyright: © 2021 by the authors. (CH3)2N−CH=CH−C≡N, which is protonated preferentially on the cyano group, displays Licensee MDPI, Basel, Switzerland. a proton affinity (897 kJ mol−1) close to that of methylamine (899 kJ mol−1)[3,4]. The This article is an open access article calculated proton affinities of nitriles bearing strong electron-donating groups, such as distributed under the terms and −1 conditions of the Creative Commons phosphazeno and diphosphazeno substituents, can exceed 1000 kJ mol [2,5,6]. Inserting Attribution (CC BY) license (https:// a group with at least one double bond (e.g., vinyl group) in the dimethyl cyanamide creativecommons.org/licenses/by/ skeleton (CH3)2N−C≡N, leading to (CH3)2N−CH=CH−C≡N, significantly enhances the −1 4.0/). push–pull effect, increasing the proton affinity from 852 to 897 kJ mol [3,4]. For this

Symmetry 2021, 13, 1554. https://doi.org/10.3390/sym13091554 https://www.mdpi.com/journal/symmetry SymmetrySymmetry 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 2323

−1 exceed 1000 kJ mol −1 [2,5,6]. Inserting a group with at least one double bond (e.g., vinyl Symmetry 2021, 13, 1554 exceed 1000 kJ mol [2,5,6]. Inserting a group with at least one double bond (e.g.,2 vinyl of 23 group) in the dimethyl cyanamide skeleton (CH3)2N−C≡N, leading to group) in the dimethyl cyanamide skeleton (CH3)2N−C≡N, leading to (CH3)2N−CH=CH−C≡N, significantly enhances the push–pull effect, increasing the proton (CH3)2N−CH=CH−C≡N, significantly enhances the push–pull effect, increasing the proton −1 affinityaffinity fromfrom 852852 toto 897897 kJkJ molmol−1 [3,4].[3,4]. ForFor thisthis reason,reason, thethe searchsearch forfor eveneven moremore efficientefficient reason,resonanceresonance the-- searchtransmittingtransmitting for even systemssystems more efﬁcient ofof thethe pushpush resonance-transmitting––pullpull effecteffect seemsseems toto systems bebe aa promisingpromising of the push–pull strategystrategy effectforfor increasingincreasing seems to the bethe a CC promising≡≡NN basicity.basicity. strategy for increasing the C≡N basicity. InInIn this thisthis study, studystudy,, we wewe extended extendedextended earlier earlierearlier quantum quantumquantumchemical chemicalchemical investigations investigationsinvestigations of ooff strong strongstrong basic basicbasic nitrilesnitrilesnitriles in inin the thethe gas gasgas phase phasephase [ [5,6]5[5,6],6] to toto two twotwo series seriesseries ofofof nitrilesnitrilesnitriles (((III and andand II IIII))) possessingpossessingpossessing interestinginteresting ππ---πππ--- andandand n- n n-π-ππ-conjugated--conjugatedconjugated systems systemssystems or or or groups groups groups (Figure (Figure(Figure1 ). 1) 1). First,. First, First, we we we included included included in inin our our our study, study, study, for fo forr comparisoncomparisoncomparison with withwith previous previousprevious reports reportsreports and andand for forfor investigation investigationinvestigation of ofof the thethe substituent substituentsubstituent effects, effects,effects, nitriles nitrilesnitriles containingcontaining simple simple acyclic acyclicπ π-systems-systems such such as as H HC=Z2C=Z ( 1 ()1) and and H HC=CH2C=CH−−CH=ZCH=Z ( (22)[) [2]2],, asas containing simple acyclic π-systems such as 2H2C=Z (1) and 2 H2C=CH−CH=Z (2) [2], as wellwellwell as as as nitriles nitriles nitriles with with with different different different cyclic cyclic cyclic scaffolds scaffolds scaffolds displaying displaying displaying strong strong strong electron electron electron delocalization delo delocalizationcalization (aromaticity), such as cyclopropene (3)[7], 1,3,5-cycloheptatriene (5)[8,9], and “quinoid” (aromaticity)(aromaticity),, suchsuch asas cyclopropenecyclopropene ((33)) [7][7],, 1,3,51,3,5--cycloheptatrienecycloheptatriene ((55)) [8,9][8,9],, andand “quinoid”“quinoid” fragments (6 and 7)[10]. Additionally, the methylenecyclopropene (3)-conjugated system fragmentsfragments ((66 andand 77)) [10][10].. Additionally,Additionally, thethe methylenecyclopropenemethylenecyclopropene ((33))--conjugatedconjugated systemsystem (with Z: CH) and its heteroatomic analog (with Z: N) was hypothesized to be an efﬁcient (with(with ZZ:: CH)CH) andand itsits heteroatomicheteroatomic analoganalog (with(with ZZ:: N)N) waswas hypothehypothesizedsized toto bebe anan efficientefficient resonance-transmitting unit between various pushing substituents and the site of protona- resonanceresonance--transmittingtransmitting unit unit between between various various pushing pushing substituents substituents and and the the site site of of tion [7,10–17]; therefore, we also decided to study the gas-phase protonation of the nitrile protonationprotonation [7,10[7,10––17]17];; ttherefore,herefore, wewe alsoalso decideddecided toto studystudy thethe gasgas--phasephase protonationprotonation ofof series shown in Figure2, for which the two X substituents are electron-donating or pushing thethe nitrile nitrile series series shown shown in in Figure Figure 2, 2, forfor which which thethe two two XX subs substituentstituents areare groupselectron of-donating medium or strongpushing power, groups such of as medium Me, NR 2or, N=C(NR strong power2)2, and, such N=P(NR as Me,2)3 (R: NR H2, electron-donating or pushing groups of medium or strong power, such as Me, NR2, andN=C(NR Me) attached2)2, and N=P(NR to the cyclopropenylidene2)3 (R: H and Me) attached ring. to the cyclopropenylidene ring. N=C(NR2)2, and N=P(NR2)3 (R: H and Me) attached to the cyclopropenylidene ring.

CN Z CN CN Z Z CN H2C Z CN CN Z H2C Z CN Z CN 11 Z CCNN ZZ

H2C CH CH Z CN H2C CH CH Z CN 2 3 4 5 6 2 3 4 5 6 FigureFigureFigure 1. 1.1. Simple SimpleSimpleπ ππ-π--ππ-conjugated--conjugatedconjugated nitriles: nitriles:nitriles: series seriesseriesI II(Z: (Z:(Z: CH) CH)CH) and andand series seriesseriesII IIII(Z: (Z:(Z: N). N).N).

CN Z CN Z 7 (X: Me) 10 {X: N=C(NH2)2} 7 (X: Me) 10 {X: N=C(NH2)2} 8 (X: NH2) 11 {X: N=C(NMe2)2} 8 (X: NH2) 11 {X: N=C(NMe2)2} 9 (X: NMe2) 12 {X: N=P(NMe2)3} X X 9 (X: NMe2) 12 {X: N=P(NMe2)3} X X FigureFigureFigure 2. 2.2. Series SeriesSeries of ofof nitriles nitrilesnitriles derived derivedderived from fromfrom methylenecyclopropene methylenecyclopropenemethylenecyclopropene and andand cyclopropenimine cyclopropeniminecyclopropenimine (series (series(seriesI with II with Z: CH and series II with Z: N, respectively) containing electron-donating substituents. Z:with CH Z: and CH series and IIserieswith II Z: with N, respectively)Z: N, respectively) containing containi electron-donatingng electron-donating substituents. substituents.

TheTheThe cyclopropenimine cyclopropeniminecyclopropenimine (or (or(or cyclopropeneimine cyclopropeneiminecyclopropeneimine, less,, lessless common commoncommon name) name)name) skeleton skeletonskeleton (Z: N) (Z(Z has:: N)N) ahashas special a a special special status status status among among among the heteroatomic the the heteroatomic heteroatomic analogs analogs analogs of methylenecyclopropene. of of methylenecyclopropene. methylenecyclopropene. It is present It It is is inpresentpresent many systems, in in many many which systems systems have,, which beenwhich largely have have studied been been largely largely experimentally studied studied and ex experimentallyperimentally theoretically, and and in particulartheoretically,theoretically, inthe inin particular lastparticular ten years, inin thethe as lastlast platforms tenten years,years, for as developingas platformsplatformssuperbases forfor developingdeveloping and organocat-superbasessuperbases alystsandand organocatalysts organocatalysts [18–34]. The imino [18[18––3434 bond]].. The The carrying imino imino a bond bond nitrile carrying carrying group ona a nitrile nitrile the nitrogen, group group on on >C=N the the nitrogen,− nitrogen,CN, is present>C=N>C=N−−CN,CN, in molecules isis presentpresent of inin biological moleculesmolecules interest, ofof biologicalbiological in particular interest,interest, the inin particularparticular neonicotinoids thethe neonicotinoidsneonicotinoids [35–37], and in[[3535 materials––3737]],, and and developed in in materials materials for their developed developed electronic for for applications their their electronic electronic [38 – applications40 applications]. These articles, [[3838––4040] as].. These These well asarticles,articles, others asas dealing wellwell asas with othersothers similar dealingdealing functionalities, withwith similarsimilar referfunctionalities,functionalities, to the corresponding referrefer toto thethe familiescorrescorrespondingponding as N- cyano-iminesfamiliesfamilies asas orNN--cyano cyano-imines.cyano--iminesimines orOn or thecyano cyano other--imines.imines. hand, On Onthe IUPAC the the other other nomenclature hand, hand, thethe describes IUPACIUPAC nomenclature describes these compounds (Z:− N) as cyanamide (H2N−CN) derivatives, thesenomenclature compounds describes (Z: N) these as cyanamide compounds (H2 N (Z: N)CN) as derivatives, cyanamide with (H2N the−CN) series derivatives, Z: CH beingwithwith deﬁned the the seriesseries as acetonitrile Z Z:: CHCH being being derivatives defined defined (see as as acetonitrile acetonitrileTable S1 in the derivatives derivatives Supplementary ((seesee Table Table Materials S1 S1 in in (SM) the the forSupplementarySupplementary IUPAC names MaterialsMaterials for series (SM)(SM) 1–6). forfor To IUPACIUPAC avoid namesnames confusion, fforor seriesseries and 11 to––66 focus)).. ToTo avoidavoid on our confusion,confusion, objective andand of comparingtoto focus focus on on nitrile our our basicity objective objective values, of of comparing comparing we adopted nitrile nitrile names basicitybasicity indicating values values a priority,, we we adopted adopted for the nitrile names names group.indicatingindicating This a choicea priority priority does forfor not thethe imply nitrile nitrilea priori group. group.that This This the favored choice choice does gas-phase does not not imply imply protonation aa prioripriori site thatthat is the the the nitrile group, although previous studies have shown that this site is often the most basic group preferred in push–pull nitriles. In the study presented here, we aimed to compare the methylenecyclopropene (CPC) and the cyclopropeneimine (CPN) systems as push–pull relays (or resonance transmission

units) using the basicity of the cyano group as the probe. In the CPN series, the imino- Symmetry 2021, 13, 1554 3 of 23

nitrogen is also a concurrent basic site due to the intrinsically higher basicity of the imino N atom in comparison with the cyano nitrogen, while the most favored protonation site is yet to be determined. The electronic structure of CPC and CPN confers to these systems specific aromaticity properties [13]. The analogous phenomena are related to the relationships of the nitriles series (Figure1) with the other groups ( 4–6). Consequently, we considered possible structural variations for neutral and protonated forms, as well as all reasonable potential protonation sites. About 200 isomeric structures were analyzed at various quantum chemical levels. We used the Gaussian series of software programs and employed DFT methods for all derivatives, as well as the G2 approach for selected simple nitriles. For more computational details, see the next section and SM. For selected isomers, bond length alternations, including the aromaticity of the cycles, were discussed. Gas-phase basicity parameters (proton affinity, PA; gas-phase basicity, GB) for N sites in each isomer were calculated and conformational and substituent effects were investigated. For compounds presenting isomers with close energies, we estimated the macroscopic PA and GB values corresponding to the isomeric mixtures. Monosubstituted CPC and CPN, with only one substituent on the cyclopropene cycle and with unsymmetrically disubstituted structures bearing two different substituents on the cycle, pose specific problems because of their Z/E isomerism. These compounds are also particularly interesting as models for the additivity (or non-additivity) of strong electron donation in push–pull systems. For these reasons, the basicity of these unsymmetrical molecules will be described in a separate forthcoming publication.

2. Conceptual Approaches and Computational Methods DFT calculations at the B3LYP/6-311++G(d,p) level [41–43] were performed for geometry optimization without symmetry constraints, as well as for gas-phase basicity estimations of an extended series of nitriles, given in Figures1 and2, including those based on methylenecyclopropene and cyclopropenimine scaffolds. For the selected structures, the B3LYP/311+G(d,p) level [41–43] was also employed to reach our previous DFT-PA scale for push–pull nitriles [5,6]. This level of theory was chosen for nitrogen bases by Koppel and co-workers [44] and is used for PA prediction of guanidines, phosphazenes, biguanides, and other imines [7,45]. For small molecules (I.1–I.3, and II.1–II.3), the G2 theory [46,47] was additionally applied. Some computational details are included in SM. We performed quantum chemical calculations for a series of nitriles (I with Z: CH) and for a series of α-imino nitriles (II with Z: N) containing simple π-π-conjugated systems (1–6 in Figure1), as well as for those possessing two electron-donating substituents attached to the cyclopropene ring, in order to explore the transmission of their cross-pushing effects to the pulling cyano group through the π-π-conjugated CPC and CPN scaffold (7–12 in Figure2). Calculations were performed for neutral derivatives and for their monoprotonated forms. When more than one nitrogen atom (N-cyano) was present in the molecule (N-imino or N-amino), potential protonated forms were considered to indicate the favored site of protonation for investigated nitriles in the gas phase. The most signiﬁcant structural phenomena that may dictate basicity of the investigated derivatives were taken into account for the neutral and monoprotonated forms. Selected thermochemical data for all considered species of simple nitriles (Table S2) and CPC and CPN derivatives containing large substituents (Table S3) are included in SM. Gas-phase basicity parameters, namely the PA (proton affinity) and GB (gas-phase basicity), for the potential sites of monoprotonation in each isomer of CH and N derivatives were determined according to Equations (1) and (2), respectively [3]. In these equations, B and BH+ correspond to the neutral and monoprotonated forms, while their H and G correspond to the enthalpy and Gibbs energy, respectively, calculated at 298 K. For the proton, the + −1 + −1 following values were used: H298(H ) = 6.2 kJ mol and G298(H ) = −26.3 kJ mol [48,49].

+ + PA = H298(B) + H298(H ) − H298(BH ) (1)

+ + GB = G298(B) + G298(H ) − G298(BH ) (2) Symmetry 2021, 13, 1554 4 of 23

The geometry-based HOMA (harmonic oscillator model of aromaticity) [50] and HOMED (harmonic oscillator model of electron delocalization) indices [51], both originat- ing from the HOMA idea proposed by Kruszewski and Krygowski [52,53], were estimated for fragments of selected neutral and monoprotonated forms of nitriles and imino nitriles according to Equation (3). In this equation, n, α, Ro, and Rx are the number of bonds in a considered fragment, the normalization constant (different for different bonds of CC and CN), the optimum bond length for the reference molecule (also different for different CC and CN bonds), and the calculated bond lengths for the studied fragment, respectively:

2 HOMA or HOMED = 1 − (ΣαΣ[Ro − Rx] )/n (3)

The HOMA and HOMED procedures are analogous, although their parametrizations (α and Ro) are different. For example, the HOMA and HOMED descriptors are equal to unity for aromatic benzene and s-triazine; however, zero is not the same in the HOMA and HOMED scales—HOMED = 0 for the Kekulé structure of benzene with non-delocalized C–C and C=C bonds [54], similar to the original HOMA, whereas HOMA = 0 for the hypothetical structure of benzene with moderately delocalized C–C and C=C bonds [50]. In HOMED(0), the bond lengths of ethane and ethene were taken for the C–C and C=C bonds in the Kekulé structure of benzene, whereas those of 1,3-butadiene were used for the hypothetical structure of benzene in HOMA(0). These differences in the reference bond lengths lead to the negative HOMA values for hydrocarbons being less delocalized than the structure taken for HOMA(0) [55,56]. On the other hand, both HOMED and HOMA are equal to zero for the Kekulé structure of s-triazine with non-delocalized C–N and C=N bonds. In both cases, C–N in methylamine and C=N in methylimine were employed for the reference single and double bond lengths, respectively. The differences in zero on the two HOMA and HOMED scales lead to some discrepancies between the HOMA and HOMED values for heterocompounds [54]; hence, it is recommended that the HOMA index be used for the delocalized systems containing the same types of bonds, e.g., hydrocarbons, while the HOMED index should be used for any π-π, n-π, or σ-π delocalized heterocompounds [51,54,57,58]. In this study, the HOMA index (α = 257.7 and Ro = 1.388) [50] was applied for cyclic fragments containing only CC bonds, while the HOMED index was applied for selected fragments with CC and CN bonds. The HOMED parameters used for the CC and CN bonds are given in Table S4 (SM). Electron delocalization in a π-electron-conjugated cycle (aromaticity) can also be related to the induced ring currents. The magnetic susceptibility of the ring indicates its aromatic character, which can be measured using the nucleus-independent chemical shift (NICS) descriptor [59,60]. According to the computational NICS procedure proposed by Schleyer and co-workers, the absolute magnetic shielding can be calculated at the ring center using the Gaussian ghost atom Bq as the probe [59–61]. In this study, the NICS index at a distance of 1 Å above the ring plane was used as the trustable criterion for aromaticity determination. The negative and positive values of NICS indicate the aromaticity and antiaromaticity of the ring, respectively.

3. Results and Discussion 3.1. Gas-Phase Basicity of Simple Nitriles The two DFT levels of theory for B3LYP/311+G(d,p) and B3LYP/6-311++G(d,p), referred to as DFT1 and DFT2, respectively, applied for selected derivatives lead to very similar basicity parameters (PA and GB) for the cyano and imino N sites, and consequently to analogous DFT gas-phase basicity scales. For simple molecules optimized at the two DFT levels, the geometry parameters are identical. Only their energy parameters slightly differ. Note that the geometry and energy (including basicity) parameters for compounds I.9 and II.9 depend not much on Me conformation. In our case, the differences in gas-phase basicity data predictions were not larger than 0.5 kJ mol−1. For simple nitriles, the PAs calculated here for the cyano and imino N (Z) atoms, together with data for DFT, G2, and G4 from the literature, are summarized in Table1. Symmetry 2021, 13, x FOR PEER REVIEW 5 of 23 Symmetry 2021,, 13,, xx FORFOR PEERPEER REVIEWREVIEW 5 of 23 Symmetry 2021, 13, x FOR PEER REVIEW 5 of 23 Symmetry Symmetry 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 55 ofof 2323

3. Results and Discussion 3. Results and Discussion 3.1.3. Results Gas-Phase and Basicity Discussion of Simple Nitriles 3.1. Gas-Phase Basicity of Simple Nitriles The two DFT levels of theory for B3LYP/311+G(d,p) and B3LYP/6-311++G(d,p), 3.1. GasThe--Phase two Basicity DFT levels ofof Simple of theoryNitriles for B3LYP/311+G(d,p) and B3LYP/6-311++G(d,p),, referredThe to two as DFT1 DFT and levels DFT2, of theory respectively, for B3LYP/311+G(d,p) applied for selected and derivatives B3LYP/6- 311++G(d,p)lead to very, referredThe to two as DFT1 DFT levelsand DFT2, of theorytheory respectively, for for B3LYP/311+G(d,p) applied for selected and derivatives B3LYP/6--311++G(d,p) lead to very,, similarreferred basicity to as DFT1 parameters and DFT2, (PA respectively, and GB) ap forplied the for cyano selected and derivatives imino N lead sites, to very and referredsimilarreferred basicitytoto asas DFT1DFT1 parameters andand DFT2,DFT2, (PA respectively,respectively, and GB) ap forplied the for cyano selected and derivatives imino N lead sites, to very and consequentlysimilar basicity to parameters analogous DFT(PA and gas -phase GB) for basicity the cyano scales. and For imino simple N sites,molecules and similarconsequentlysimilar basicity basicity to parameters parameters analogous (PA (PADFT and and gas -phase GB) GB) for for basicity the the cyano cyano scales. and and For imino imino simple N N sites, sites, molecules and and optimizedconsequently at the to two analogous DFT levels, DFT the gas -geometryphase basicity parameters scales. are For identical. simple Only molecules their consequentlyoptimizedconsequently at the to to analogoustwo analogous DFT levels, DFT DFT gasthe gas --phasegeometry basicity parameters scales. are For identical. simple Only molecules their energyoptimized parameters at the twoslightly DFT differ. levels, Note the that geometry the geometry parameters and energy are identical. (including Only basicity) their optimizedenergy parameters at the two slightly DFT differ. levels, Note thethe that geometry the geometry parameters and energy are identical. (including Only basicity) their parametersenergy parameters for compounds slightly differ. I.9 and Note II.9 that depend the geometry not much and on energy Me conformation. (including basicity) In our energyparameters parameters for compounds slightly differ. I.9 and Note II.9 that depend thethe geometry not much and on energy Me conformation. (including basicity) In our case,parameters the differences for compounds in gas- phaseI.9 and basicity II.9 depend data predictionsnot much onwe Mere notconformation. larger than In 0.5 our kJ parameterscase, the differences for compounds in gas -I.9phaseI.9 and basicity II.9II.9 depend data predictionsnot much on we Mere notconformation. larger than In 0.5 our kJ case,−1 the differences in gas-phase basicity data predictions were not larger than 0.5 kJ mol −1. case,molcase,−1−1 ..thethe differences in gas--phase basicity data predictions werere not not larger larger than than 0.5 0.5 kJ kJ Symmetry 2021, 13, 1554 mol For. simple nitriles, the PAs calculated here for the cyano and imino N (Z) 5atoms of 23 , mol−1−1For.. simple nitriles, the PAs calculated here for the cyano and imino N (Z) atoms,, togetherFor withsimple data nitriles, for DFT, the G2,PAs and calculated G4 from here the forliterature the cyano, are andsummarized imino N in(Z) Table atoms 1., togetherFor simplewith data nitriles, for DFT, the PAsG2, andcalculated G4 from here the for literature the cyano,, areare and summarizedsummarized imino N (Z)inin TableTable atoms 1.1.,, Generally,together with applications data for DFT,of the G2, DFT and met G4hods from lead the toliterature considerably, are summarized higher PAs in(and Table GBs) 1. togetherGenerally,together withwith applications data forfor DFT, of the G2, DFT and met G4hods fromfrom lead thethe toliteratureliterature considerably,, areare summarizedsummarized higher PAs inin(and TableTable GBs) 1.1. Generally, applications of the DFT methods lead to considerably higher PAs−1 (and GBs) for the N-cyano site than those of the Gn theories (differences 10–20 kJ mol −1), with the Generally,Generally,for the N applications-cyano applications site than of of the thosethe DFT DFT of methods themet Ghodsn theories lead lead to to considerably(differences considerably 10 higher –higher20 kJ PAs molPAs (and−1−1 )(and,, with GBs) GBs) the exceptionfor the N -ofcyano HCN. site On than the thoseother ofhand, the Gthen theoriesDFT and (differences G2 methods 10 predict–20 kJ molsimilar), withPAs forthe forforexceptionfor the thethe N-cyano NN-- cyanocyanoof HCN. site sitesite than On thanthan the those thosethose other of theof ofhand, thethe Gn GGthetheoriesn theoriestheoriesDFT (differencesand (differences(differences G2 methods 10–20 1010 predict– kJ20 molkJ molsimilar−1),−1−1 with)),, with PAs the thefor exception of HCN. On the other hand, the DFT and G2 methods predict−1 similar PAs for the N-imino site in series II (differences lower than 10 kJ mol −1). Consequently, the exceptionexceptionthe N-imino of of HCN. HCN. site On in Onthe series the other other II hand, (diff hand,erences the DFTthe DFT lower and and G2 than methods G2 10methods kJ predict mol predict−1−1). similar Consequently, similar PAs for PAs the for the differencesthe N-imino between site in the series PA(N II- cyano)(differences and PA(N lower-imino) than dramatically 10 kJ mol ). change Consequently, when going the N-iminothedifferencesthe N N-- siteiminoimino in between series site site in inII the series(differences series PA(N IIII -cyano)(diff(diff lowererences and than PA(N lower 10 kJ-imino) mol than−1 ). 10dramatically Consequently, kJ mol−1−1).). change Consequently, Consequently, the differences when going the the fromdifferences DFT to between G2 levels. the PA(N This - meanscyano) thatand PA(N the favored-imino) sitedramatically of monoprotonation change when can going be betweendifferencesfrom DFT the PA(N-cyano) tobetween G2 levels. the andPA(N This PA(N-imino) --cyano) meanscyano) andand that dramatically PA(NPA(N the favored--imino)imino) change dramatically sitedramatically of when monoprotonation going changechange from whenwhen DFT can goinggoing to be predictedfrom DFT without to G2 levels.any doubt This when means the that DFT the-calculated favored siteΔPA of for monoprotonation the cyano and imino can beN G2frompredictedfrom levels. DFT DFT This without to tomeans G2 G2 levels. levels.any that doubt the This This favored when means means the site that that DFT of the themonoprotonation-calculated favored favored site siteΔPA of of canfor monoprotonation monoprotonation the be predicted cyano and without imino can can be beN predicted without any doubt −1when the DFT-calculated ΔPA for the cyano and imino N atoms is higher than 20 kJ mol −1. In other cases, a conclusion on favored monoprotonation anypredictedatoms doubt is whenhigher without the than DFT-calculatedany 20 doubtkJ mol when−1−1.. InIn∆ otherother PAthethe for DFT cases,cases, the--calculatedcalculatedcyano aa conclusionconclusion and Δ iminoPA onon for favoredfavored N the atoms cyano monoprotonationmonoprotonation is higher and imino than N sites should−1 be carefully derived−1−1 on the basis of DFT calculations. 20atomssites kJ mol should is higher. In be other carefullythan cases,20 kJ derived mol a conclusion.. InIn on otherother the basis oncases,cases, favored of aa DFT conclusionconclusion monoprotonationcalculations. onon favoredfavored monoprotonation sitesmonoprotonation should be carefullysites should derived be oncarefully the basis derived of DFT on calculations. the basis of DFT calculations. sites should−1 be carefully derived on the basis of DFT calculations. Table 1. Comparison of PAs (in kJ mol −1 at 298 K) for selected nitriles and imino nitriles calculated with different levels of Table 1. Comparison of PAs (in kJ mol−1−1 at 298 K) for selectedlected nitrilesnitriles andand iminoimino nitrilesnitriles calculatedcalculated with different levels of theory,Table 1. together Comparison with experimentalof PAs (in kJ molvalues at when 298 K) available. for selected nitriles and imino nitriles calculated with different levels of theory, together with experimental −values1 −1−1 when available. TableTabletheory,theory, 1. Comparison1. togethertogether Comparison withwith of PAs ofexperimentalexperimental PAs (in (in kJ mol kJ mol valuesvaluesat−1 atat 298 whenwhen298298 K) K)K) for available.available. forfor selected seselectedlected nitriles nitrilesnitriles and andand imino iminoimino nitriles nitrilesnitriles calculated calculatedcalculated with with different different levels levels of of theory,theory,theory, togetherLevel togethertogether with withwith experimental experimentalexperimental valuesBase valuesvalues when whenwhen available. available.available.PA(Ncyano ) Base PA(Ncyano) PA(Nimino) Level Base PA(Ncyano) Base PA(Ncyano) PA(Niminoimino) Level Base PA(Ncyanoa ) Base PA(Ncyanoa ) PA(Nimino) B3LYP/6-311++G(d,p) 707.9cyano a 785.8cyano a imino B3LYP/6LevelLevel-311++G(d,p) Base Base PA(N PA(N707.9cyanocyano aa ))) Base Base PA(N PA(N785.8cyano aa ))) PA(NPA(Nimino imino))) B3LYP/6-311++G(d,p) 707.9 b 785.8 a B3LYP/6-311+G(d,p) 708.0 aba 785.5 aa B3LYP/6-311++G(d,p)B3LYP/6B3LYP/6---311++G(d,p)311+G(d,p) 707.9708.0707.9 ab 785.8785.5785.8 aa B3LYP/6-311+G(d,p) CN 708.0 c CN 785.5 c G2 CN 712.0 bbc 780.1 aac B3LYP/6-311+G(d,p)B3LYP/6--G2311+G(d,p) CN 708.0712.0708.0 cc CN 785.5780.1785.5 cc G2 H CN 712.0 H3C CN 780.1 G2MP2 713.8 dc 781.7 cc G2MP2 H 713.8 cdc H3C CN 781.7 cc G2MP2G2G2 H CN 712.0713.8 712.0 d H3C CN 780.1781.7780.1 c G2MP2 713.8 781.7 e H d H3C ec G2MP2G4MP2 H 713.8 dd 3 781.2781.7 cec G2MP2G4MP2 713.8 781.7781.2 ee G4MP2G4MP2 f 781.2781.2 fe Exp. 712.9 f 779.2 efe G4MP2Exp. 712.9 fff 781.2779.2 ff Exp.Exp. 712.9712.9 a 779.2779.2 a a B3LYP/6-311++G(d,p) 793.4 faf 797.5 faf 738.3 a B3LYP/6Exp.-311++G(d,p) 712.9793.4 aa 779.2797.5 aa 738.3 aa B3LYP/6-311++G(d,p)B3LYP/6-311++G(d,p) 793.4793.4 a 797.5797.5 aa 738.3738.3a a B3LYP/6-311+G(d,p) CN 793.3 aa CN 797.4 aa 738.3 aa B3LYP/6B3LYP/6---311++G(d,p)311+G(d,p) CN 793.4793.3 aa CN 797.5797.4 aa 738.3738.3a aa B3LYP/6-311+G(d,p)B3LYP/6-311+G(d,p) CN 793.3 793.3 a N CN 797.4797.4 a 738.3738.3 a G2 784.7 aa 785.3 aa 743.0 aa B3LYP/6G2--G2311+G(d,p) CN 793.3784.7 784.7 aa N CN 797.4785.3785.3 aa 743.0738.3743.0a aa G2 784.7 a 785.3 a 743.0 a G2MP2 785.4 aa N 786.2 aaa 743.7a aa G2MP2G2MP2G2 784.7785.4 785.4 aa 785.3786.2786.2 aa 743.7743.0743.7 aa G2MP2 I.1 785.4 ee II.1 786.2 743.7 G4MP2G4MP2 783.8 783.8 aea aa aa G2MP2G4MP2 I.1I.1 785.4783.8 ee II.II.11 786.2 743.7 G4MP2 783.8 ff Exp.Exp. 784.7784.7 e G4MP2 I.1I.1 783.8 e ff II.II.1 G4MP2Exp. 783.8784.7 f B3LYP/6-311++G(d,p)B3LYP/6-Exp.311++G(d,p) CN 784.7 ff CN B3LYP/6-311++G(d,p) CN CN B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) CN 913.6913.6 b N CN 917.8917.8 bb 864.9864.9 b b B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) 913.6 b 917.8 b 864.9 b B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) CN 913.6 gb N CN 917.8 bg 864.9 g b B3LYP/6G2-311+G(d,p) 913.6 895.4 g 917.8900.8 g 867.9864.9 g G2 895.4 b 900.8 b 867.9 b B3LYP/6--311+G(d,p) H N NH 913.6 bg H N N NH 917.8 bg 864.9g bg G2MP2G2 H2N NH2 895.4 896.0 g H2N NH2 900.8901.9 g 867.4867.9 g H2N NH2 g H2N NH2 g g G2MP2 H2N NH2 896.0 gg H2N NH2 901.9 gg 867.4 gg G2MP2G2 895.4896.0 g 900.8901.9 g 867.9867.4 g G2MP2 H22N NH22 896.0 a H22N NH22 901.9 a 867.4 a B3LYP/6-311++G(d,p) CN 834.1 g CN 854.7 g 807.6 g B3LYP/6G2MP2-311++G(d,p) CN 834.1896.0 ga CN 854.7901.9 ga 807.6867.4 ga B3LYP/6-311++G(d,p)B3LYP/6G2MP2-311++G(d,p) CN 896.0834.1834.1 aa N CN 901.9854.7854.7 aa 807.6867.4807.6a a B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) CN 834.0834.1 a N CN 854.7854.7 a 807.6807.6 a B3LYP/6-311+G(d,p) 834.0 aa N 854.7 aaa 807.6a aa B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6---311++G(d,p)311+G(d,p) CN 834.1834.0 834.0 a CN 854.7854.7854.7 a 807.6807.6807.6 a B3LYP/6-311+G(d,p) 834.0 aa N 854.7 aa 807.6a a G2G2 814.3 814.3 aa 831.0831.0 aa 802.1802.1 aa B3LYP/6--G2311+G(d,p) 834.0814.3 aa 854.7831.0 aa 807.6802.1 aa G2MP2G2 814.5814.3 aa 831.3831.0 aa 802.3802.1a a G2MP2G2MP2 814.5 814.5 aa 831.3831.3 aa 802.3802.3 aa G2MP2G2 814.3814.5 ea 831.0831.3 a 802.1802.3 a G4MP2G2MP2 814.5 812.2 e 831.3 802.3 G4MP2 I.2a 812.2 eaa II.2a aa aa G4MP2G2MP2 I.2a 812.2814.5 e II.2a 831.3 802.3 G4MP2 I.2a 812.2 e II.2a G4MP2 812.2 a a a B3LYP/6-311++G(d,p) 828.4 aee 851.8 a 815.1 a B3LYP/6G4MP2-311++G(d,p) I.2aI.2aCN 828.4812.2 a II.2aII.2aCN 851.8 a 815.1 a B3LYP/6-311++G(d,p) CN 828.4 a N CN 851.8 a 815.1 a B3LYP/6-311++G(d,p) CN 828.4 a N CN 851.8 a 815.1 a B3LYP/6-311+G(d,p) 828.3 a N 851.7 a 815.1 a B3LYP/6--311++G(d,p) 828.4 aa N 851.8 aaa 815.1a aa B3LYP/6-311++G(d,p)B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) CN 828.4828.3828.4 a CN 851.8851.7851.8 a 815.1815.1 a G2 809.0 aa N 827.6 aa 809.0a a B3LYP/6-311+G(d,p)B3LYP/6G2-311+G(d,p) 809.0828.3 828.3 aa 827.6851.7851.7 aa 815.1809.0815.1 aa SymmetryB3LYP/6 2021, -13G2311+G(d,p), x FOR PEER REVIEW 828.3809.0 a 851.7827.6 a 815.1809.0 a 6 of 23 SymmetrySymmetry 20212021,,, 1313G2,,, xxx FORFORFOR PEERPEERPEER REVIEWREVIEWREVIEW 809.0 aa 827.6 aa 809.0a a 66 ofof 2323 G2MP2G2 809.2 809.0 aa 828.0827.6 aa 809.0809.1 aa G2MP2G2 809.0809.2 aa 827.6828.0 aa 809.0809.1 aa G2MP2G2MP2 809.2 809.2 a 828.0828.0 a 809.1809.1a G2MP2 809.2 aa 828.0 aa 809.1 aa G4MP2G2MP2 809.2 806.8 e 828.0 809.1 I.2b II.2b e G4MP2 I.2bI.2b 806.8 ee II.2bII.2b G4MP2 806.8 a a a B3LYP/6-311++G(d,p)B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 885.5885.5885.5 aa CCNN 892.1892.1892.1 aa 841.7841.7841.7a a a N a a B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 885.4885.4 885.4 aa N 892.1892.1892.1 aa 841.6841.6841.6a aa a aa a a G2G2G2 867.6867.6 867.6 aa 875.1875.1875.1 aa 845.0845.0845.0 aa G2MP2 867.9 a 875.8 a 845.5 a G2MP2 867.9 a 875.8 a 845.5 a G2MP2G2MP2 I.3I.3I.3 867.9867.9 a II.3II.3II.3 875.8875.8 a 845.5845.5 a a a a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 910.0910.0 a CCNN 939.3939.3 a 909.0909.0 a NN B3LYP/6-311++G(d,p) 910.0 a 939.3 a 909.0 a aa a a a B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 910.1910.1 910.1 aa 939.3939.3939.3 aa 909.3909.3909.3 aa

I.4I.4I.4 II.4II.4II.4 a a a B3LYP/6-311++G(d,p) CN 884.1 aa CN 918.5 aa 892.6 aa B3LYP/6-311++G(d,p) CN 884.1 N CN 918.5 892.6 NN

a a a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 884.1884.1 aa 918.4918.4 aa 892.7892.7 aa

I.5I.5 II.5II.5 a a a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 972.9972.9 a CCNN 1004.41004.4 a 987.1987.1 a NN

a a a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 972.9972.9 aa 1004.31004.3 aa 987.0987.0 aa

I.6I.6 II.6II.6

CCNN CCNN NN a a a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) 924.7924.7 aa 933.2933.2 aa 897.3897.3 aa a a a B3LYP/6-311+G(d,p) 924.6 aa 933.1 aa 897.3 aa B3LYP/6-311+G(d,p) Me Me 924.6 Me Me 933.1 897.3 Me Me Me Me I.7I.7 II.7II.7

CCNN CCNN NN a a a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) 971.6971.6 aa 975.6975.6 aa 935.4935.4 aa a a a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 971.5971.5 aa 975.6975.6 aa 935.3935.3 aa HH2NN NNHH2 HH2NN NNHH2 2 2 2 2 I.8I.8 II.8II.8 a a a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 998.1998.1 a CCNN 1004.61004.6 a 967.6967.6 a NN

a b a B3LYP/6-311+G(d,p) 998.5 aa 1004.5 bb 967.4 aa B3LYP/6-311+G(d,p) Me2N NMe2 998.5 Me2N NMe2 1004.5 967.4 Me22N NMe22 Me22N NMe22 I.9I.9 II.9II.9 a b c d e f a DataData takentaken fromfrom tthishis studystudy.. b TakenTaken fromfrom ref.ref. [[66]].. c TakenTaken fromfrom ref.ref. [[6262]].. d TakenTaken fromfrom ref.ref. [[6363]].. e TakenTaken fromfrom ref.ref. [[22]].. ff TakenTaken g fromfrom ref.ref. [[33]].. g TakenTaken fromfrom ref.ref. [[55]]..

3.2.3.2. IsomericIsomeric PhenomenaPhenomena inin NeutralNeutral FormsForms AAmongmong derivatives derivatives of of simplesimple π π--ππ--conjugatedconjugated seriesseries II andand IIII ((FigureFigure 1),1), two two geometricalgeometrical isomers isomers about about the the C=C C=C and and C=N C=N doubledouble bonds bonds ((aa andand bb)) and and their their two two rotationalrotational isomersisomers aboutabout thethe CC––CC bondbond ((cc andand dd)) cancan bebe distinguisheddistinguished forfor compoundscompounds I.2I.2 andand II.2II.2 (Chart(Chart S1S1 inin SM).SM). FourFour isomisomericeric structuresstructures withwith differentdifferent stabilitystability levelslevels areare,, thusthus,, possiblepossible forfor thethe neutralneutral formsforms ofof I.2I.2 andand II.2II.2.. WeWe foundfound thatthat atat thethe DFTDFT levellevel ofof theorytheory,, thethe

Symmetry 2021, 13, x FOR PEER REVIEW 6 of 23 Symmetry Symmetry 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 66 ofof 2323 Symmetry 2021, 13, x FOR PEER REVIEW 6 of 23 Symmetry Symmetry 20212021,, 1313,, xx FORFOR PEERPEER REVIEWREVIEW 66 ofof 2323

G4MP2 I.2b 806.8 e II.2b I.2b ee II.2b G4MP2G4MP2 I.2bI.2b 806.8806.8 e II.2bII.2b B3LYP/6G4MP2G4MP2-311++G(d,p) I.2bI.2bCN 806.8885.5806.8 eae II.2bII.2bCN 892.1 a 841.7 a aa aa aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 885.5885.5 aa N CCNN 892.1892.1 a 841.7841.7 aa B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) CN 885.4885.5 aa CN 892.1892.1 aa 841.6841.7 aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 885.5885.5 aa NN CCNN 892.1892.1aa 841.7841.7 aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 885.4885.4 aa N 892.1892.1 aa 841.6841.6 aa B3LYP/6B3LYP/6--G2311+G(d,p)311+G(d,p) 885.4867.6885.4 aa NN 892.1875.1892.1 aa 841.6845.0841.6 aa G2 867.6 aa 875.1 aa 845.0 aa G2G2 867.6867.6 a 875.1875.1 a 845.0845.0 a G2MP2G2G2 I.3 867.6867.9867.6 aa II.3 875.1875.8875.1 aa 845.0845.5845.0 aa Symmetry 2021, 13, 1554 aa aa 6 aa of 23 G2MP2G2MP2 I.3I.3 867.9867.9 a II.3II.3 875.8875.8 a 845.5845.5 a G2MP2 I.3 867.9 aa II.3 875.8 aa 845.5 aa B3LYP/6G2MP2G2MP2-311++G(d,p) I.3I.3 CN 867.9910.0867.9 a II.3II.3C N 875.8939.3875.8 a 909.0845.5845.5 a aa aa aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 910.0910.0 a N CCNN 939.3939.3 a 909.0909.0 a B3LYP/6-311++G(d,p) CN 910.0 aa N CN 939.3 aa 909.0 aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 910.0910.0 NN CCNN 939.3939.3 909.0909.0 NN Table 1. Cont. B3LYP/6-311+G(d,p) 910.1 a 939.3 a 909.3 a aa aa aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 910.1910.1 a 939.3939.3 a 909.3909.3 a B3LYP/6B3LYP/6Level--311+G(d,p)311+G(d,p) Base PA(N910.1910.1cyano aa ) Base PA(N939.3939.3cyano aa ) PA(N909.3909.3imino aa ) I.4 II.4

I.4I.4 II.4II.4 B3LYP/6-311++G(d,p) I.4I.4C N 884.1 a II.4II.4C N 918.5 a 892.6 a aa N aa aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 884.1884.1 a N CCNN 918.5918.5 a 892.6892.6 a B3LYP/6-311++G(d,p) CN 884.1 aa N CN 918.5 aa 892.6 aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 884.1884.1 NN CCNN 918.5918.5 892.6892.6 B3LYP/6-311++G(d,p) 884.1 a NN 918.5 a 892.6 a B3LYP/6-311+G(d,p) 884.1 a 918.4 a 892.7 a B3LYP/6-311+G(d,p) 884.1 a 918.4 a 892.7 a aa aa aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 884.1884.1 a 918.4918.4 a 892.7892.7 a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 884.1884.1 aa 918.4918.4 aa 892.7892.7 aa I.5I.5 II.5

I.5I.5 II.5II.5 B3LYP/6-311++G(d,p) I.5I.5C N 972.9 a II.5II.5C N 1004.4 a 987.1 a aa aa aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 972.9972.9 a N CCNN 1004.41004.4 a 987.1987.1 a B3LYP/6-311++G(d,p) CN 972.9 aa N CN 1004.4 aa 987.1 aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 972.9972.9 NN CCNN 1004.41004.4 987.1987.1 NN

B3LYP/6-311++G(d,p) 972.9 a 1004.4 a 987.1 a B3LYP/6-311+G(d,p) 972.9 aa 1004.3 a 987.0a a B3LYP/6-311+G(d,p) 972.9 aa 1004.3 aa 987.0 aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 972.9972.9 a 1004.31004.3 a 987.0987.0 a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 972.9972.9 aa 1004.31004.3 aa 987.0987.0 aa

I.6 II.6

I.6I.6 II.6II.6 I.6I.6 C N II.6II.6C N CN CN CCNN N CCNN CCNN NN CCNN a N a a B3LYP/6-311++G(d,p) 924.7 NN 933.2 897.3 aa aa aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) 924.7924.7 aa 933.2933.2 aa 897.3897.3a aa B3LYP/6-311++G(d,p)B3LYP/6B3LYP/6B3LYP/6---311++G(d,p)311++G(d,p)311+G(d,p) 924.7924.6924.7924.7 aa 933.2933.1933.2933.2 aa 897.3897.3897.3 aa B3LYP/6-311++G(d,p) Me Me 924.7 aa Me Me 933.2 aa 897.3a aa B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) Me Me 924.6924.6924.6 a Me Me 933.1933.1933.1 a 897.3897.3897.3 a B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) MMee MMee 924.6924.6 aa MMee MMee 933.1933.1 aa 897.3897.3 aa Me I.7 Me Me II.7 Me MMee MMee MMee MMee I.7I.7 II.7II.7 I.7I.7 C N II.7II.7C N CN CN CCNN N CCNN CCNN NN CCNN a N a a B3LYP/6-311++G(d,p) 971.6 a NN 975.6 a 935.4 a B3LYP/6-311++G(d,p) 971.6 aa 975.6 aa 935.4a aa B3LYP/6-311++G(d,p)B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) 971.6971.6 aa 975.6975.6975.6 aa 935.4935.4935.4 aa B3LYP/6B3LYP/6--311++G(d,p)311+G(d,p) 971.5971.6 aa 975.6 aa 935.3935.4a aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) H N NH 971.6971.6 aa H N NH 975.6975.6 aa 935.4935.4 aa B3LYP/6-311+G(d,p)B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 2 2 971.5971.5971.5 a 2 2 975.6975.6975.6 a 935.3935.3935.3 a B3LYP/6-311+G(d,p) H N NH 971.5 aa H N NH 975.6 aa 935.3 aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) HH22NN NNHH22 971.5971.5 HH22NN NNHH22 975.6975.6 935.3935.3 HH2NN I.8 NNHH2 HH2NN II.8 NNHH2 22 22 22 22 I.8I.8 II.8II.8 B3LYP/6-311++G(d,p) I.8I.8 C N 998.1 a II.8II.8C N 1004.6 a 967.6 a B3LYP/6-311++G(d,p) CN 998.1 aa CN 1004.6 aa 967.6 aa B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 998.1998.1 a N CCNN 1004.61004.6 a 967.6967.6 a B3LYP/6B3LYP/6--311++G(d,p)311++G(d,p) CCNN 998.1998.1 aa N CCNN 1004.61004.6 aa 967.6967.6 aa NN NN B3LYP/6-311++G(d,p)B3LYP/6-311+G(d,p) 998.998.15 aa 1004.51004.6 ab 967.6967.4a a B3LYP/6-311+G(d,p) Me2N NMe2 998.5 aa Me2N NMe2 1004.5 bb 967.4 aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) 998.998.55 aa 1004.51004.5 bb 967.4967.4a a B3LYP/6-311+G(d,p)MMee22NN NNMMee22 998.5 aa MMee22NN NNMMee22 1004.5 bb 967.4 aa B3LYP/6B3LYP/6--311+G(d,p)311+G(d,p) Me2N NMe2 998.998.55 Me2N NMe2 1004.51004.5 967.4967.4 MMee22NN I.9 NNMMee22 MMee22NN II.9 NNMMee22 I.9I.9 II.9II.9 a Data taken from this study. b TakenI.9I.9 from ref. [6]. c Taken from ref. [62]. d TakenII.9II.9 from ref. [63]. e Taken from ref. [2]. f Taken aa bb cc dd ee ff a DataData takentaken fromfromg tthishis studystudy.. b TakenTaken fromfrom ref.ref. [[66]].. c TakenTaken fromfrom ref.ref. [[6262]].. d TakenTaken fromfrom ref.ref. [[6363]].. e TakenTaken fromfrom ref.ref. [[22]].. f TakenTaken afroma Data ref. taken [3] .from Taken this from study ref.. bb Taken [5]. from ref. [6]. cc Taken from ref. [62]. dd Taken from ref. [63]. ee Taken from ref. [2]. ff Taken DataData takentaken fromfromgg tthishis studystudy.. TakenTaken fromfrom ref.ref. [[66]].. TakenTaken fromfrom ref.ref. [[6262]].. TakenTaken fromfrom ref.ref. [[6363]].. TakenTaken fromfrom ref.ref. [[22]].. TakenTaken a fromfrom ref.ref. [[33]].. g TakenTaken fromfromb ref.ref. [[55]].. c d e f Datafrom taken ref.from [3]. g this Taken study. fromTaken ref. from[5]. ref. [6]. Taken from ref. [62]. Taken from ref. [63]. Taken from ref. [2]. Taken from ref. [3]. g fromfrom ref.ref. [[33]].. g TakenTaken fromfrom ref.ref. [[55]].. Taken from ref. [5]. 3.2. Isomeric Phenomena in Neutral Forms 3.2.3.2. IsomericIsomeric PhenomenaPhenomena inin NeutralNeutral FormsForms 3.2.3.2. IsomericIsomericAmong Phenomena Phenomena derivatives inin NeutralNeutral of simple FormsForms π - π -conjugated series I and II (Figure 1), two 3.2. IsomericAmong Phenomena derivatives in Neutral of simple Forms π-π-conjugated series I and II (Figure 1), two geometricalAAmongmong isomers derivatives derivatives about of of the simplesimple C=C πand π--ππ- -conjugatedconjugated C=N double seriesseries bonds II (andaand and IIII b(()FigureFigure and their 1),1), two geometricalAmongAAmongmong derivatives isomers derivatives derivatives aboutof simple of of the simplesimpleπ - C=Cπ-conjugated πand π--ππ- -conjugatedconjugated C=N series doubleI andseriesseries bondsII (Figure II (andanda and1 ),IIII two b(()FigureFigure geometricaland their 1),1), two two geometricalrotationalgeometrical isomers isomers isomers about about about the the theC– C C=C C=C bond and and (c and C=N C=N d )double doublecan be distinguished bonds bonds ((aa andand for bb)) compounds and and their their two two I.2 isomersgeometricalrotationalgeometrical about isomers the isomers isomers C=C about and about about the C=N the theC– double C C=C C=C bond and and bonds (c and C=N C=N (a d and )double doublecanb be) and distinguished bonds bonds their (( twoaa andand rotational for bb)) compounds and and isomers their their two two I.2 rotationalandrotational II.2 (Chart isomersisomers S1 in aboutabout SM). thethe Four CC– –isomCC bondbonderic ( (structurescc andand dd)) cancan with bebe differentdistinguisheddistinguished stability forfor levelscompoundscompounds are, thus I.2I.2, aboutrotationalandrotational theII.2 C–C(Chart isomersisomers bond S1 in (aboutaboutc SM).and thethe dFour) can CC–– isomCC be bondbond distinguishederic (( cstructuresc andand dd)) cancan for with compoundsbebe differentdistinguisheddistinguished stabilityI.2 and forfor II.2 levelscompoundscompounds(Chart are, thus S1 I.2I.2, andpossibleand II.2II.2 (Chart(Chartfor the S1 S1neutral inin SM).SM). forms FourFour of isomisom I.2 andericeric II.2structuresstructures. We found withwith that differentdifferent at the stability stabilityDFT level levelslevels of theory areare,, thusthus, the,, inandand SM). II.2II.2 Four (Chart(Chart isomeric S1S1 inin structuresSM).SM). FourFour isom withisomericeric different structuresstructures stability withwith levels differentdifferent are, stabilitystability thus, possible levelslevels are forare,,the thusthus,, possiblepossible forfor thethe neutralneutral formsforms ofof I.2I.2 andand II.2II.2.. WeWe foundfound thatthat atat thethe DFTDFT levellevel ofof theorytheory,, thethe neutralpossiblepossible forms forfor the oftheI.2 neutralneutraland II.2 formsforms. We ofof found I.2I.2 andand that II.2II.2 at.. WeWe the foundfound DFT level thatthat ofatat the theory,the DFTDFT the levellevel Gibbs ofof theorytheory energy,, thethe of structure I.2a is lower than that of I.2b (by only 1 kJ mol−1) and is signiﬁcantly lower than those of the less favorable structures c and d. On the other hand, the G2 level of

theory predicted the reverse. In the case of neutral α-imino nitriles II.2, the stability order of structures a–d at the DFT levels is analogous to that for I.2. The presence of the imino N atom only affects the relative Gibbs energies (∆Gs), although by no more than 4 kJ mol−1. Slight differences occur at the G2 level. The isomer a has the lowest G similarly, as found at the DFT levels. The isomer b has higher G by 2 kJ mol−1. For both derivatives (I.2 and Symmetry 2021, 13, 1554 7 of 23

II.2), the isomers c and d may be neglected in the isomeric mixtures owing to their high ∆Gs (≥10 kJ mol−1); hence, their basicity data calculated at different levels of theory are not compared in Table1. The structural investigations for simple π-π-conjugated nitriles encouraged us to perform an extended analysis of isomeric phenomena for the series, in which the push– pull effect is transmitted by the CPC or by the CPN scaffolds (Figure2). When large donor substituents (guanidino N=C(NR2)2 and phosphazeno N=P(NR2)3 groups) are introduced at the cyclopropene ring, rotational isomerism about the single C–X bonds can affect geometric and energetic parameters and cannot be neglected for these derivatives. Note that rotation of the Me groups was not studied here in detail for I.11, I.12, II.11, and II.12, because for compounds I.9 and II.9, we observed only slight structural and energetic effects. Although prototropic tautomerism (amino–imino conversions) may additionally occur for guanidino derivatives with two N=C(NH2)2 groups, this phenomenon can be neglected owing to the very strong electron-accepting effect of the C2C=Z–C≡N fragment, as well as the commonly known rule based on the Brønsted theory and substituent effects that pulling groups strongly stabilize the imino tautomer of weaker basicity [64,65]. According to this rule, the labile protons are preferentially bonded to the amino N atoms in guanidine and the imino N atoms of the two guanidine groups are linked to the C2C=Z–C≡N fragment, leading to the following favored tautomeric form, [(H2N)2C=N]2C2C=Z–C≡N, for I.10 (Z: CH) and II.10 (Z: N). Replacement of H by Me at the amino N atoms in I.11 and II.11 eliminates amino-imino tautomerism in the guanidine group. The same is true for the diphosphazeno derivatives I.12 and II.12. In order to reduce the number of drawings for the representation of the possible isomers of I.10–I.12 and II.10–II.12, the guanidino and phosphazeno groups are abbreviated here as N=Y(NR2)n, where R is H or Me, Y is C or P, and n is 2 or 3, respectively. If we look at the single-bonds of Cring–N=Y(NR2)n, about which rotations are possible, four major isomers are possible (not including methyl group rotations), which we examined separately for each derivative regarding the C=Z moiety; therefore, we decided to analyze these four particular isomers (a, b, c, and d in Chart S2 in SM) for derivatives I.10–I.12 and II.10–II.12. In our analyses, we neglected other intermediate positions as well as the minor conformational changes induced by the methyl group rotations. The relative Gibbs energies calculated at the DFT1 or DFT2 level for a–d of the neutral CH and N derivatives are summarized in Chart S2 (SM). They indicate some differences in stability of a–d in I and II. Generally, the isomer a is favored (except I.10), and in some cases c is also favored (I.10, I.11, and I.12). Possible intramolecular interactions in selected nitriles that can inﬂuence their stability are shown in Figures S1 and S2 (SM).

3.3. Possible and Favored Sites of Monoprotonation For compounds containing different functional groups, such as cyano, imino, and amino groups, the N atom(s) are potential sites of protonation. Quantum chemical methods have an advantage in that they allow the possibility of investigating all potential sites of protonation, then indicating the atom(s) that can preferentially bind one proton. On the basis of our calculations performed for series I and II of simple π-π-conjugated nitriles and imino nitriles given in Figure1, we can conclude that the cyano N atom is the favored site of protonation. Generally, imines are much stronger bases than nitriles [1–4,32]; however, the combination of the strong electron-accepting effect of the cyano group, considerably de- creasing the basicity of the imino N atom, and the push–pull effect on the nitrile, increasing its basicity, reverse the usual order. Consequently, the difference in Gibbs energies between the imino-protonated cation (C=NH+) and the cyano-protonated cation (C≡NH+) is not lower than 20 kJ mol−1; therefore, the imino-protonated isomers can be neglected (<0.1%) for monoprotonated forms, at least for the simple systems considered in Chart S3 (SM). We paid particular attention to the two derivatives, I.2 and II.2, which display isomeric phenomena about the double C=C and C=N bonds and about the single C–C bond, not Symmetry 2021, 13, 1554 8 of 23

only for the neutral molecules (Chart S1 in SM), but also for their monoprotonated forms (Chart S3 in SM). We found that for the cyano-protonated forms of I.2 and II.2, the structure a is favored at each level of theory applied here for basicity prediction (DFT and Gn). Its Gibbs energy is lower than that of structure b by more than 5 kJ mol−1. The other cyano- protonated isomers (c and d) have higher Gibbs energies than a and can be considered as minor (c) or even as rare (d) forms in the isomeric mixture of monoprotonated I.2 and II.2. The imino-protonated isomers a–d of II.2 can be neglected, as their ∆Gs are exceptionally high (≥50 kJ mol−1). The cyano N atom also appears to be the preferred site of protonation for the derivatives given in Figure2, containing additional N atoms in the substituents, for which Z is CH or N. For example, protonation of the amino N atoms at the syn-(a) and anti-position (b) regarding C≡N for the diamino derivatives I.8 and II.8 leads to monocations (Chart S4 in SM), for which the DFT1-calculated Gs are dramatically higher than those of the cyano-protonated forms (by ca. 180 and 210 kJ mol−1, respectively). For II.8 (Z: N), this effect seems to be stronger due to an additional pull effect of the imino group. Since it is commonly recognized that amines are stronger bases than nitriles, the reverse orders of Gs for the cyano- and amino-protonated forms of I.8 and II.8 conﬁrm very strong push–pull effects in these molecules between the amino and cyano groups through the CPC or CPN scaffolds. The protonation at the imino nitrogen in II.8 is unfavored by the strong electron- accepting effect of the cyano group combined with the push–pull effect on the nitrile, as already mentioned. The Gibbs energy of the imino-protonated form is higher than that of the cyano monocation by more than 40 kJ mol−1. An analogous difference (37 kJ mol−1 at the DFT2 level) is found for the cyclopropenimine derivative II.9 containing two NMe2 groups, indicating also that the cyano N atom is preferentially protonated. Taking into account the negligible probability of amino protonation in I.8 and II.8, as well as in the investigated earlier series of amino, amidino, guanidino, and phosphazeno nitriles possessing the substituent directly linked with the cyano group, X–C≡N[5,6], the amino-protonated forms for other CPC (I.10–I.12) and CPN derivatives (II.10–II.12) were not considered in this study; however, two extreme conformations (syn and anti regarding C=Z) for the guanidino and phosphazeno groups, which are possible for the cyano and imino-protonated forms and analogously as neutral forms (Chart S2 in SM), have to be considered. As such, DFT calculations were performed for four isomers (a–d) of each monoprotonated form (cyano and imino). Their relative Gibbs energies are summarized in Chart S5 (SM). The DFT results indicate Ncyano as the favored site of protonation in the gas phase for all disubstituted derivatives. Generally, the isomer b has the lowest Gibbs energy for the cyano monocation, probably owing to possible favorable intramolecular interactions (see Figure S3 and discussion in SM for diguanidino derivatives). For the diphosphazeno CH derivative I.12, isomer d is favored in the monoprotonation reaction leading to the cyano monocation of the lowest Gibbs energy. For other derivatives with large substituents, this isomer belongs to the minor form. The probability of protonation of the imino N (Z) seems to be very low (∆G > 15 kJ mol−1). The same is true for the imino N (X), particularly for N derivatives, where the electron-accepting effect of the imino C=N(Z) group increases ∆Gs between the cyano and imino (X) protonated forms. An exception is the diguanidino CH derivative I.11, for which some isomers of the Nimino (guanidino) protonated forms (∆G < 20 kJ mol−1) cannot be neglected in the isomeric mixture. A tentative explanation for this phenomenon is the polarizability effect of Me-groups in I.11 that increases the PA of imino N(X) to a higher degree than that of cyano N (Table S5 in SM). When compared to I.10, the ∆Gs decrease for isomers a–c of I.11.

diguanidino CH derivative I.11, for which some isomers of the Nimino (guanidino) protonated forms (ΔG < 20 kJ mol−1) cannot be neglected in the isomeric mixture. A tentative explanation for this phenomenon is the polarizability effect of Me-groups in I.11 that increases the PA of imino N(X) to a higher degree than that of cyano N (Table S5 in SM). When compared to I.10, the ΔGs decrease for isomers a–c of I.11.

3.4. Gas-Phase Basicity of N Atoms in Isomers For compounds I.2 and II.2, for which two types of isomerism (geometrical about a double C=C or C=N bond and rotational about a single C–C bond) can be considered for neutral (Chart S1 in SM) and monoprotonated forms (Chart S3 in SM), we calculated the Symmetry 2021, 13, 1554 9 of 23 basicity parameters, namely the PAs and GBs (Table S5 in SM), for each potential site of protonation (cyano and imino N atoms) in four isomers (a–d). Comparing the theDFT basicity-calculated parameters, PAs namely for two the pairs PAs and of GBsisomers, (Table a S5 and in SM), b and for eachseparately potential c and d (Figure 3), sitethe of effects protonation of E/Z (cyano isomerism and imino on N basicity atoms) in of four the isomers cyano ( aN–d atom). Comparing are slightly the stronger for the DFT-calculatedsecond pair PAsof these for two isomers pairs of isomers,(ca. 10 kJa and molb −1and) than separately for thec and firstd (Figure one (3),–6 kJ mol−1). On the the effects of E/Z isomerism on basicity of the cyano N atom are slightly stronger for the secondother pairhand, of these comparing isomers (ca. the 10 PAs kJ mol of− 1the) than two for other the ﬁrst pairs one (3–6 of isomers, kJ mol−1). a On and the c and separately b otherand hand,d, the comparing effects the of PAs rotational of the two isomerism other pairs of seem isomers, toa and be c slightlyand separately weakerb (1–2 and 6–7 kJ andmold−1, the, respectively) effects of rotational than isomerism those seem of E/Z to be isomerism. slightly weaker Generally, (1–2 and 6–7 kJthe mol structural−1, (isomeric) respectively) than those of E/Z isomerism. Generally, the structural (isomeric) effects on −1 effects on PA(Ncyano) are not very strong for I.2 and−1 II.2 (ΔPA  10 kJ mol ). For II.2, the PA(Ncyano) are not very strong for I.2 and II.2 (∆PA ≤ 10 kJ mol ). For II.2, the analogous analogous effects on PA(Nimino) are only slightly stronger; ΔPAs−1 do not exceed 13 kJ mol−1. effects on PA(Nimino) are only slightly stronger; ∆PAs do not exceed 13 kJ mol .

807.6 CN 815.1 CN Z Z 828.3 834.0 796.0 CN 808.4 854.7 851.7 CN Z 832.0 Z 822.4 855.8 845.1

2a 2b 2c 2d FigureFigure 3. Variations3. Variations of PAs of estimated PAs estimated at the DFT1 at levelthe DFT1 (in kJ mol level−1 at (in 298 kJ K) mol for−1 N at atoms 298 inK) four for N atoms in four isomersisomers (2a (–22da)– of2dI.2) of(Z: I.2 CH, (Z: in normalCH, in style) normal and II.2style)(Z: N,and shown II.2 in (Z: italics). N, shown in italics).

For I.8 and II.8 containing the CPC or CPN scaffold with two NH2 groups, gas- phase basicityFor I.8 values and were II.8 estimated containing for the the cyano, CPC imino, or and CPN amino scaffold N atoms. Figure with4 two NH2 groups, presentsgas-phase the PAsbasicity calculated values for these were sites. estimated When we compare for the the cyano, PAs estimated imino, for and N amino N atoms. atoms in I.8 and II.8 to those estimated at the same level of theory (DFT1) for cross-n- Figure 4 presents the PAs calculated for these sites. When we compare the PAs estimated π-conjugated derivatives without the CPC or CPN fragment, (H2N)2C=CH–C≡N and (Hfor2N) N2C=N–C atoms≡ N[ in6 ]I.8, we and can see II.8 that to the thoseCPC or estimatedCPN part increases at the the same PA of level the cyano of theory (DFT1) for −1 −1 Ncross atom-n in-I.8π-conjugatedand II.8 by ca. derivatives 60 kJ mol . To without a higher degreethe CPC (by ca. or 70 CPN kJ mol fragment,), this part (H2N)2C=CH–C≡N also increases the PA of the imino N atom in II.8, but it does not change the general order and (H2N)2C=N–C≡N [6], we can see that the CPC or CPN part increases the PA of the of basicity parameters: PA(Ncyano) > PA(N ) > PA(N ). All of these increases of imino −1amino −1 gas-phasecyano N basicity atom forin theI.8 iminoand II.8 and by cyano ca. N 60 atoms kJ mol give information. To a higher about degree the particular (by ca. 70 kJ mol ), this transmissionpart also increases of the electron-donating the PA of (push)the imino effects N of twoatom NH in2 groups II.8, but through it does the CPC notor change the general CPNordertransmitter of basicity to C=N parameters: and next to C PA(N≡N, andcyano also) > about PA(N particularimino) > electron PA(N delocalizationamino). All of these increases of effectsgas-phase in the system.basicity Note for that the the iminoCPC orandCPN cyanopart only N atoms slightly give changes information the PAs of the about the particular amino N atoms (by 0–15 kJ mol−1). The PAs estimated for the amino groups in I.8 and II.8transmissionare considerably of the lower electron (by 50–100-donating kJ mol−1) (push) than the effects experimental of two PA ofNH ammonia2 groups at through the CPC −1 Symmetry 2021, 13, x FOR PEER REVIEW853.6or CPN kJ mol transmitter[3]. This observation, to C=N together and with next earlier to C reports≡N, on and strong also PA aboutdecreases particular10 electronof 23 fordelocalization amino groups in effects push–pull in the nitriles system. [5,6], allows Note us that to omit the PACPC estimations or CPN for part all NH only2 slightly changes and for all NMe groups in other derivatives. the PAs of the2 amino N atoms (by 0–15 kJ mol−1). The PAs estimated for the amino groups in I.8 and II.8 are considerably lower (by 50–100 kJ mol−1) than the experimental PA of CN 971.5 975.6 −1 ammonia935.3 Z at 853.6 kJ mol [3]. This observation, together with earlier reports on strong CN 913.6 PA decreases for amino groups in 91push7.8 –pull nitriles [5,6], allows us to omit PA 788.7 797.2 864.9 Z estimations for all NH2 and for all NMe2 groups in other derivatives. 759.2 761.9 785.8 797.6 H2N NH2 755.4 H2N NH2 747.0 Z: CH (I.8), N (II.8) Taken from ref. [6] FigureFigure 4. Comparison4. Comparison of PAs of estimated PAs estimated at the DFT1 at the level DFT1 (in kJ level mol− 1(inat kJ 298 mol K) for−1 at N 298 atoms K) in forI.8 N atoms in I.8 (Z: (Z:CH) CH) and and II.8II.8 (Z:(Z: N, N, values values in italics)in italics with) with those foundthose previouslyfound previously at the same at level the ofsame theory level for of theory for analogousanalogous cross-n- crossπ-conjugated-n-π-conjugated derivatives derivatives without CPC withoutor CPN CPCfragments. or CPN fragments. Taking into account the rotational isomerism of substituent X about the single C– X bondTaking for neutral into (Chart account S2 inthe SM) rotational and monoprotonated isomerism formsof substituent (Chart S5 inX SM)about of the single C–X disubstitutedbond for neutralCPC or CPN (Chartderivatives S2 in SM) bearing and large monoprotonated groups (I.10–I.12 and formsII.10 – (ChartII.12), S5 in SM) of disubstituted CPC or CPN derivatives bearing large groups (I.10–I.12 and II.10–II.12),

we calculated the PAs and GBs for the potential sites of protonation (Ncyano and Nimino) in possible individual isomers, where substituent X adopts a syn or anti conformation regarding Z=N. The basicity data (PA and GB) estimated by the DFT1 or DFT2 methods are included in Table S5 (SM). Since the neutral isomer d of I.10–I.12 and II.10–II.12 is not stable and during optimization goes to another more stable isomer (b or c) or to another molecule, PAs and GBs are given in Table S5 (SM) only for three rotamers (a–c). Some exceptions were also found for cyano-N-protonated II.12c, which is not stable at the DFT2 level and after optimization transforms into II.12b. This observation shed some light on the energy barrier of the CNH+ group rotation about the C=Z bond. This barrier seems to be negligible in the protonated form. The differences in PAs for extreme rotamers a–c of I.10–I.12 and II.10–II.12 are considerably larger than those for conformational isomers of compounds I.2 and II.2 (Table S5 in SM). For the favored site of protonation (Ncyano) in CH derivatives, the strongest effect (ΔPA 34 kJ mol−1) is observed for isomers of I.10 possessing two N=C(NH2)2 groups, for which PA varies from 985 (isomer a) to 1019 kJ mol−1 (isomer b), and the weakest effect (ΔPA 22 kJ mol−1) for isomers of I.12 containing two N=P(NMe2)3 groups, for which PA varies from 1066 (isomer a) to 1088 kJ mol−1 (isomer b). For isomers of I.11 with two N=C(NMe2)2 groups, the difference in PAs (27 kJ mol−1) is lower than that for isomers of I.10, although larger than that for isomers of I.12. Analogous PA variations are found for isomers of N derivatives (37, 28, and 22 kJ mol−1 for II.10, II.11, and II.12, respectively). For the N-imino sites, changes in the conformation of X substituents lead to ΔPAs higher than 20 kJ mol−1 and lower than 40 kJ mol−1 for the CH derivative. The differences in PAs for individual isomers quantitatively inform us about the strong sensitivity of N-sites in terms of structural changes in compounds with large flexible substituents. They also provide information how significant errors can be made in PA prediction when conformational analysis is not considered and when PA is calculated only for rotamers of neutral and protonated forms that do not correspond to true energy minima. For example, on the basis of DFT calculations performed only for conformation a of I.11a (Figure 5), one could conclude that the CH derivative does not belong to the family of nitriles, because PA(Ncyano) is lower (by ca. 11 kJ mol−1) than the PA of the imino N atom in the guanidino group at the syn-position regarding C≡N.

C N C N C N 1017.2 Z 1023.2 1031.8 Z 1050.2 1041.1 Z 1035.6 1033.5 1061.3 1046.8 1021.1 1015.3 (Me2N)2C C(NMe2)2 (Me2N)2C 1036.2 C(NMe2)2 N N N N 1019.6 N N 1021.1 1034.4 1000.1 1014.4 1016.2 1021.6 993.3 C(NMe2)2 C(NMe2)2 1000.6 11a 11b 11c Figure 5. Variations of PAs estimated at the DFT2 level (in kJ mol−1 at 298 K) for N atoms in three rotamers (11a–11c) of diguanidino derivatives (I.11 (Z: CH) and II.8 (Z = N, values in italics)).

Symmetry 2021, 13, x FOR PEER REVIEW 10 of 23

971.5 CN 975.6 935.3 Z 913.6 CN 917.8 788.7 797.2 864.9 Z 759.2 761.9 785.8 797.6 H2N NH2 755.4 H2N NH2 747.0 Z: CH (I.8), N (II.8) Taken from ref. [6] Figure 4. Comparison of PAs estimated at the DFT1 level (in kJ mol−1 at 298 K) for N atoms in I.8 (Z: CH) and II.8 (Z: N, values in italics) with those found previously at the same level of theory for analogous cross-n-π-conjugated derivatives without CPC or CPN fragments.

Taking into account the rotational isomerism of substituent X about the single C–X Symmetry 2021, 13, 1554 10 of 23 bond for neutral (Chart S2 in SM) and monoprotonated forms (Chart S5 in SM) of disubstituted CPC or CPN derivatives bearing large groups (I.10–I.12 and II.10–II.12), we calculated the PAs and GBs for the potential sites of protonation (Ncyano and Nimino) in wepossible calculated individual the PAs isomers, and GBs where for the substituent potential sites X ofadopt protonations a syn or (N cyanoanti andconformation Nimino) inregarding possible Z=N. individual The basicity isomers, data where (PA substituentand GB) estimated X adopts by a thesyn DFT1or anti orconformation DFT2 methods regardingare included Z=N. in Table The basicity S5 (SM). data Since (PA the and neutral GB) estimated isomer d byof I.10 the– DFT1I.12 and or DFT2 II.10– methodsII.12 is not arestable included and during in Table optimization S5 (SM). Since goes the to neutral another isomer mored stableof I.10 isomer–I.12 and (b II.10or c)– orII.12 to anotheris not stablemolecule, and duringPAs and optimization GBs are given goes in to Table another S5 more(SM) stableonly for isomer three ( brotamersor c) or to(a another–c). Some molecule,exceptions PAs we andre also GBs found are given for cyano in Table-N- S5protonated (SM) only II.12c for three, which rotamers is not ( a stable–c). Some at the exceptionsDFT2 level were and also after found optimization for cyano-N-protonated transforms intoII.12c II.12b, which. This is observationnot stable at the shed DFT2 some levellight andon the after energy optimization barrier of transforms the CNH+ into groupII.12b rotation. This observationabout the C=Z shed bond. some This light barrier on + theseems energy to be barrier negligible of the in CNH the protonategroup rotationd form. about the C=Z bond. This barrier seems to be negligibleThe differences in the protonated in PAs for form. extreme rotamers a–c of I.10–I.12 and II.10–II.12 are The differences in PAs for extreme rotamers a–c of I.10–I.12 and II.10–II.12 are consid- considerably larger than those for conformational isomers of compounds I.2 and II.2 erably larger than those for conformational isomers of compounds I.2 and II.2 (Table S5 (Table S5 in SM). For the favored site of protonation (Ncyano) in CH derivatives, the in SM). For the favored site of protonation−1 (Ncyano) in CH derivatives, the strongest effect strongest effect−1 (ΔPA 34 kJ mol ) is observed for isomers of I.10 possessing two (∆PA 34 kJ mol ) is observed for isomers of I.10 possessing two N=C(NH2)2 groups, for N=C(NH2)2 groups, for which PA varies from 985 (isomer a) to 1019 kJ mol−1 (isomer b), which PA varies from 985 (isomer a) to 1019 kJ mol−1 (isomer b), and the weakest effect and the weakest effect (ΔPA 22 kJ mol−1) for isomers of I.12 containing two N=P(NMe2)3 (∆PA 22 kJ mol−1) for isomers of I.12 containing two N=P(NMe ) groups, for which PA 2 3−1 variesgroups, from for which 1066 (isomer PA variesa) tofro 1088m 1066 kJ mol(isomer−1 (isomer a) to 1088b). kJ For mol isomers(isomer of I.11 b). Forwith isomers two of I.11 with two N=C(NMe2)2 groups, the difference in−1 PAs (27 kJ mol−1) is lower than that N=C(NMe2)2 groups, the difference in PAs (27 kJ mol ) is lower than that for isomers of I.10for ,isomers although of largerI.10, although than that larger for isomers than that of I.12 for. isomers Analogous of I.12 PA. variationsAnalogous are PA found variations for isomersare found of Nfor derivatives isomers of (37,N derivatives 28, and 22 kJ(37, mol 28,− 1andfor II.1022 kJ, II.11mol−1, andfor II.10II.12,, II.11 respectively)., and II.12, Forrespectively). the N-imino For sites, the N changes-imino insites, the changes conformation in the of conformation X substituents of leadX substituents to ∆PAs higher lead to thanΔPAs 20 higher kJ mol than−1 and 20 lowerkJ mol than−1 and 40 lower kJ mol than−1 for 40 thekJ mol CH−1 derivative. for the CH derivative. TheThe differences differences in in PAs PAs for for individual individual isomers isomers quantitatively quantitatively inform inform us us about about the the strongstrong sensitivity sensitivity of of N-sites N-sites in termsin terms of structural of structural changes changes in compounds in compounds with large with ﬂexible large substituents.flexible substituents. They also They provide also provide information information how signiﬁcant how significant errors can errors be made can be in made PA predictionin PA prediction when conformational when conformational analysis is not analysis considered is not and considered when PA is and calculated when onlyPA is forcalculated rotamers only of neutral for rotamers and protonated of neutral forms and that protonated do not correspond forms that to do true not energy correspond minima. to Fortrue example, energy minima. on the basis For ofexample, DFT calculations on the basis performed of DFT only calculations for conformation performeda of onlyI.11a for (Figureconformation5), one coulda of I.11a conclude (Figure that 5), the one CH could derivative conclude does that not the belong CH derivative to the family does of not −1 nitriles,belong to because the family PA(N ofcyano nitriles,) is lower because (by ca.PA(N 11 kJcyano mol) is lower) than (by the ca. PA 11 of kJ the mol imino−1) than N atomthe PA inof thethe guanidinoimino N atom group in atthe the guanidinosyn-position group regarding at the syn C≡-positionN. regarding C≡N.

C N C N C N 1017.2 Z 1023.2 1031.8 Z 1050.2 1041.1 Z 1035.6 1033.5 1061.3 1046.8 1021.1 1015.3 (Me2N)2C C(NMe2)2 (Me2N)2C 1036.2 C(NMe2)2 N N N N 1019.6 N N 1021.1 1034.4 1000.1 1014.4 1016.2 1021.6 993.3 C(NMe2)2 C(NMe2)2 1000.6 11a 11b 11c FigureFigure 5.5. VariationsVariations ofof PAsPAs estimated estimated at at the the DFT2 DFT2 level level (in (in kJ kJ mol mol−−11 at 298 K) for N atomsatoms inin threethree rotamersrotamers ((11a11a––11c11c)) of of diguanidino diguanidino derivatives derivatives (I.11 (I.11(Z: (Z: CH) CH) and andII.8 II.8(Z (Z = N,= N, values values in in italics)). italics)).

3.5. Substituent Effects in the Simple Nitrile Series On the basis of our DFT calculations, we considered all compounds studied as functional nitriles in the gas phase, because protonation occurs on the nitrile group. Conse- quently, we investigated the substituent effects in the two series of nitriles (I and II). First, we compared the PAs of acyclic and cyclic nitriles containing H2C=CH–CH=Z (2) and (HC)2C=Z (3) with those possessing the simplest π-electron group, H2C=Z(1). Compounds 2 and 3 are the π-π-conjugated systems and have the same numbers of heavy atoms and π-electrons, although they exhibit completely different PAs. When proceeding from I.1 to I.2 and I.3, and also from II.1 to II.2 and II.3, the total electronic effects for the cyclic part (HC=CH closed in the ring) in I.3 and II.3 (ca. 90 kJ mol−1) are about twice those −1 for the acyclic part (H2C=CH in acyclic group) in I.2 and II.2 (ca. 40 kJ mol ). The analogous effects of the HC=CH part in the ring increase the PAs of I.6 and II.6 (by ca. Symmetry 2021, 13, x FOR PEER REVIEW 11 of 23

3.5. Substituent Effects in the Simple Nitrile Series On the basis of our DFT calculations, we considered all compounds studied as functional nitriles in the gas phase, because protonation occurs on the nitrile group. Consequently, we investigated the substituent effects in the two series of nitriles (I and II). First, we compared the PAs of acyclic and cyclic nitriles containing H2C=CH–CH=Z (2) and (HC)2C=Z (3) with those possessing the simplest π-electron group, H2C=Z (1). Compounds 2 and 3 are the π-π-conjugated systems and have the same numbers of heavy atoms and π-electrons, although they exhibit completely different PAs. When proceeding from I.1 to I.2 and I.3, and also from II.1 to II.2 and II.3, the total electronic effects for the cyclic part (HC=CH closed in the ring) in I.3 and II.3 (ca. 90 kJ mol−1) are about twice those for the acyclic part (H2C=CH in acyclic group) in I.2 and II.2 (ca. 40 kJ mol−1). The analogous effects of the HC=CH part in the ring increase the PAs of I.6 and II.6 (by ca. 90 kJ mol−1) when going from I.5 and II.5, respectively. Interestingly, the π-π-conjugated compounds I.4 and II.4 possess higher PAs (by 20–30 kJ mol−1) than their constitutional isomers I.5 and II.5. This analysis of substituent effects on the PAs of simple nitriles evidently showed an exceptionally large increase in basicity for Symmetry 2021, 13, 1554 derivatives containing CPC, methylene-1,3,5-cycloheptatriene,11 of 23 methylenequinoid, methylenequinoidcyclopropene, and their heteroanalog-transmitting systems. The basicity orders of the investigated nitriles are a consequence of their exceptional internal −1 90electronic kJ mol ) when effects going, which from I.5 areand II.5discussed, respectively. in detail Interestingly, below. the π-π-conjugated compounds I.4 and II.4 possess higher PAs (by 20–30 kJ mol−1) than their constitutional isomersAssessmentI.5 and II.5. This of analysis the gas of- substituentphase basicity effects on data the PAs for of all simple simple nitriles derivatives evi- of series I and II dentlysummarized showed an exceptionally in Table S5alarge increase (SM) ledin basicity to additional for derivatives observations containing CPC, concerning gas-phase methylene-1,3,5-cycloheptatriene, methylenequinoid, methylenequinoidcyclopropene, and theirinternal heteroanalog-transmitting effects. The total systems. electronic The basicity substituent orders of theeffects investigated, measured nitriles as differences between arethe a consequencePAs of simple of their nitriles exceptional of internalseries electronicI and II effects, (compounds which are discussed1–9, including in only 2a) and that detailof HCN below. calculated at the same level of theory, vary from ca. 90 kJ mol−1 for 1 to ca. 300 kJ Assessment of the gas-phase basicity data for all simple derivatives of series I and II −1 summarizedmol for in9 Table (Figure S5a (SM) 6). led toThe additional greater observations size of concerning the π gas-phase-π-conjugated internal group and stronger effects.electronic The total pushing electronic effects substituent of effects,n-π-conjugated measured as differences X substituents between theare PAs related to the higher PA ofvalues. simple nitrilesMoreover, of series replacementI and II (compounds of the1–9, includingCH group only in2a) series and that I of by HCN the imino N (Z) atom in calculated at the same level of theory, vary from ca. 90 kJ mol−1 for 1 to ca. 300 kJ mol−1 for 9series(Figure 6II). Thedoes greater not size always of the π -affectπ-conjugated the groupbasicity and stronger of nitriles electronic in pushing the same way. For example, effectsdifferences of n-π-conjugated between X substituents PAs of are the related CPC to thederivatives higher PA values. I.3 Moreover,and I.7–I.9 and of the CPN replacement of the CH group in series I by the imino N (Z) atom in series II does not −1 alwaysderivatives affect the II.3 basicity and of II.7 nitriles–II.9 in theare same close way. to For those example, between differences PAs between of I.1 and II.1 (<10 kJ mol ), PAswhereas of the CPC thosederivatives betweenI.3 and theI.7–I.9 otherand of theπ-πCPN-conjugatedderivatives II.3 derivativesand II.7–II.9 are are considerable higher, −1 closebeing to thoseclose between to 20 PAs and of I.130and kJ II.1mol(<10−1 for kJ mol acyclic), whereas (I.2 thoseand betweenII.2) and the othercyclic (I.4–I.6 and II.4–II.6) π-π-conjugated derivatives are considerable higher, being close to 20 and 30 kJ mol−1 for acyclicmolecules, (I.2 and II.2respectively.) and cyclic (I.4 –I.6 and II.4–II.6) molecules, respectively.

300 DPA 250 [kJ/mol] 200

150

100

series I 50 series II 0 1 2 3 4 5 6 7 8 9 Compound

FigureFigure 6. Variations 6. Variations of PAs relativeof PAs to relative HCN estimated to HCN at the estimated DFT1 level for at Z: the CH (DFT1I.1–I.9) andlevel Z: Nfor Z: CH (I.1–I.9) and Z: N −1 ((II.1II.1–II.9–II.9) derivatives) derivatives (∆PA in kJ(Δ molPA inat kJ 298 mol K). −1 at 298 K). This variations of the relative PAs indicate that the electron-donating effects of π-π- conjugatedThis groups variation in seriessI ofof simple the nitriles relative1–9 containing PAs indicate different transmitter that the parts electron are -donating effects of not identical but somewhat parallel to those in series II; however, we can distinguish some subfamiliesπ-π-conjugated for the investigation groups ofin substituent series I effects, of simple with one nitriles subfamily 1 containing–9 containi com-ng different transmitter poundsparts 4 are, 5, and not6 (1,3,5-cycloheptatriene, identical but somewhat quinoid, and parallel quinoid cyclopropene to those derivatives, in series II; however, we can respectively),distinguish for somewhich the subfamilies electron-donating for effect the is considerablyinvestigation stronger of in substituent series II effects, with one than in series I; and the other subfamily with compounds 3, 7, 8, and 9, for which the differ- encessubfamily in electron-donating containing effects compounds in series I and II are4, smaller5, and than those6 (1,3,5 for the-cycloheptatr ﬁrst family iene, quinoid, and butquinoid analogous cyclopropene to those in CH and derivatives N derivatives, ofrespectively1 (see Figure S4), in for SM). which Interestingly, the electron all -donating effect is simpleconsiderably nitriles 3, 7 , 8 stronger, and 9 in the in second series subfamily II than possess in a cyclopropene series I; partand with the two other subfamily with X (X: H, Me, NH2, and NMe2). Taking this simple observation into account, we included derivatives (10–12) containing larger X substituents (X: N=C(NH2)2, N=C(NMe2)2, and N=P(Nme2)3), for which the effects of isomerism on PAs were investigated. In this way, we could directly compare the total electronic effects of all X substituents in series I of CPC derivatives with those in the CPN series II. Symmetry 2021, 13, x FOR PEER REVIEW 12 of 23

compounds 3, 7, 8, and 9, for which the differences in electron-donating effects in series I and II are smaller than those for the first family but analogous to those in CH and N derivatives of 1 (see Figure S4 in SM). Interestingly, all simple nitriles 3, 7, 8, and 9 in the second subfamily possess a cyclopropene part with two X (X: H, Me, NH2, and NMe2). Taking this simple observation into account, we included derivatives (10–12) containing larger X substituents (X: N=C(NH2)2, N=C(NMe2)2, and N=P(Nme2)3), for which the effects of isomerism on PAs were investigated. In this way, we could directly compare the total electronic effects of all X substituents in series I of CPC derivatives with those in the CPN series II.

3.6. Substituent Effects in the Methylenecyclopropene and Cyclopropeneimine Series Symmetry 2021, 13, 1554 12 of 23 For investigation of the substituent effects in the CPC (I.7–I.12) and CPN series (II.7– II.12), we used the unsubstituted CH (I.3) and N (II.3) compounds as reference (parent) molecules. We calculated the differences between the PA of substituted derivatives (or its 3.6. Substituent Effects in the Methylenecyclopropene and Cyclopropeneimine Series isomers) and the PA of the parent molecules. These differences, abbreviated as δPA, For investigation of the substituent effects in the CPC (I.7–I.12) and CPN series (correspondII.7–II.12), we to used the thetotal unsubstituted substituent CH effects (I.3) andof two N (II.3 X )groups compounds in CPC as reference and CPN derivatives. (parent)They vary molecules. from We 0 calculated (for H) the to differences ca. 200 between kJ mol the−1 PA(for of substituted two phosphazeno derivatives groups in b (orconformation). its isomers) and S theince PA the of the basicity parent molecules. data found These at differences, the DFT1 abbreviated and DFT2 as δ PA,levels for simple correspondderivatives to d theidtotal not substituentdiffer significantly effects of two (differences X groups in CPCin PAsand CPNlowerderivatives. than 0.5 kJ mol−1), we −1 Theycompared vary from the 0 (for estimated H) to ca. δ 200PAs kJ mol of CH(for derivatives two phosphazeno with groups those in ofb conforma- N derivatives, without tion). Since the basicity data found at the DFT1 and DFT2 levels for simple derivatives didindication not differ of significantly the DFT method (differences used in PAsfor lowercalculation than 0.5, as kJ molshown−1), wein comparedFigure 7. We found an theinteresting estimated linearδPAs ofrelationship CH derivatives between with those δPAs of Ndetermined derivatives, for without series indication I and II. The slope of ofthe the regression DFT method line used forclose calculation, to unity as shown (correlation in Figure coefficient7. We found anR interesting= 0.998) indicates that linearintroducti relationshipon of between the NδPAs imino determined atom for in series seriesI and IIII .does The slope not of thesignificantly regression perturb π-π line close to unity (correlation coefficient R = 0.998) indicates that introduction of the N iminoconjugation atom in seriesor transmissionII does not significantly of substituent perturb (pushing)π-π conjugation effects or through transmission the of π-π-conjugated substituentsystems to (pushing) the cyano effects N site. through the π-π-conjugated systems to the cyano N site.

200

150

) [kJ/mol] ) II 100

dPA(II) = 1.02dPA(I) − 2.14 50

R = 0.998 PA(series

0 0 50 100 150 200 dPA(series I) [kJ/mol]

− Figure 7. 7.Linear Linear relationship relationship between between the total the substituent total substituent effects (δPA effects in kJ mol (δPA1 at in 298 kJ K) mol in the−1 at 298 K) in the methylenecyclopropene series series (I) and (I in) and the cyclopropenimine in the cyclopropenimine series (II) estimated series ( atII) the estimated DFT1 or at the DFT1 or DFT2 level. level. The strong electron-donating effects of the two X substituents (push–pull cross-effects) can additionallyThe strong explain electron the higher-donating PA/GB values effects of disubstituted of the versustwo unsubstitutedX substituents se- (push–pull riescrossI and-effects)II. As expected,can additionally the orders ofexplain basicity increasethe higher for series PA/GBI and valuesII are analogous of disubstituted to versus thatunsubstituted for nitriles X–C series≡N, substituted I and II. directlyAs expected, by the X group,the orders containing of basicity H, Me, NH increase2, NMe2 ,for series I and N=C(NH2)2, N=C(NMe2)2, and N=P(NMe2)3 [6]. Conformation of the large substituents, andII are consequently analogous favorable to that and for unfavorable nitriles intramolecular X–C≡N, substituted interactions directly of functional by the X group, groups,containing are additional H, Me, signiﬁcant NH2, (but NMe not2, main) N=C(NH factors2)2 that, N=C(NMe affect basicity2)2, parameters and N=P(NMe2)3 [6]. forConformation investigated disubstituted of the largCPCe substituents,and CPN derivatives. and consequently Figure8 shows the favorable linear trend and unfavorable (intramolecularR > 0.95) between interactions the DFT-estimated of functional PAs of series groupsI and, IIareand additional X–C≡N studied significant previ- (but not main) I II CPC ouslyfactors [6]. that The cross-push–pull affect basicity effects parameters of the two X for substituents investigated in series disubstitutedand ( and CPC and CPN CPN derivatives, respectively) seem to be attenuated by the cyclo-C2C=Z scaffold (slope derivatives. Figure 8 shows the linear trend (R > 0.95) between the DFT-estimated PAs of ca. 0.6). For a more limited series of substituents (X: H, NH2, NMe2, data from Table1 and ref.series [6]), I the and comparison II and X of–C calculated≡N studied PAs forpreviously the two disubstituted [6]. The cross cyclopropene-push–pull systems effects of the two cyclo-XX substituents2C2C=Z–C ≡inN andseries X2C=Z–C I and≡ NII (substituted(CPC and by CPN3 and derivatives,1, respectively) respectively) give a slope seem to be (Figure8) of 0.7, which can be viewed as a transmission factor of substituent effects (see attenuated by the cyclo-C2C=Z scaffold (slope ca. 0.6). For a more limited series of Figure S5 in SM). The cyclopropene scaffolds somewhat reduce the electron donor effect assubstituents compared to direct(X: H, substitution NH2, NMe in X–C2, ≡ dataN or from to transmission Table 1 by and intercalating ref. [6] the), the C=Z comparison of double bond. Nevertheless, the substituted CPC and CPN molecules still present PAs larger than X–C≡N and X2C=Z–C≡N analogs. This is due to the basicity enhancement of the nitrile functional group by the intrinsic effects (polarizability and resonance) of the scaffold cyclo-X2C2C=Z. Symmetry 2021, 13, x FOR PEER REVIEW 13 of 23

calculated PAs for the two disubstituted cyclopropene systems cyclo-X2C2C=Z–C≡N and X2C=Z–C≡N (substituted by 3 and 1, respectively) give a slope (Figure 8) of 0.7, which can be viewed as a transmission factor of substituent effects (see Figure S5 in SM). The cyclopropene scaffolds somewhat reduce the electron donor effect as compared to direct substitution in X–C≡N or to transmission by intercalating the C=Z double bond. Nevertheless, the substituted CPC and CPN molecules still present PAs larger than X– C≡N and X2C=Z–C≡N analogs. This is due to the basicity enhancement of the nitrile Symmetry 2021, 13, 1554 functional group by the intrinsic effects (polarizability and13 resonance) of 23 of the scaffold cyclo-X2C2C=Z.

1200

PA(X2C2C=ZCN) = 0.59PA(XCN) + 469.1

1100 R = 0.967 C=ZCN)

2 1000

2 [kJ/mol]

900 series I PA(X series II

800 600 700 800 900 1000 1100 PA(XCN) [kJ/mol]

FigureFigure 8. 8.Linear Linear trend trend between between DFT-estimated DFT-estimated PAs of disubstituted PAs of cyclopropenedisubstituted derivatives cyclopropene derivatives X2C2C=Z–CN and X–CN (X: H, Me, NH2, NMe2, N=C(NH2)2, N=C(NMe2)2, and N=P(NMe2)3). X2C2C=Z–CN and X–CN (X: H, Me, NH2, NMe2, N=C(NH2)2, N=C(NMe2)2, and N=P(NMe2)3). 3.7. Changes in Electron Delocalization Caused by Protonation 3.7.Electron Changes delocalization in Electron in Delocalization organic conjugated Caused systems by can Protonation be related totheir bond lengths. For delocalized systems, single and double bond lengths are usually different from those forElectron the corresponding delocalization non-conjugated in organic molecules. conjugated Depending onsystems the conjugation can be related to their bond strength,lengths. they For are delocalized more or less close systems, to those single of aromatic and systems double (e.g., bond CC 1.394 lengths and are usually different CN 1.334 Å for benzene and s-triazine, respectively, calculated at the DFT1 level) [51]. Observationsfrom those of DFT-calculated for the corre geometricsponding parameters non for- simpleconjugatedπ-π-conjugated molecules. nitriles Depending on the andconjugation imino nitriles, strength, as well as forthey more are complex more disubstituted or less closeCPC andto CPNthosederivatives, of aromatic systems (e.g., CC show1.394 signiﬁcant and CN variations 1.334 ofÅ single for benzene and double and bond s lengths-triazine, when respectively, proceeding from calculated at the DFT1 neutral to protonated forms; for example, the Z=C double bond lengthens and the Z–Ccyano singlelevel) bond [51 shortens]. Observations (see Table S6 in SM forof selectedDFT nitriles).-calculated Analogous geometric changes also take parameters for simple placeπ-π- forconjugated other single andnitriles double and bonds imino in investigated nitriles systems., as well Generally, as for more single bondscomplex disubstituted CPC shorten and double bonds lengthen. This alternation is a consequence of differences in resonanceand CPN hybrids derivatives for the neutral, show and protonated significant forms variations(Scheme S1 in SM),of single but does and not double bond lengths leadwhen to full proceeding equalization offrom bond neutral lengths—even to prot for cycliconated fragments—as forms; f itor does example, benzene the Z=C double bond and s-triazine. lengthens and the Z–Ccyano single bond shortens (see Table S6 in SM for selected nitriles). To quantitatively describe changes in electron delocalization for simple neutral and cyanoAnalogous N protonated changes derivatives, also the take geometry-based place for otherHOMED single index [51 and,54] doublehas been bonds in investigated applied.systems. Based Generally, on the geometries, single bonds optimized shorten at the DFT1 and level,double HOMEDs bonds have lengthen. been This alternation is a calculated for selected fragments using equation (3) and parameters from Table S4 (SM). Generally,consequence the estimated of differences HOMEDs increase in resonance when the number hybrids of heavyfor the atoms neutral and π and protonated forms bonds(Scheme increase, S1 andin SM), also when but proceedingdoes not from lead the to neutral full equalization to cyano N protonated of bond forms lengths—even for cyclic (fragmentsFigure9 ). Moreover,—as it theydoes are ben higherzene for and the cyclic s-triazine. derivatives I.3 and II.3 than for the acyclic ones I.2 and II.2 containing the same number of heavy atoms and π bonds. They are also higherTo quantitatively for cyclic I.4 and II.4 describethan for cyclic changesI.5 and II.5 in, bothelectron being isomericdelocalization forms, and for simple neutral and additionallycyano N for protonated bicyclic I.6 and derivatives,II.6 than for monocyclic the geometryI.5 and II.5-.based The highest HOMED HOMEDs index [51,54] has been (>0.9),applied. close Basedto those for on aromatic the geometries, compounds (HOMED optimized≈ 1), areat foundthe DFT1 for the level,entire HOMEDs have been group R in R–C≡NH+ of I.3, II.3, I.4, II.4, I.6, and II.6 as well as for their cyclic fragment(s). Forcalculated these monocations, for selected we can distinguishfragments the using resonance equation structures (3) with and well parameters delocalized from Table S4 (SM). 3-memberedGenerally, (cyclopropenyl) the estimated and 7-membered HOMEDs cyclic increase (cycloheptatrienyl) when the cations number as well of heavy atoms and π as of the neutral benzene ring (Scheme S1 in SM). This tendency conﬁrms strong electron delocalizationbonds increase, in the cyclic and fragmentsalso when that becomeproceeding aromatic from for unsubstituted the neutral systems. to cyano N protonated forms (FigureIn the 9). case Moreover, of CPC and CPN theyderivatives are higher substituted for the by two cyclic X groups derivatives (I.7–I.12 and I.3 and II.3 than for the II.7acyclic–II.12): ones Me, NH I.22, NMeand2 ,II.2 N=C(NH containing2)2, N=C(NMe the2 )same2, and N=P(NMenumber2) 3of, substituents heavy atoms X and π bonds. They additionally participate in electron and charge delocalization (Scheme S2 in SM). The Me groupsare also are σ - higherπ hyperconjugated for cyclic and theI.4 other and groups II.4 arethan n-π conjugated for cyclic with I.5 the and ring, andII.5, both being isomeric nextforms, with theand cyano additionally group. Hence, for larger bicyclic number ofI.6 resonance and II.6 structures than can for be monocyclic written I.5 and II.5. The highest HOMEDs (>0.9), close to those for aromatic compounds (HOMED  1), are found for the entire group R in R–C≡NH+ of I.3, II.3, I.4, II.4, I.6, and II.6 as well as for their cyclic fragment(s). For these monocations, we can distinguish the resonance structures with well delocalized 3-membered (cyclopropenyl) and 7-membered cyclic (cycloheptatrienyl) cations as well as of the neutral benzene ring (Scheme S1 in SM). This

Symmetry 2021, 13, 1554 14 of 23

Symmetry 2021, 13, x FOR PEER REVIEW 14 of 23 and stronger electron delocalization can be expected than for I.3 and II.3 (Scheme S1 in SM), although differences between the resonance hybrids of the neutral and cyano protonated forms have analogous origin as those for simple π-π conjugated systems (Scheme S1 in SM). Consequently,tendency confirms the HOMED strong indiceselectron increase delocalization for disubstituted in the cyclic derivatives fragments when that compared become toaromatic unsubstituted for unsubstituted ones (I.3 and systems.II.3).

+ CN CNH CN CNH+ Z Z 0.780 + H+ 0.920 Z Z 0.838 0.933 0.699 + H+ 0.850 0.708 0.889 0.823 0.917 0.898 0.949 I.2a (Z: CH) I.3 (Z: CH) II.2a (Z: N) II.3 (Z: N) CN CNH+ Z Z 0.826 0.947 0.865 + H+ 0.964 0.822 0.960 0.862 0.973

I.4 (Z: CH) II.4 (Z: N) CN CNH+ Z Z 0.823 0.932 0.848 + 0.943 CN CNH+ + H Z Z 0.782 0.941 0.762 0.857 0.810 0.955 0.764 + H+ 0.868 0.718 0.831 0.720 0.842

0.831 0.919 0.855 0.925 I.5 (Z: CH) I.6 (Z: CH) II.5 (Z: N) II.6 (Z: N) FigureFigure 9.9. Change of HOMEDs for for selected selected struc structurestures when when going going from from the the neutral neutral to to protonated protonated formsforms (italicized(italicized valuesvalues forfor seriesseriesII II)) estimatedestimated atat thethe DFT1DFT1 level.level.

ForIn the example, case of the CPC DFT1-estimated and CPN derivatives HOMEDs substituted change for by the two cyclopropenylidene X groups (I.7–I.12 scaf- and foldII.7– (CII.122C=)): Me, when NH going2, NMe from2, N=C(NH the neutral2)2, N=C(NMe to protonated2)2, and form N=P of (NMeI.7, I.82),3,I.9 substituents, I.10a, I.10b X, andadditionallyI.10c (Table participate2). Analogous in electron changes and are charge found delocalization for the C 2C=CH (Scheme fragment S2 in withSM). slightlyThe Me lowergroups HOMEDs. are σ-π hyperconjugated The corresponding and imino the other derivatives groups of are series n-πII conjugateddisplay similar with HOMEDthe ring, trendsand next for with the cyclopropene the cyano group. ring and Hence, cyclopropenimine larger number part of re (Csonance2C=N) when structures going can from be thewritten neutral and to stronger protonated electron form. delocalization The introduction can ofbe Nexpected atom in than series forII I.3increases and II.3 HOMEDs (Scheme alreadyS1 in SM), for neutralalthough molecules. differences This between is a consequence the resonance of possible hybrids intramolecular of the neutral interactions and cyano betweenprotonated functional forms have groups analogous that increase origin electron as those delocalization. for simple Hence,π-π conjugated smaller HOMED systems changes(Scheme take S1 place in SM). inprotonation Consequently, reaction the for HOMED derivatives indices of series increaseII. for disubstituted derivativesNote that when for n-comparedπ-conjugated to unsubstituted pushing substituents ones (I.3 and (X: NHII.32)., NMe2, N=C(NH2)2), sat- urationFor of example, electron delocalization the DFT1-estimated can be observed HOMEDs for change neutral for disubstituted the cyclopropenylidene 3-membered cyclesscaffold (HOMEDs (C2C=) wh betweenen going 0.9 from and 1.0).the neutral The effect to protonated of the strong form pushing of I.7 groups, I.8, I.9 causes, I.10a, aI.10b step, and toward I.10c electron (Table 2). delocalization Analogous changes in the highare found PA/GB for range the C2 forC=CH these fragment derivatives with (slightlyFigure 10 lower). Their HOMEDs. exceptionally The corresponding strong gas-phase imino derivatives basicity is of rather series a II consequence display similar of ≡ push–pullHOMED trendseffects—analogous for the cyclopropeneto those ringfor series and cyclopropenimine X–C N (Figure8 )—which part (C2C=N) occur when be- tweengoing the from substituent the neutral X and to protonated site of protonation form. The (cyano introduction N) through of the N Catom2C=Z in fragment. series II Electronincreases delocalization HOMEDs already appears for be neutral the second molecules. factor that This enhances is a consequence the PA/GB of range possible for push–pullintramolecular nitriles. interactions between functional groups that increase electron delocalization. Hence, smaller HOMED changes take place in protonation reaction for derivatives of series II.

Symmetry 2021, 13, x FOR PEER REVIEW 15 of 23

Table 2. HOMED indices estimated at the DFT1 level for the rings in selected neutral and monoprotonated cyano (C≡NH+) nitriles.

HOMED(C2C=) HOMED(C2C=Z) Series X Isomer Neutral C≡NH+ Neutral C≡NH+ Z: CH Me I.7 0.860 0.962 0.828 0.965 NH2 I.8 0.927 0.988 0.911 0.980 NMe2 I.9 0.954 0.994 0.942 0.976 N=C(NH2)2 I.10a 0.909 0.999 0.907 0.976 I.10b 0.917 0.9998 0.901 0.987 Symmetry 2021, 13, 1554 I.10c 0.929 0.999 0.919 15 of 230.981 Z: N Me II.7 0.931 0.981 0.891 0.978 NH2 II.8 0.973 0.986 0.950 0.987 Table 2. HOMED indicesNMe2 estimated at theII.9 DFT1 level for the0.991 rings in selected0.974 neutral and monoprotonated0.976 cyano 0.972 (C≡NH+) nitriles. N=C(NH2)2 II.10a 0.980 0.989 0.979 0.973

II.10b HOMED(C0.982 2C=)0.981 HOMED(C0.9662 C=Z) 0.972 Series X IsomerII.10c Neutral0.976 C≡NH+0.984 Neutral0.968 C≡NH+ 0.980 Z: CH Me I.7 0.860 0.962 0.828 0.965 NH2 NoteI.8 that for n-π-0.927conjugated pushing 0.988 substituents 0.911 (X: NH2, 0.980 NMe2, N=C(NH2)2), NMe2 saturationI.9 of electron0.954 delocalization 0.994 can be observed 0.942 for neutral 0.976 disubstituted N=C(NH ) I.10a 0.909 0.999 0.907 0.976 2 23-membered cycles (HOMEDs between 0.9 and 1.0). The effect of the strong pushing I.10b 0.917 0.9998 0.901 0.987 groups causesI.10c a step toward0.929 electron 0.999delocalization 0.919in the high PA/GB 0.981 range for these Z: N Me derivativesII.7 (Figure 10).0.931 Their exceptionally 0.981 strong 0.891 gas-phase basicity 0.978 is rather a NH2 consequenceII.8 of push–0.973pull effects—analogous 0.986 to 0.950 those for series 0.987 X–C≡N (Figure NMe2 II.9 0.991 0.974 0.976 0.972 N=C(NH2)28)—whichII.10a occur between0.980 the substituent 0.989 X and site of 0.979protonation (cyano 0.973 N) through the C2C=Z fragment.II.10b Electron0.982 delocalization 0.981 appears be the 0.966 second factor 0.972 that enhances the PA/GB rangeII.10c for push–pull0.976 nitriles. 0.984 0.968 0.980

FigureFigure 10. 10.Plots Plots between between HOMEDs HOMEDs for C for2C=Z C2C=Z fragments fragments and PAs and estimated PAs estimated at the DFT1 at the level DFT1 for level for selectedselected derivatives derivatives of series of seriesI (Z: I CH) (Z: andCH)II and(Z: N)II with(Z: N) X: with H, Me, X: NH H,2 Me,, NMe NH2, and2, NMe N=C(NH2, and2 )N=C(NH2. 2)2.

The additional estimations of the HOMA and NICS indices for cyclic parts in selected simpleThe nitriles additional shown in estimations Table3 conﬁrm of increases the HOMA of the and electron NICS delocalization indices for and cyclic the parts in magneticselected susceptibility simple nitriles of the shown ring when in Table proceeding 3 confirm from theincrease neutrals of molecule the electron to its cyano delocalization N-protonatedand the magnetic form (C susceptibility≡NH+) in both of series the ofring nitriles whenI and proceedingII, and also from in series the IIneutralwhen molecule goingto its from cyano the N neutral-protonated form to itsform imino (C monocation≡NH+) in both (ZH+ seriesfor Z =of N). nitriles Generally, I and negative II, and also in NICSseries values II when are found going for from the neutral the neutral and monoprotonated form to its structures. imino monocation An exception (ZH is the+ for Z = N). neutralGenerally, nitrile negativeI.4, for which NICS a positive values NICS are value found (close for to zero) the is neutral found. and monoprotonated structures. An exception is the neutral nitrile I.4, for which a positive NICS value (close Table 3. HOMA and NICS indices estimated at the DFT2 level for the rings in selected neutral and monoprotonated cyano (C≡NH+) and imino (ZH+) nitriles.to zero) See is Table found.1 for structures.

Number of Atoms Neutral C≡NH+ ZH+ (Z: N) Compound In the Ring HOMA NICS HOMA NICS HOMA NICS I.3 3 0.17 −9.08 0.69 −11.79 - - I.4 7 0.45 2.70 0.88 −5.65 - - 3 0.20 −8.10 0.73 −10.51 I.6 -- 6 0.43 −2.53 0.79 −6.65 I.9 3 0.62 −9.34 0.82 −9.76 - - II.3 3 0.48 −9.94 0.87 −12.40 0.91 −12.25 II.4 7 0.57 −1.48 0.92 −7.26 0.92 −7.23 3 0.33 −8.48 0.75 −10.99 0.79 −10.36 II.6 6 0.47 −3.71 0.81 −7.10 0.85 −7.53 II.9 3 0.75 −8.54 0.71 −8.86 0.85 −8.92 Symmetry 2021, 13, 1554 16 of 23

3.8. Macroscopic Basicity Values For polyfunctional compounds displaying isomerism, gas-phase basicity parameters (PAs and GBs) can be estimated using quantum chemical methods for separate isomers, as well as for their isomeric mixtures. A distinction between the two approaches can be made using different terminology and different microscopic basicity levels for individual isomers and for their mixtures. The microscopic basicity parameters discussed in the previous + + subchapter refer to partial equilibria for individual isomers, BiH → Bi + H , whereas the macroscopic basicity parameters correspond to the global equilibrium for the isomeric + + + + mixture, y1B1H + y2B2H + y3B3H + ... → x1B1 + x2B2 + x3B3 + ... + H . Each isomer mole fraction xi in the neutral isomeric mixture can be found on the basis of the relative Gibbs energies n calculated for neutral individual isomers: xi ≈ (exp(–∆G(Bi)/RT))/(Σ1 [exp(–∆G(Bi)/RT)]). In a similar way, the isomer mole fractions yi in the isomeric mixture of monocations can be estimated on the basis of the relative Gibbs energies calculated for the corresponding + n + protonated isomers: yi ≈ (exp(–∆G(BiH )/RT))/(Σ1 [exp(–∆G(BiH )/RT)]). As discussed above, the microscopic PAs and GBs indicate the basicity of selected sites of protonation for separate isomers, which can be distinguished as major, minor, and rare, as appropriate. They can be applied for analysis of the pure internal effects in individual isomers. The macroscopic PA or GB values give general information on the basicity of the isomeric mixture in the monoprotonation reaction, and can be compared with basicity data for other molecules already placed in the PA or GB scales in order to characterize its strength. For newly synthesized compounds, the predicted PA or GB can also be useful when selecting reference bases for experimental PA or GB determination. To our knowledge, the gas-phase basicity values of the simple derivatives I.2 and II.2, which exhibit various types of isomerism (E/Z and rotational) and can exist in mixtures of the four isomers, have not yet been experimentally determined. There is only a theoretical report on the microscopic basicity values of the two isomers I.2a and I.2b [2]. Considering the four isomers (a–d), we found that microscopic PAs and GBs do not differ very much (Figure3), while the favored neutral and protonated forms correspond to the same isomer. In such cases, the macroscopic PAs and GBs are not very different from the microscopic ones for the favored isomer. Using the relative Gibbs energies for the rotamers a and c of the E form and separately for the rotamers b and d of the Z form, we obtained the following PAs and GBs at the DFT1 level: 834.0 and 805.6 for E-I.2, 828.3 and 799.5 for Z-I.2, 854.7 and 826.7 for E-II.2, 851.8 and 824.3 kJ mol−1 for Z-II.2. If we assume that protonation of the cyano N atom reduces the energy barrier for E/Z isomerization, we can estimate the macroscopic basicity for the mixture of the four isomers a–d (Scheme S3 in SM). For this consideration, we take the following observation into account. First, the DFT-calculated double C=Z bonds signiﬁcantly lengthen (e.g., from 1.348 to 1.369 Å for I.2a and from 1.289 to 1.312 Å for II.2a) and the single Z–CN bonds shorten (e.g., from 1.421 to 1.384 Å for I.2a and from 1.332 to 1.269 Å for II.2a) when going from the neutral to cyano-protonated forms. For estimation of the isomer mole fractions xi and yi, in the neutral and protonated isomeric mixtures of the four isomers a–d, we used the corresponding relative Gibbs energies between b–d and a found at the DFT1 level (Chart S1 and S3 in SM). The percentage contents calculated for individual isomers in the isomeric mixtures of the neutral and protonated forms and the macroscopic PAs and GBs estimated for the monoprotonation equilibria are included in Scheme S3 (SM). Indeed, the macroscopic PAs and GBs shown in Table4 are not very different from the microscopic PAs and GBs of the favored isomer a given in Table S5 (SM). The macroscopic PAs and GBs were estimated for all derivatives (Z: CH and N) with two large substituents. For the estimations, we considered only major and minor isomers with ∆G < 25 kJ mol−1 that contribute signiﬁcantly in the PAs and GBs of the isomeric mixtures. As shown below, the macroscopic PAs and GBs estimated for I.10–I.12 and II.10–II.12 differ from the microscopic ones found for individual isomers. The reasons are as follows. First, the microscopic basicity data strongly depend on the syn and anti conformation of X groups. Second, the favored conformation for the neutral form Symmetry 2021, 13, 1554 17 of 23

(Chart S2 in SM) is not the same as that for the monocation (Chart S5 in SM). Next, intramolecular interactions in I.10–I.12 and II.10–II.12 that inﬂuence their relative Gibbs energies seem to not always be analogous when proceeding from guanidino to phosphazeno groups and from CH (series I) to N (series II) derivatives (vide infra). Consequently, the estimated macroscopic PAs and GBs may be placed between the lowest and highest PAs and GBs for individual isomers or close to one of them.

Table 4. Macroscopic PAs and GBs (in kJ mol−1 at 298 K) estimated at the DFT1 or DFT2 level for nitriles displaying isomerism. See Table1 for structures.

Compound PA GB Compound PA GB I.2 834.0 a 805.6 a II.2 854.9 a 826.9 a I.10 995.5 a 971.0 a II.10 1011.8 a 987.1 a I.11 1035.1 b 1004.7 b II.11 1043.2 b 1015.2 b I.12 1087.5 b 1059.3 b II.12 1079.2 b 1052.4 b a DFT1. b DFT2.

For the CH and N derivatives containing two N=C(NH2)2 groups (I.10 and II.10, Scheme S4 in SM), in the isomeric mixture three isomers are important for the neutral form (Chart S2 in SM) and four isomers for the monoprotonated form (Chart S5 in SM). The imino-protonated forms are not signiﬁcant and they can be neglected in the isomeric mixture of monocation. For estimation of the isomer mole fractions xi and yi in the isomeric mixtures, we used the corresponding relative Gibbs energies found for neutral and protonated isomers. The macroscopic PAs and GBs estimated at the DFT1 level (Table4 ) are between the lowest (for isomers a) and the highest (for isomer b) microscopic PAs and GBs (Table S5 in SM). Some imino-N-protonated forms, particularly guanidino protonated isomers (Chart S5 in SM), have to be considered for the CH and N derivatives containing two N=C(NMe2)2 groups (I.11 and II.11). Methylation of amino groups seems to increase the basicity of the guanidino N imino atom in comparison to the cyano N atom. For estimation of the macroscopic PAs and GBs, we used the isomers mole fractions calculated from the ∆Gs of three neutral isomers (Chart S2 in SM), four isomers of cyano monocations, and the isomers of imino-N-protonated forms, for which ∆G < 25 kJ mol−1 (Chart S5 in SM). The DFT2-estimated macroscopic PAs and GBs (Table4) are also between the lowest and highest microscopic PAs and GBs calculated for the isomers a and b (Table S5 in SM). Particular cases are diphosphazeno CH and N derivatives (I.12 and II.12), for which isomeric preferences are different for both the neutral (isomer c for I.12 and isomer a for II.12, see in Chart S2 in SM) and monoprotonated forms (isomer d for I.12 and isomer b for II.12, see in Chart S5 in SM); hence, these differences strongly affect the macroscopic PAs and GBs estimated at the DFT2 level (Scheme S6 in SM). For the N derivative, they are between the lowest and highest microscopic PA and GB calculated for the isomers a and b of II.12, although for the CH derivative they are close to the highest microscopic PA and GB values found for I.12b (Table S5 in SM). Consequently, II.12 seems to be a weaker base than I.12 at the DFT2 level (Table4). This order of basicity data is reversed in comparison to other derivatives of series I and II. For simple nitriles investigated here that do not exhibit rotational isomerism, N derivatives are stronger bases than CH derivatives (Figure6 ). The analogous trend is found for individual isomers of I.10–I.12 and II.10–II.12. They obey linear relationship given in Figure7. The exceptionally high macroscopic PA and GB values for the diphosphazeno CH derivative I.12 result from the strong stability of the cyano-protonated isomer d. For the N derivative II.12, this isomer belongs to the rare form, similar to the diguanidino N derivative II.10d.

3.9. New π-π- and n-π-Conjugated Nitriles on the DFT-PA Scale In our previous studies on the gas-phase basicity of push–pull nitriles [5,6], we investigated series of compounds with strong pushing groups, such as R2N, R2N–CH=CH, R2N– Symmetry 2021, 13, 1554 18 of 23

CH=N, (R2N)2C=N, (R2N)3P=N, and (R2N)3P=N(R2N)2P=N, directly linked to the pulling C≡N group. In this way, we extended the DFT basicity scale for nitriles up to superbasic 1,8-bis(dimethylamino)naphthalene (DMAN, experimental PA 1028.2 kJ mol−1 [3]). The most basic nitrile in this series with the biphosphazene group (Me2N)3P=N(Me2N)2P=N has a DFT-calculated PA value even higher than that of DMAN by ca. 30 kJ mol−1 [6]. The new simple π-π-conjugated nitriles investigated here containing methylenecyclopropene, methylene-1,3,5-cycloheptatriene, methylenequinoid, and methylenequinoidcyclopropene, as well as their heteroanalog transmitter systems, seem to be very promising for the future extension of the PA scale for nitriles. Their unsubstituted derivatives (I.3–I.6 and II.3–II.6) already display higher PAs (Table1) than the push–pull dimethylcyanamide −1 Me2N–C≡N (DFT-calculated PA 868.7 kJ mol [6]). Substitution of CPC and CPN parts by two NMe2 groups in I.9 and II.9 leads to derivatives with PAs (Table1) higher than −1 those of phosphazenenitrile (H2N)3P=N–C≡N (DFT calculated PA 978.8 kJ mol [6]). The positions of all these simple new π-π-conjugated nitrile bases (I.1–I.9 and II.1–II.9) on the DFT-calculated PA scale are given in Figure 11. Although the simple nitriles with unsubstituted transmitter parts (I.3–I.6 and II.3–II.6) investigated here are weaker bases than the strongest base studied previously [6], namely −1 biphosphazenenitrile (Me2N)3P=N(Me2N)2P=N–C≡N (DFT-calculated PA 1055.5 kJ mol ), we show here that substitution of the cyclopropene ring in I.3 and II.3 by two pushing groups increases the PAs by ca. 200 kJ mol−1 (Figure7). Diphosphazene derivatives ( I.12 and II.12, macroscopic PA 1088 and 1079 kJ mol−1, respectively; Table4) are the strongest bases in the current DFT-calculated PA scale for nitriles. This observation suggests that analogous substitution of the methylenequinoid, methylene-1,3,5-cycloheptatriene, and methylenequinoidcyclopropene transmitters and their N analogs by two strong pushing groups in I.4–I.6 and II.4–II.6 may lead to derivatives for which the DFT-calculated PAs will be close to the limit of the experimental PA scale for push–pull N imino bases (PA < 1200 kJ mol−1)[1]. Transmission of the strong pushing effects in such π-π-conjugated systems has already been proved in the literature for imines by quantum-chemical methods [7,8,10]. Symmetry 2021, 13, 1554 19 of 23 Symmetry 2021, 13, x FOR PEER REVIEW 19 of 23

PA [kJ/mol]

(Me2N)3P=N-CN Simple nitriles with - conjugated transmitter

CN CN N -1000 CN N

Me2N NMe2

Me2N NMe2 (H N) P=N-CN 2 3 CN CN CN N

(Me2N)2C=N-CN H2N NH2 H2N NH2 - 950

CN N CN N CN CN (H2N)2C=N-CN N Me Me CN Me Me

- 900

CN N CN CN

Me2N-CN

CN N - 850

H2N-CN - 800 H2C=N-CN H C=CH-CN 2 Figure 11. SimpleFigureπ-π- and11. Simple n-π-conjugated π-π- and nitriles n-π-conjugatedI.1–I.9 and nitrilesII.1–II.9 I.1–onI.9 the and DFT-calculated II.1–II.9 on the PA DFT scale-calculated of push–pull PA nitriles. scale of push–pull nitriles.

Symmetry 2021, 13, 1554 20 of 23

4. Conclusions On the basis of our quantum chemical estimations of proton affinities (mainly DFT and also Gn for some parent systems), we proposed new π-π- and n-π-conjugated nitrogen bases reaching PA values above 1000 kJ mol−1. Using the electron acceptor (pulling) nitrile functional group as a probe, we explored the efficiency of the methylenecyclopropene (CPC) and cyclopropenimine (CPN) π-systems (3 with Z: CH and N, respectively, in Figure1 ) as resonance transmission scaffolds for strong electron donor (pushing) substituents. By applying robust DFT methods, we analyzed the effects of pushing groups X (NH2, NMe2, (H2N)2C=N, (M2N)2C=N, and (Me2N)3P=N) linked to 2- and 3-positions of the cyclopropene ring on the gas-phase basicity of the cyano N site in compounds I.8–I.12 and II.8–II.12 (Figure2). As the CPN and pushing X groups contain N atoms (imino and amino) that are potential sites of protonation, we carefully examined various neutrals and monocations in possible conformations to determine the structures of their most favored forms. In all cases for the favored isomers, the nitrile N atom emerges as the strongest basic site. The cyano group in the two CPC and CPN series have similar calculated proton affinities, with a small advantage for the later. The CPC and CPN scaffolds efficiently transmit the push–pull effect from the X to CN group with very similar transmission power (Figure7). Although the transmission of the X donor effect is ca. 60% of that found for X–C≡N (Figure8), the calculated PAs of the two series of nitriles containing the cyclopropene ring and bearing two electron donor X substituents are larger than their X–C≡N and X2C=Z–C≡N analogs (Figure 11). The enhanced PAs for investigated nitriles can be attributed to the extended electron delocalization and polarizability resulting from the intercalation of the CPC and CPN π-systems. The gas-phase basicity values calculated for the cyano N atom in nitriles containing the methylene-1,3,5-cycloheptatriene, methylenequinoid, and methylenequinoidcyclopropene and their heteroanalog transmitter π-systems (derivatives I.4–I.6 and II.4–II.6, respectively) also reveal some similarities; however, the imino N (Z) effect seems to be stronger for these larger scaffolds than that for the CPN derivatives (Figure6). Nitriles I.6 and II.6 (Table1) exhibit the highest PAs in series of simple parent compounds (without pushing X groups). Their exceptionally high PAs (973 and 1004 kJ mol−1, respectively) and the strong pushing effects of the two phosphazene groups in II.12 containing the CPN system when compared to the parent system II.3 (ca. 200 kJ mol−1) lead us to believe that the basicity values of derivatives containing two pushing groups at the cyclopropene ring in II.6 can reach PA values of 1200 kJ mol−1. Note that in solution, simple nitriles are exceptionally weak N bases (pKas of monofunctional RCN in water ca. –10) [66,67]. Nitriles have only been protonated in sulfuric acid and oleum systems [66]. It will be interesting to study in the future the theoretical pKas of push–pull nitriles to indicate first the favored site of protonation (particularly in nitriles containing the guanidine and phosphazene pushing groups), and next to estimate solvent effects. For Me2N–CH=N–C≡N, the imino N atom has been found to be the favored site of protonation at the PCM (water)//HF/6-31G* level for both geometrical isomers (E and Z)[68]. The degrees of electron delocalization in the π-π-conjugated transmitter systems were described by applying two aromaticity descriptors, namely structural (HOMA) and magnetic (NICS) indices. The cyclopropene π-systems exhibit a significant π-electron delocalization in neutral nitriles (stronger than that in π-π-conjugated butadiene—the reference molecule for the C–C and C=C bonds in the HOMA procedure—and weaker than that in aromatic benzene). The cyano protonation amplifies electron and charge delocalization and these scaffolds display stronger aromatic characters, as indicated by more negative NISC indices (Table3). The same is true for larger π-electron cycles (Figure9), which display analogous variations of aromaticity indices; however, the aromatic character of the transmitter π-systems seems to be less dependent on the electron donor effect of the X groups (NH2, NMe2, (H2N)2C=N, (M2N)2C=N, and (Me2N)3P=N) than the basicity Symmetry 2021, 13, 1554 21 of 23

of the electron acceptor cyano group (Figure 10). We found that the push–pull effect between X and C≡N is the main factor that enhances the PAs of nitriles (Figure8). Despite slight attenuation of the substituent effect by the cyclic π-systems, as compared to shorter conjugated systems, the intrinsic basicity enhancement of the nitrile functional group by the CPC and CPN scaffolds leads to highly basic nitriles.

Supplementary Materials: The following is available online at https://www.mdpi.com/article/10 .3390/sym13091554/s1: docx file Nitriles_SM_Symmetry. Author Contributions: E.D.R., supervision, methodology, computational, writing, editing. J.-F.G., project administration, supervision, writing. P.-C.M., supervision, writing. H.S., methodology, computation, writing. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The data presented in this study are available as supplementary material. Acknowledgments: J.F.G. and P.C.M. thank the Université Côte d’Azur and the Institut de Chimie de Nice (CNRS UMR 7272) for their continuous support. Conflicts of Interest: The authors declare no conflict of interest.

References 1. Raczyńska,E.D.; Gal, J.-F.; Maria, P.-C. Enhanced Basicity of Push-Pull Nitrogen Bases in the Gas Phase. Chem. Rev. 2016, 116, 13454–13511. [CrossRef][PubMed] 2. Bouchoux, G. Gas phase basicities of polyfunctional molecules. Part 6: Cyanides and isocyanides. Mass Spectrom. Rev. 2018, 37, 533–564. [CrossRef][PubMed] 3. Hunter, E.P.; Lias, S.G. Evaluated Gas Phase Basicities and Proton Affinities of Molecules: An Update. J. Phys. Chem. Ref. Data 1998, 27, 413–656. [CrossRef] 4. NIST Chemistry WebBook, NIST Standard Reference Database, No. 69; Linstrom, P.J.; Mallard, W.G. (Eds.) National Institute of Standards and Technology: Gaithersburg, MD, USA, 2014. Available online: http://webbook.nist.gov/chemistry (accessed on 7 May 2021). 5. Raczyńska,E.D.; Gal, J.-F.; Maria, P.-C. Exceptional proton affinities of push–pull nitriles substituted by the guanidino and phosphazeno groups. RSC Adv. 2015, 5, 25513–25517. [CrossRef] 6. Raczyńska,E.D.; Makowski, M.; Maria, P.-C.; Gal, J.-F. Can Nitriles Be Stronger Bases than Proton Sponge in the Gas Phase? A Computational Analysis. J. Phys. Chem. A 2015, 119, 8225–8236. [CrossRef][PubMed] 7. Maksić,Z.B.; Kovaˇcević,B.; Vianello, R. Advances in Determining the Absolute Proton Affinities of Neutral Organic Molecules in the Gas Phase and Their Interpretation: A Theoretical Account. Chem. Rev. 2012, 112, 5240–5270. [CrossRef][PubMed] 8. Valadbeigi, Y. Superbasicity of 1,3,5-cycloheptatriene derivatives and their proton sponges in gas phase. Chem. Phys. Let. 2017, 689, 1–7. [CrossRef] 9. Gilani, M.; Saeidian, H.; Mirjafary, Z. Harnessing aromaticity and intramolecular hydrogen bondingto tailor organosuperbases by using 2,4,6-cycloheptatriene-1-imine scaffold. Struct. Chem. 2020, 31, 1545–1551. [CrossRef] 10. Despotović,I.; Maksić,Z.B.; Vianello, R. Computational design of Brønsted neutral organic superbases-[3]iminoradialenes and quinonimines are important synthetic targets. New J. Chem. 2007, 31, 52–62. [CrossRef] 11. Höltzl, T.; Nguyen, M.T.; Veszprémi, T. Mono-, di-, tri- and tetraphosphatriafulvenes: Electronic structure and aromaticity. J. Mol. Struct. (THEOCHEM) 2007, 811, 27–35. [CrossRef] 12. Saeidian, H.; Mirjafary, Z. Engineering non-ionic carbon super- and hyperbases by a computational DFT approach: Substituted allenes have unprecedented cation affinities. New J. Chem. 2020, 44, 12967–12977. [CrossRef] 13. Wang, Y.; Fernández, I.; Duvall, M.; Wu, J.I.-C.; Li, Q.; Frenking, G.; Schleyer, P.v.R. Consistent Aromaticity Evaluations of Methylenecyclopropene Analogues. J. Org. Chem. 2010, 75, 8252–8257. [CrossRef] 14. Burk, P.; Abboud, J.-L.M.; Koppel, I.A. Aromaticity of substituted cyclopropenes: A theoretical study. J. Phys. Chem. A 1996, 100, 6992–6997. [CrossRef] 15. Merchant, M.; González-Luque, R.; Roos, B.O. A theoretical determination of the electronic spectrum of Methylenecyclopropene. Theor. Chim. Acta 1996, 94, 143–154. [CrossRef] 16. Bachrach, S.M.; Liu, M. Structure, topological electron density analysis and aromaticity of 4-heterosubstituted methylenecyclo- propenes: X=CCH=CH, X = CH2, NH, O, SiH2, PH and S. J. Phys. Org. Chem. 1991, 4, 242–250. [CrossRef] 17. Norden, T.D.; Staley, S.W.; Taylor, W.H.; Harmony, M.D. Electronic character of methylenecyclopropene: Microwave spectrum, structure, and dipole moment. J. Am. Chem. Soc. 1986, 108, 7912–7918. [CrossRef] Symmetry 2021, 13, 1554 22 of 23

18. Bandar, J.S.; Lambert, T.H. Enantioselective Brønsted base catalysis with chiral cyclopropenimines. J. Am. Chem. Soc. 2012, 134, 5552–5555. [CrossRef] 19. Bandar, J.S.; Lambert, T.H. Cyclopropenimine-Catalyzed Enantioselective Mannich Reactions of tert-Butyl Glycinates with N-Boc-Imines. J. Am. Chem. Soc. 2013, 135, 11799–11802. [CrossRef][PubMed] 20. Bandar, J.S.; Sauer, G.S.; Wulff, W.D.; Lampert, T.H.; Vetticatt, M.J. Transition State Analysis of Enantioselective Brønsted Base Catalysis by Chiral Cyclopropenimines. J. Am. Chem. Soc. 2014, 136, 10700–10707. [CrossRef] 21. Bandar, J.S.; Barthelme, A.; Mazori, A.Y.; Lambert, T.H. Structure–activity relationship studies of cyclopropenimines as enantioselective Brønsted base catalysts. Chem. Sci. 2015, 6, 1537–1547. [CrossRef][PubMed] 22. Nacsa, E.D.; Lambert, T.H. Higher-order cyclopropenimine superbases: Direct neutral Brønsted base catalyzed Michael reactions with α-aryl esters. J. Am. Chem. Soc. 2015, 137, 10246–10253. [CrossRef] 23. Belding, L.; Dudding, T. Synthesis and Theoretical Investigation of a 1,8-Bis (bis (diisopropylamino) cyclopropeniminyl) naphthalene Proton Sponge Derivative. Chem. Eur. J. 2014, 20, 1032–1037. [CrossRef][PubMed] 24. Belding, L.; Stoyanov, P.; Dudding, T. Synthesis, Theoretical Analysis, and Experimental pKa Determination of a Fluorescent, Nonsymmetric, In–Out Proton Sponge. J. Org. Chem. 2016, 81, 6–13. [CrossRef][PubMed] 25. Belding, L.; Stoyanov, P.; Dudding, T. Phase-transfer catalysis via a proton sponge: A bifunctional role for biscyclopropenimine. J. Org. Chem. 2016, 81, 553–558. [CrossRef] 26. Guest, M.; Le Sueur, R.; Pilkington, M.; Dudding, T. Development of an Unsymmetrical Cyclopropenimine-Guanidine Platform for Accessing Strongly Basic Proton Sponges and Boron-Difluoride Diaminonaphthalene Fluorophores. Chem. Eur. J. 2020, 26, 8608–8620. [CrossRef][PubMed] 27. Çiftcio˘glu,G.A.; Trindle, C. Computational estimates of thermochemistry and pKa values of cyclopropenyl imine superbases. Int. J. Quantum Chem. 2014, 114, 392–399. [CrossRef] 28. Krawczyk, H.; Dzi˛egielewski,M.; Deredas, D.; Albrecht, A.; Albrecht, Ł. Chiral Iminophosphoranes-An Emerging Class of Superbase Organocatalysts. Chem. Eur. J. 2015, 21, 10268–10277. [CrossRef] 29. Barić,D.; Dragiˇceviˇc,I.; Kovaˇcević,B. Cyclopropenimine as a hydrogen bond acceptor-towards the strongest non-phosphorus superbases. Tetrahedron 2014, 70, 8571–8576. [CrossRef] 30. Barić,D.; Kovaˇcević,B. Cyclopropenimine as pincer ligand and strong electron donor in proton sponges. J. Phys. Org. Chem. 2016, 29, 750–758. [CrossRef] 31. Saadat, K.; Shiri, A.; Kovaˇcević,B. Substituted troponimines: When aromatization of the conjugate acid leads to very strong neutral organic superbases. New J. Chem. 2018, 42, 14568–14575. [CrossRef] 32. Bouchoux, G. Gas phase basicities of polyfunctional molecules. Part 5: Non-aromatic sp2 nitrogen containing compounds. Mass Spectrom. Rev. 2018, 37, 139–170. [CrossRef] 33. Cao, W.; Liu, X.; Feng, X. Chiral organobases: Properties and applications in asymmetric catalysis. Chin. Chem. Lett. 2018, 29, 1201–1208. [CrossRef] 34. Wang, Y.-H.; Cao, Z.-Y.; Li, Q.-H.; Lin, G.-Q.; Zhou, J.; Tian, P. Activating Pronucleophiles with High pKa Values: Chiral Organo-Superbases. Angew. Chem. Int. Ed. 2020, 59, 8080–8090. [CrossRef] 35. Casida, J.E. Neonicotinoid metabolism: Compounds, substituents, pathways, enzymes, organisms, and relevance. J. Agric. Food Chem. 2011, 59, 2923–2931. [CrossRef][PubMed] 36. Zhou, L.-Y.; Zhang, L.-J.; Sun, S.-L.; Ge, F.; Mao, S.-Y.; Ma, Y.; Liu, Z.-H.; Dai, Y.-J.; Yuan, S. Degradation of the Neonicotinoid Insecticide Acetamiprid via the N-Carbamoylimine Derivate (IM-1-2) Mediated by the Nitrile Hydratase of the Nitrogen-Fixing Bacterium Ensifer meliloti CGMCC 7333. J. Agric. Food Chem. 2014, 62, 9957–9964. [CrossRef] 37. Zhang, H.; Wei, Z.; Zhang, A.H.; Yu, S. Access to Cyanoimines Enabled by Dual Photoredox/Copper-Catalyzed Cyanation of O-Acyl Oximes. Org. Lett. 2020, 22, 7315–7320. [CrossRef] 38. Peltier, J.-D.; Heinrich, B.; Donnio, B.; Jeannin, O.; Rault-Berthelot, J.; Jacques, E.; Poriel, C. N-Cyanoimine as an electron- withdrawing functional group for organic semiconductors: Example of dihydroindacenodithiophene positional isomers. J. Mater. Chem. C 2018, 6, 13197–13210. [CrossRef] 39. Zarren, G.; Nisar, B.; Sher, F. Synthesis of anthraquinone-based electroactive polymers: A critical review. Mater. Today Sustain. 2019, 5, 100019. [CrossRef] 40. Hodsden, T.; Thorley, K.J.; Basu, A.; White, A.J.P.; Wang, C.; Mitchell, W.; Glöcklhofer, F.; Anthopoulos, T.D.; Heeney, M. The influence of alkyl group regiochemistry and backbone fluorination on the packing and transistor performance of N-cyanoimine functionalised indacenodithiophenes. Mater. Adv. 2021, 2, 1706–1714. [CrossRef] 41. Becke, A.D. Density Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648–5652. [CrossRef] 42. Lee, C.; Yang, W.; Parr, R.G. Density-functional exchange-energy approximation with correct asymptotic behaviour. Phys. Rev. B 1988, 37, 785–789. [CrossRef][PubMed] 43. Hehre, W.J.; Radom, L.; Schleyer, P.v.R.; Pople, J.A. Ab initio Molecular Theory; Wiley: New York, NY, USA, 1986. 44. Kaljurand, I.; Koppel, I.A.; Kütt, A.; Rõõm, E.-I.; Rodima, T.; Koppel, I.; Mishima, M.; Leito, I. Experimental gas-phase basicity scale of superbasic phosphazenes. J. Phys. Chem. A 2007, 111, 1245–1250. [CrossRef][PubMed] 45. Leito, I.; Koppel, I.A.; Koppel, I.; Kaupmees, K.; Tshepelevitsh, S.; Saame, J. Basicity limits of neutral organic superbases. Angew. Chem. Int. Ed. 2015, 54, 9262–9265. [CrossRef][PubMed] Symmetry 2021, 13, 1554 23 of 23

46. Curtiss, L.A.; Raghavachari, K.; Trucks, G.W.; Pople, J.A. Gaussian-2 theory for molecular energies of first-and second-row compounds. J. Chem. Phys. 1991, 94, 7221–7230. [CrossRef] 47. Curtiss, L.A.; Raghavachari, K.; Pople, J.A. Gaussian-2 theory using reduced Møller–Plesset orders. J. Chem. Phys. 1993, 98, 1293–1298. [CrossRef] 48. Bartmess, J.E. Thermodynamics of the electron and the proton. J. Phys. Chem. 1994, 98, 6420–6424. [CrossRef] 49. Fifen, J.J.; Dhaouadi, Z.; Nsangou, M. Revision of the Thermodynamics of the Proton in Gas Phase. J. Phys. Chem. A 2014, 118, 11090–11097. [CrossRef] 50. Krygowski, T.M. Crystallographic studies of inter-and intramolecular interactions reflected in aromatic character of π-electron systems. J. Chem. Inform. Comput. Sci. 1993, 33, 70–78. [CrossRef] 51. Raczyńska,E.D.; Hallmann, M.; Kolczyńska,K.; St˛epniewski,T.M. On the harmonic oscillator model of electron delocalization (HOMED) index and its application to heteroatomic π-electron systems. Symmetry 2010, 2, 1485–1509. [CrossRef] 52. Kruszewski, J.T.; Krygowski, M. Definition of aromaticity basing on the harmonic oscillator model. Tetrahedron Lett. 1972, 13, 3839–3842. [CrossRef] 53. Kruszewski, J.T.; Krygowski, M. Aromaticity of thiophene, pyrrole and furan in terms of aromaticity indices and Hammett ρ constants. Bull. Acad. Pol. Sci. Sér. Sci. Chim. 1974, 22, 871–876. 54. Raczyńska,E.D. Application of the Extended HOMED (Harmonic Oscillator Model of Aromaticity) Index to Simple and Tautomeric Five-Membered Heteroaromatic Cycles with C, N, O, P, and S Atoms. Symmetry 2019, 11, 146. [CrossRef] 55. Ostrowski, S.; Dobrowolski, J.C. What does the HOMA index really measure? RSC Adv. 2014, 4, 44158–44161. [CrossRef] 56. Dobrowolski, J.C.; Ostrowski, S. On the HOMA index of some acyclic and conducting systems. RSC Adv. 2015, 5, 9467–9471. [CrossRef] 57. Krygowski, T.M.; Szatyłowicz, H.; Stasiuk, O.A.; Dominikowska, J.; Palusiak, M. Aromaticity from the viewpoint of molecular geometry: Application to planar systems. Chem. Rev. 2014, 114, 6383–6422. [CrossRef][PubMed] 58. Raczyńska,E.D. Quantum-chemical studies on the favored and rare isomers of isocytosine. Comput. Theor. Chem. 2017, 1121, 58–67. [CrossRef] 59. Schleyer, P.v.R.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N.J. Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. J. Am. Chem. Soc. 1996, 118, 6317–6318. [CrossRef][PubMed] 60. Chen, Z.; Wannere, C.S.; Corminboeuf, C.; Puchta, R.; Schleyer, P.v.R. Nucleus-independent chemical shifts (NICS) as an aromaticity criterion. Chem. Rev. 2005, 105, 3842–3888. [CrossRef] 61. Gershoni-Poranne, R.; Stanger, A. Magnetic criteria of aromaticity. Chem. Soc. Rev. 2015, 44, 6597–6615. [CrossRef][PubMed] 62. Smith, B.J.; Radom, L. Assigning absolute values to proton affinities: A differentiation between competing scales. J. Am. Chem. Soc. 1993, 115, 4885–4888. [CrossRef] 63. Smith, B.J.; Radom, L. Calculation of proton affinities using the G2 (MP2, SVP) procedure. J. Phys. Chem. 1995, 99, 6468–6471. [CrossRef] 64. Elguero, J.; Marzin, C.; Katritzky, A.R.; Linda, P. The Tautomerism of Heterocycles; Academic Press: New York, NY, USA, 1976. 65. Raczyńska,E.D.; Kosińska,W.; O´smiałowski,B.; Gawinecki, R. Tautomeric equilibria in relation to pi-electron delocalization. Chem. Rev. 2005, 105, 3561–3612. [CrossRef][PubMed] 66. Deno, N.C.; Gaugler, R.W.; Wisotsky, M.J. The base strengths and chemical behavior of nitriles in sulfuric acid and oleum systems. J. Org. Chem. 1966, 31, 1967–1968. [CrossRef] 67. Perrin, D.D. Dissociation Constants of Organic Bases in Aqueous Solution; Butterworth: London, UK, 1965. 68. Makowski, M.; Raczyńska,E.D.; Chmurzyński,L. Ab initio study of possible and preferred basic site(s) in polyfunctional N1,N1-dimethyl-N2-cyanoformamidine. J. Phys. Chem. A 2001, 105, 869–874. [CrossRef]