Z,E-Isomerism in a Series of Substituted Iminophosphonates: Quantum Chemical Research

Article Z,E-Isomerism in a Series of Substituted Iminophosphonates: Quantum Chemical Research

Alexander B. Rozhenko 1,2,*, Andrey A. Kyrylchuk 1 , Yuliia O. Lapinska 2, Yuliya V. Rassukana 1,2, Vladimir V. Trachevsky 1,3, Volodymyr V. Pirozhenko 1, Jerzy Leszczynski 4 and Petro P. Onysko 1,*

1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Murmans’ka Str. 5, 02094 Kyiv, Ukraine; [email protected] (A.A.K.); [email protected] (Y.V.R.); [email protected] (V.V.T.); [email protected] (V.V.P.) 2 National Technical University of Ukraine “Kyiv Polytechnic Institute named after Igor Sikorsky”, Peremogy Ave. 37, 03056 Kyiv, Ukraine; [email protected] 3 Technical Center of the National Academy of Sciences of Ukraine, Pokrovs’ka Str. 13, 04070 Kyiv, Ukraine 4 Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, USA; [email protected] * Correspondence: [email protected] (A.B.R.); [email protected] (P.P.O.); Tel.: +380-44-499-4610 (A.B.R.); +380-44-573-2594 (P.P.O.)

Abstract: Esters of iminophosphonic acids (iminophosphonates, or IPs), including a fragment, >P(=O)-C=N, can be easily functionalized, for instance to aminophosphonic acids with a wide range

of biological activity. Depending on the character of the substitution, the Z- or E-conﬁguration is favorable for IPs, which in turn can inﬂuence the stereochemistry of the products of chemical

Citation: Rozhenko, A.B.; Kyrylchuk, transformations of IPs. While the Z,E-isomerism in IPs has been thoroughly studied by NMR A.A.; Lapinska, Y.O.; Rassukana, Y.V.; spectroscopy, the factors stabilizing a definite isomer are still not clear. In the current work, density Trachevsky, V.V.; Pirozhenko, V.V.; functional theory (DFT, using M06-2X functional) and ab initio spin-component–scaled second- Leszczynski, J.; Onysko, P.P. order Møller–Plesset perturbation theory (SCS-MP2) calculations were carried out for a broad series Z,E-Isomerism in a Series of of IPs. The calculations reproduce well a subtle balance between the preferred Z-configuration Substituted Iminophosphonates: inherent for C-trifluoromethyl substituted IPs and the E-form, which is more stable for C-alkyl- or Quantum Chemical Research. aryl-substituted IPs. The predicted trend of changing activation energy values agrees well with Organics 2021, 2, 84–97. 6= the recently determined experimental ∆G 298 magnitudes. Depending on the substitution in the https://doi.org/10.3390/org2020008 aromatic moiety, the Z/E-isomerization of N-aryl-substituted IPs proceeds via two types of close-in energy transition states. Not a single main factor but a combination of various contributions should Academic Editor: Tomasz be considered in order to explain the Z/E-isomerization equilibrium for different IPs. K. Olszewski

Keywords: DFT calculations; SCS-MP2 calculations; Z,E-isomerism; iminophosphonates; thermody- Received: 8 March 2021 Accepted: 20 April 2021 namic stability Published: 23 April 2021

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- Aminophosphonic acids, as phosphorus analogs of amino acids, are biologically iations. persistent analogues of unstable tetrahedral carbon intermediates formed in enzymatic processes, and therefore act as enzyme inhibitors [1]. Derivatives of aminophosphonic acids are widely used as antibacterial, anticancer and antiviral drugs, herbicides, and enzyme regulators, etc. [1–3]. Copyright: © 2021 by the authors. Esters of iminophosphonic acids or iminophosphonates (IPs) include an ‘oxidized’ Licensee MDPI, Basel, Switzerland. fragment of aminophosphonic acids (>P(=O)-C=N), which can easily be functionalized. This article is an open access article Therefore, they are convenient precursors in the synthesis of aminophosphonic acids, as distributed under the terms and well as a wide range of other biologically active compounds. Fluorine-substituted IPs conditions of the Creative Commons deserve special attention because the introduction of fluorine into the molecule is not Attribution (CC BY) license (https:// always an easy task. At the same time, the presence of fluorine atoms in the molecule creativecommons.org/licenses/by/ significantly affects its chemical, physicochemical and pharmacological properties [4,5]. 4.0/).

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Similarly to other imines, E/Z-isomerism is inherent for IPs (Scheme 1). Two main mechanisms of isomerization are discussed in the literature: an imino-nitrogen inversion in a plane through a transition state (TS) with a CNX bond angle ≈ 180° and a rotational process, wherein the substituent X in the TS is out of the plane with the CNX bond angle < 180° (Figure 1) [6,7]. It should be noted that, at present, there are no unambiguous experimental criteria for assigning the mechanism of isomerization to inversion or rotation. However, as shown by our quantum chemical study of quinonimines [7], a mixed isomerization mechanism including the rotation component in the process of inversion is realized only under certain conditions, and is determined mainly by the steric influence of the neighboring substituents. One year later, Gálvez and Guirado [8] have reported on the similar mixed isomerization mechanism in other imine derivatives. Moreover, according to [8], electron acceptor substituents determine the inversion mechanism for the isomerization, whereas the electron donor groups contribute to the rotational one. This conclusion is also consistent with the data of earlier works [9,10].

R1 N X R2 R1 R1 X inversion N N 2 X 2 R R R1 N 2 R X rotation Figure 1. Two possible mechanisms of the Z/E-isomerization of imines.

IPs can exist as an equilibrium of E- and Z-isomers (Table 1) [9]. The assignment of IPs to Z- or E-isomers has recently been performed by means of 19F and 31P NMR spectroscopy [9,11,12]. The resonance signals of phosphorus and fluorine nuclei in Z-isomers of IPs (δР−0.1–3.3 ppm, δF−66.2–70.2 ppm) are high-field shifted compared to the corre- Organics 2 2021, sponding E-isomers (δР 1.5–4.9 ppm, δF−61–62 ppm) [9,11–13]. Structural features, the85 charge distribution in the molecules, electronic interactions, and reaction paths are tradi- tional subjects of quantum chemistry investigations. Recently, we published the first ex- ampleSimilarly of quantum to other chemical imines, calculations E/Z-isomerism for the is inherentprocess of for the IPs Z/E-isomerization (Scheme1). Two mainof IPs mechanisms[14]. Theoretical of isomerization studies of the are same discussed proce inss the have literature: previously an imino-nitrogen been performed inversion for other in asubstituted plane through imines a transition [7,8]. The state isomeric (TS) withratio ais CNX determined bond angle by the≈ 180nature◦ and ofa the rotational substituents process,at the wherein C = N thedouble substituent bond, Xand in thethe TS decisive is out of contribution the plane with to thethe CNXstability bond of angle each < of 180 the◦ (Figureisomers1)[ belongs6,7]. It to should the substituent be noted that, R2 (Scheme at present, 1). there Thus, are it is no known unambiguous that most experimental derivatives Organics 2021, 2, FOR PEER REVIEWcriteriawith R2 for = aryl assigning exist mainly the mechanism in the E-form of isomerization [Z/E ≈ 1:(12–20)], to inversion while IPs or rotation.with fluoroalkyl However, R22

asgroups shown are by preferably our quantum Z-isomers chemical [Z/E study ≈ (6–10):1] of quinonimines (Table 1). The [7 ],variation a mixed of isomerization the alkyl sub- mechanismstituent R3 in including the phosphoryl the rotation group component has little ineffe thect, process while the ofinversion nature of is the realized fluoroalkyl only under certain2 conditions, and is determined mainly by the steric inﬂuence of the neigh- groupSimilarly R can significantlyto other imines, influence E/Z-isomerism the Z/E-isomeric is inherent ratio for for IPs IPs. (Scheme Interestingly, 1). Two in main the boring substituents. One year later, Gálvez and Guirado [8] have reported1 on the similar mechanismsmore stable Z-isomer of isomerization of trifluoromet are discussedhyl-substituted in the literature: IPs, the substituent an imino-nitrogen R at the inversion nitrogen mixed isomerization mechanism in other imine derivatives. Moreover, according to [8], inatom a plane is in thethrough cis-position a transition relative state to the (TS) bulky with dialkylphosphonyl a CNX bond angle group, ≈ 180° i.e.,and the a rotational sterically electron acceptor substituents determine the inversion mechanism for the isomerization, process,less-favorable wherein isomer the substituent is more advantageous X in the TS is. In out turn, of the the plane structure with ofthe these CNX compounds bond angle whereas the electron donor groups contribute to the rotational one. This conclusion is also

1 R N X R2 R1 R1 X inversion N N 2 X 2 R R R1 N 2 R X rotation FigureFigure 1.1.Two Two possible possible mechanisms mechanisms of of the the Z/E-isomerization Z/E-isomerization ofof imines.imines.

IPsIPs cancan existexist asas an equilibrium of of E- E- and and Z-isomers Z-isomers (Table (Table 1)1)[ [9].9]. The The assignment assignment of ofIPs IPs to Z- to or Z- E-isomers or E-isomers has recent has recentlyly been beenperformed performed by means by means of 19F and of 19 31FP andNMR31 spectros-P NMR spectroscopycopy [9,11,12]. [9 The,11,12 resonance]. The resonance signals of signals phosphorus of phosphorus and fluorine and nuclei fluorine in Z-isomers nuclei in Z-of isomersIPs (δР− of0.1–3.3 IPs (δ Pppm,−0.1–3.3 δF−66.2–70.2 ppm, δF− 66.2–70.2ppm) are ppm)high-field are high-field shifted shiftedcompared compared to the tocorre- the correspondingsponding E-isomers E-isomers (δР 1.5–4.9 (δP 1.5–4.9 ppm, ppm, δF−δ61–62F−61–62 ppm) ppm) [9,11–13]. [9,11– 13Structural]. Structural features, features, the thecharge charge distribution distribution in the in molecules, the molecules, electron electronicic interactions, interactions, and reaction and reaction paths paths are tradi- are traditionaltional subjects subjects of quantum of quantum chemistry chemistry investigations. investigations. Recently, Recently, we wepublished published the the first first ex- exampleample of of quantum quantum chemical chemical calculations calculations for for the the process process of ofthe the Z/E-isomerization Z/E-isomerization of IPs of IPs[14]. [14 Theoretical]. Theoretical studies studies of ofthe the same same proce processss have have previously previously been been performed forfor otherother substitutedsubstituted imines imines [ [7,8].7,8]. TheThe isomericisomeric ratioratio isis determineddetermined byby thethe naturenature of of the the substituents substituents atat thethe CC == NN doubledouble bond,bond, andand thethe decisivedecisive contributioncontribution toto thethe stabilitystability ofof eacheach ofof thethe 2 isomersisomers belongsbelongs toto the the substituent substituent R R2(Scheme (Scheme1 ).1). Thus, Thus, it it is is known known that that most most derivatives derivatives 2 withwith RR2 == aryl exist mainly in the E-form [Z/E ≈≈ 1:(12–20)],1:(12–20)], while while IPs IPs with with fluoroalkyl fluoroalkyl R2 2 Rgroupsgroups are are preferably preferably Z-isomers Z-isomers [Z/E [Z/E ≈ (6–10):1]≈ (6–10):1] (Table (Table 1). The1). The variation variation of the of thealkyl alkyl sub- 3 substituentstituent R3 Rin inthe the phosphoryl phosphoryl group group has has little little effe effect,ct, while while the the nature of thethe fluoroalkylfluoroalkyl 2 groupgroup RR2 cancan significantlysignificantly influenceinfluence thetheZ/E-isomeric Z/E-isomeric ratioratio forfor IPs.IPs. Interestingly,Interestingly, inin thethe 1 moremore stablestable Z-isomerZ-isomer ofof trifluoromethyl-substitutedtrifluoromethyl-substituted IPs, IPs, the the substituent substituent R R1at atthe thenitrogen nitrogen atomatom isis inin thethe cis-positioncis-position relativerelative toto thethe bulkybulky dialkylphosphonyldialkylphosphonyl group,group, i.e., i.e., thethe stericallysterically less-favorableless-favorable isomerisomer isis moremore advantageous.advantageous. InIn turn,turn, thethe structurestructure ofof these these compounds compounds can significantly affect their chemical properties: their reactivity and the stereochemical outcome of enantio- and diastereoselective reactions, etc.

R1 R2 R2 N 3 k1 N OR OR3 P R1 P O 3 O 3 OR k-1 OR

Z-IP E-IP

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can signiﬁcantly affect their chemical properties: their reactivity and the stereochemical outcome of enantio- and diastereoselective reactions, etc. Table 1. The ratio of isomers of iminophosphonates (see Scheme 1). Table 1. The ratio of isomers of iminophosphonates (see Scheme1). Entry R1 R2 R3 Z/E ΔG(Z/E) a Entry1 RH1 R2CF3 REt3 10:1Z/E [12] ∆G(Z/E) a 2 H CHF2 Et 5:1 1 H CF3 Et 10:1 [12] 3 H C3F7 Et 20:1 2 H CHF2 Et 5:1 4 3Ph H C3FCF7 3 EtEt 7:1 20:1 −16.0 5 44-MeOC Ph6H4 CF3CF3 EtMe 5:17:1 [9] −14.4−16.0 6 5 4-MeOC4-CNC6H4 CF3CF3 MeMe 7:1 5:1 [9] [9 ] −19.7−14.4 6 4-CNC H CF Me 7:1 [9] −19.7 7 Me6 4 3CF3 Et 10:1 7 Me CF3 Et 10:1 8 сус-Pr CF3 Et 11:1 [11] −5.9 8 cyc-Pr CF3 Et 11:1 [11] −5.9 9 9 MeMe PhPh EtEt 1:17 1:17 [9] [9 ] 1010 CHMeCHMe22 PhPh EtEt 1:20 1:20 1111 4-MeOC4-MeOC66HH44 PhPh Et Et 1:13 1:13 aa CalculatedCalculated (M06-2X/6-311+G**, (M06-2X/6-311+G**, PCM PCM solvent solvent model, model, solvent: solvent: toluene) toluene) difference difference in Gibbs in free Gibbs energy free (kJ mol−1) betweenenergy (kJ E and mol Z−1 isomers.) between Negative E and Z values isomers. mean Negative a higher values stability mean of the aZ-isomer. higher stability of the Z-isomer. In this work, we investigated Z/E-isomerism for IPs 1–10 using density functional In this work, we investigated Z/E-isomerism for IPs 1–10 using density functional theory (DFT) (M06-2X/6-311+G** level) and ab initio spin-component-scaled second- theory (DFT) (M06-2X/6-311+G** level) and ab initio spin-component-scaled second-order orderMøller–Plesset Møller–Plesset perturbation perturbation theory (SCS-MP2/cc-pVTZ theory (SCS-MP2/cc-pVTZ level) calculations level) calculations [15,16] (Figure [15 ,16] (Figure2). In particular,2) . In particular, the stability the of stability the structures of the structurescorresponding corresponding to the local toenergy the local minima energy minimaand transition and transition states for the states Z/E-isomerization for the Z/E-isomerization process, their process,relative energies, their relative charge energies, dis- chargetribution, distribution, and bond critical and bond points critical will be points discussed will be in discusseddetail. in detail.

R2 O

P OMe N OMe

1 2 1 2 1 2 1 2 1 2 1 (R =Me;R =CF3); 2 (R =cyc-Pr;R =CF3);3(R =R =Me);4 (R =R =Ph);5 (R =Ph;R =CF3); 1 2 1 2 1 2 1 2 6 (R =p-NCC6H4;R =CF3); 7 (R =p-MeOC6H4;R =CF3); 8 (R =H;R =CF3); 9 (R =H;R =Ph); 1 2 10 (R =SiMe3;R =CF3) FigureFigure 2. Calculated iminophosphonates iminophosphonates 1–101–10. .

2. Methods of Calculations 2. Methods of Calculations All of the calculations were performed with the GAUSSIAN-09 set of programs [17]. All of the calculations were performed with the GAUSSIAN-09 set of programs [17]. The M062X [15,16] function in combination with 6–31+G** basis sets [18,19] were used for The M062X [15,16] function in combination with 6–31+G** basis sets [18,19] were used the geometry optimization and calculations of the vibrational frequencies. The equilib- forrium the structures geometry were optimization utilized for andthe generati calculationson of the of thePROAIMS vibrational wave frequencies.function files The(wfn) equi- libriumat the RHF/6–31G* structures werelevel of utilized theory. for NBO the charges generation were of derived the PROAIMS using the waveNBO function3.1 proce- ﬁles (wfn)dure [20–22] at the RHF/6–31G*implemented into level the of GAUSSIAN-09 theory. NBO charges set of programs were derived at the usingM062X/6–311 the NBO + 3.1 procedureG** level of [ 20approximation.–22] implemented The same into level the GAUSSIAN-09 of theory was used set offor programs the single-point at the energy M062X/6– 311calculations + G** level in combination of approximation. with the The PCM same [23] level and CPCM of theory [24,25] was solvent used for models, the single-point as im- energyplemented calculations into the GAUSSIAN-09 in combination package with the (see PCM ESI, [23 Table] and S3). CPCM The [ 24Jmol,25 ]program solvent models,[26,27] as implementedwas used for the into graphical the GAUSSIAN-09 presentation package of the structures. (see ESI, Table Single-point S3). The MP2 Jmol energy program calcu- [26,27] waslations used for for5–7 the were graphical carried out presentation using the TURBOMOLE of the structures. program Single-point package MP2(version energy 6.4) calculations[28,29] and for SCS-MP25–7 were level carried of approximation out using the [30–33] TURBOMOLE with triple-zeta program cc-pVTZ package Dunning’s (version 6.4)basis [28 sets,29 ][34]. and Resolution SCS-MP2 of level the ofIdentity approximation (RI) approximation [30–33] with [35,36] triple-zeta was utilized cc-pVTZ in all Dun- ning’scases to basis increase sets [the34]. calculation Resolution speed of the and Identity efficiency. (RI) approximation Topological Bader’s [35,36 ‘atoms] was utilizedin the in allmolecule’ cases to (AIM) increase [37] the and calculation Non-Covalent speed Interactions and efﬁciency. (NCI) Topological analyses [38] Bader’s were performed ‘atoms in the

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molecule’ (AIM) [37] and Non-Covalent Interactions (NCI) analyses [38] were performed usingusing the the Multiwfn program [39]. [39]. The The energies energies of of the hydrogen bonds were estimated accordingaccording to the values of the potential energy at the critical points [[40].40].

3.3. Results Results TheThe structures structures of of the the Z- and E- E-isomersisomers of of N-methyl derivative derivative 11 (respectively,(respectively, 1-Z andand 1-E1-E)) and and the the transition transition state state of ofthe the isomerization isomerization reaction reaction (1-TS (1-TS) optimized) optimized in the in ap- the proximationapproximation M06-2X/6-311+G** M06-2X/6-311+G** are areshown shown in Figure in Figure 3. 3.

FigureFigure 3. 3. OptimizedOptimized structures of the Z-Z- andand E-isomersE-isomers ((1-Z1-Zand and1-E 1-E,, respectively), respectively), and and the the transition transi- tionstate state of the of isomerizationthe isomerization reaction reaction1-Z →1-Z1-E → (1-E1-TS (1-TS). Hereinafter,). Hereinafter, the structuresthe structures are presented are presented using usingthe Jmol the programJmol program [26,27 ,[26,27,41].41].

OurOur calculations predict higherhigher thermodynamicthermodynamic stabilitystability for for the the Z-structure Z-structure of of1 (11-Z (1-) Z(by) (by 8.8 8.8 kJ kJ mol mol−1−)1) compared compared to to the the E-form E-form ( 1-E(1-E)) (Table(Table S1). S1). TheThe calculatedcalculated values of the activationactivation energies for the E →ZZ( (Δ∆G)G) and and Z Z→→EE transformations transformations ( (Δ∆G’)G’) are are 83.0 and 91.8 kJ − molmol−1,1 respectively., respectively. However, However, the the data data of of quantum quantum chemical chemical calculations calculations do do not not allow allow us toto find find a a trivial trivial explanation explanation of of the the observed observed advantage advantage of ofthe the Z-isomer Z-isomer over over the the E-form. E-form. In particular,In particular, the the Z-structure Z-structure seems seems to to be be st stabilizedabilized by by two two hydrogen hydrogen bonding (HB) HH···⋅⋅⋅F (2.410(2.410 Å) Å) and and H H⋅⋅⋅···OO (2.532 (2.532 Å). Å). These These are are confirmed confirmed by by the the existence existence of of corresponding corresponding (3, (3, – –1)1) critical critical points points (CPs) (CPs) obtained obtained by by the the analysis analysis of of the the electron electron density by Bader’s ‘atoms inin the the molecule’ molecule’ method method (AIM) (AIM) [37] [37 ](Figure (Figure 4,4 ,left, left, CPs CPs 1 1and and 2). 2). The The estimated estimated energies energies of −1 theofthe hydrogen hydrogen bonding bonding [40] [ 40are] are−10.2− 10.2and and−10.6− kJ10.6 mol kJ−1 mol, respectively., respectively. However, However, the corre- the spondingcorresponding energies energies of the of three the three HBs HBs H⋅⋅⋅N H ···(2.745N (2.745 Å) and Å) and H⋅⋅⋅ HF ···(2.407F (2.407 and and 2.408 2.408 Å) Å)found found in −1 1-Ein 1-E (Figure(Figure 4, right)4, right) for for CPs CPs 1, 2 1, and 2 and 3 (− 36.9, ( − −6.9,11.5− and11.5 −12.9 and kJ−12.9 mol− kJ1, respectively) mol , respectively) in total evenin total exceed even the exceed energy the of energy the HBs of thein the HBs more in the favorable more favorable 1-Z structure.1-Z structure. Therefore, Therefore, hydrogenhydrogen bonding bonding by itself by does itself not does explain not th explaine higher the thermodynamic higher thermodynamic stability of stability the 1-Z ofstruc- the ture1-Z structurecompared compared to 1-E. No to new1-E. Noconclusions new conclusions can be drawn can be either drawn from either the from analysis the analysis of the of the NBO charge distributions in either isomers (Figure5). For example, the favorable NBO charge distributionsδ in eitherδ isomers (Figure 5). For example, the favorable Cou- Coulomb interactionδ (C –Hδ –C +F ) could rather be expected for 1-E, whereas for the more – 3 +3 3 3 lomb interaction (C H –C F ) could rather beδ –expectedδ+ for 1-E, whereas for the more sTa- sTable 1-Z, the similar charge configuration Cδ H3–Pδ is identical to that predicted for the ble 1-Z, the similar charge configuration C –H3–P + is identical to that predicted for the equilibrium structure of the less favorable 3-Z isomer without the trifluoromethyl group equilibrium structure of the less favorable 3-Z isomer without the trifluoromethyl group (vide infra). (vide infra). The replacement of the methyl substituent with the cyclopropyl group (Figure6, structures 2-E and 2-Z, models of the real compound, see Table1, entry 8) does not pro- vide significant changes in the relative stability of the isomers: the structure of 2-E is still noticeably (7.5 kJ mol−1) less favorable than the 2-Z isomer. The only structural feature is a conformational isomerism due to the rotation of the cyc-Pr substituent: in the most advantageous structure, the hydrogen atom N-CH forms an HB with P = O oxygen of the phosphonyl group (Z-isomer), or with the fluorine atom (E-isomer) (Figure6). The calculated ∆G and ∆G’ values (2-E→2-Z ∆G 78.4 kJ mol−1, 2-Z→2-E ∆G‘ 86.5 kJ mol−1) are slightly lower than the corresponding values predicted for the isomerization process of methyl derivative 1 (see above). At first sight, the transition state structure 2-TS could be stabilized via two weak C–F···H–C hydrogen bonds, and electron density distribution analysis using the NCI method [38] indicated weak attraction between fluorine and hydrogen

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Organics 2021, 2, FOR PEER REVIEW 6 Organics 2021, 2, FOR PEER REVIEWatoms (see ESI, Figure S1, left). However, the absence of the corresponding bond-critical6 points in the AIM analysis (Figure S1, right) does not support this assumption. Figure 4. Bond-critical points of type (3, −1) (CPs) for 1-Z and 1-E.

H O OMe -0.41 O OMe +2.34 P OMe H C P +2.31 -0.38 -0.14 H OMe NC NC-0.15 H F -0.35 C C F C F -0.42 +1.05 H H F +1.05 FF 1-E 1-Z

H H H C O O -0.42 O OMe H P +2.34 H C P +2.29 -0.44 OMe H OMe NC-0.04 -0.43NC-0.06 H C -0.67C H -0.63 C -0.41 H H H H H H H Figure 4. Bond-critical points of type (3, −1)1) (CPs) (CPs) for for 1-Z1-Z andand 1-E1-E. . 3-E Figure 4. Bond-critical3-Z points of type (3, −1) (CPs) for 1-Z and 1-E.

Figure 5. Charges on theO atomsOMe in compoundsH 1 andO OMe3, calculated by the NBO method. O -0.41 H O OMe +2.34 P OMe H-0.41C P +2.31 -0.38 +2.34 P OMe H C P +2.31OMe The replacement-0.38NC -0.14of OMethe methyl substituentH NC OMewith the cyclopropyl group (Figure 6, NC-0.14 NC-0.15 H C C F -0.35 C-0.15F structures 2-E-0.42H and 2-Z, modelsFF of the real-0.35 compound, see Table 1, entry 8) does not pro- C C+1.05F F C+1.05F vide significant-0.42 HchangesH F in the relative stabilityF +1.05of the isomers: the structure of 2-E is still H H F +1.05 FF noticeably (7.5 kJ mol1-E−1) less favorable than1-Z the 2-Z isomer. The only structural feature is 1-E 1-Z a conformational isomerism due to the rotation of the cyc-Pr substituent: in the most ad- H vantageous structure,H H the hydrogen atom N-CH forms an HB with P = O oxygen of the H C O O H O OMe phosphonyl groupC (Z-isomer),O or with-0.42 theH fluoOrineOMe atom (E-isomer) (Figure 6). The calcu- H P +2.34O -0.42 +2.29 +2.34 → H C P +2.29 −1 → −1 lated ΔG and -0.44ΔG’H valuesP OMe (2-E 2-Z ΔHG C78.4 kJP OMemol , 2-Z 2-E ΔG‘ 86.5 kJ mol ) are -0.44NC-0.04OMe H NC-0.06OMe NC-0.04 -0.43 NC slightly lowerH thanC -0.67 theC correspondingH -0.43values-0.63 predictedC-0.06 for the isomerization process of -0.41H C -0.67C HH -0.63 C H methyl derivative-0.41 1 (see above). At first sight,H the Htransition state structure 2-TS could be H H H H HH stabilized via twoH HweakH C–F⋅⋅⋅H–C hydrogenH bonds, and electron density distribution 3-E 3-Z analysis using the NCI3-E method [38] indicated3-Z weak attraction between fluorine and hy- Figure 5. Charges on the atoms in compounds 1 and 3, calculated by the NBO method. drogen atomsFigureFigure (see 5.ESI,5. ChargesCharges Figure onon S1, thethe left). atomsatoms Howe inin compoundscompoundsver, the absence1 1and and3, 3, ofcalculated calculated the corresponding byby thethe NBONBO method.bond-method. critical points in the AIM analysis (Figure S1, right) does not support this assumption. The replacement of the methyl substituent with the cyclopropyl group (Figure 6, The replacement of the methyl substituent with the cyclopropyl group (Figure 6, structures 2-E and 2-Z, models of the real compound, see Table 1, entry 8) does not pro- structures 2-E and 2-Z, models of the real compound, see Table 1, entry 8) does not pro- vide significant changes in the relative stability of the isomers: the structure of 2-E is still vide significant changes in the relative stability of the isomers: the structure of 2-E is still noticeably (7.5 kJ mol−1) less favorable than the 2-Z isomer. The only structural feature is noticeably (7.5 kJ mol−1) less favorable than the 2-Z isomer. The only structural feature is a conformational isomerism due to the rotation of the cyc-Pr substituent: in the most ad- a conformational isomerism due to the rotation of the cyc-Pr substituent: in the most advantageous structure, the hydrogen atom N-CH forms an HB with P = O oxygen of the vantageous structure, the hydrogen atom N-CH forms an HB with P = O oxygen of the phosphonyl group (Z-isomer), or with the fluorine atom (E-isomer) (Figure 6). The calcu- phosphonyl group (Z-isomer), or with the fluorine atom (E-isomer) (Figure 6). The calculated ΔG and ΔG’ values (2-E→2-Z ΔG 78.4 kJ mol−1, 2-Z→2-E ΔG‘ 86.5 kJ mol−1) are lated ΔG and ΔG’ values (2-E→2-Z ΔG 78.4 kJ mol−1, 2-Z→2-E ΔG‘ 86.5 kJ mol−1) are slightly lower than the corresponding values predicted for the isomerization process of slightly lower than the corresponding values predicted for the isomerization process of methyl derivative 1 (see above). At first sight, the transition state structure 2-TS could be methyl derivative 1 (see above). At first sight, the transition state structure 2-TS could be stabilized via two weak C–F⋅⋅⋅H–C hydrogen bonds, and electron density distribution Figure 6. Optimized structuresstabilized of Z- and via E-isomers two weak (2-Z andC–F2-E⋅⋅⋅H–C, respectively) hydrogen and bonds, the transition and elec statetron of thedensity isomerization distribution analysis using the NCI method [38] indicated weak attraction between fluorine and hy- reaction 2-Z → 2-E (2-TS). analysis using the NCI method [38] indicated weak attraction between fluorine and hydrogen atoms (see ESI, Figure S1, left). However, the absence of the corresponding bond- drogen atoms (see ESI, Figure S1, left). However, the absence of the corresponding bond- critical points in the AIM analysis (Figure S1, right) does not support this assumption. criticalIn contrastpoints in to the compounds AIM analysis1 and (Figure2, for S1, methyl right) derivative does not support3 (Figure this7), theassumption.3-E isomer proved to be more stable than the corresponding 3-Z structure by 4.6 kJ mol−1, and the inversion barriers increased sharply (3-E→3-Z ∆G 102.0 kJ mol−1, ∆G’ 3-Z→3-E 97.4 kJ mol−1). The only important difference in the charge distribution in the molecule, compared to 1, is the lack of a positive charge on the carbon atom of the methyl group, which replaces the CF3 group (Figure5). The close proximity of the similarly charged carbon atoms in 3E should destabilize the more stable E-structure compared with the Z-isomer. Thus, the different charge distributions in 1 and 3 that inﬂuence the Coulomb interactions in the

Organics 2021, 2, FOR PEER REVIEW 7

Figure 6. Optimized structures of Z- and E-isomers (2-Z and 2-E, respectively) and the transition → state of the isomerizationFigure 6. Optimized reaction 2-Zstructures 2-Е (of2-TS Z- ).and E-isomers (2-Z and 2-E, respectively) and the transition state of the isomerization reaction 2-Z → 2-Е (2-TS). In contrast to compounds 1 and 2, for methyl derivative 3 (Figure 7), the 3-E isomer proved to be moreIn stablecontrast than to compoundsthe corresponding 1 and 2 ,3-Z for structuremethyl derivative by 4.6 kJ 3mol (Figure−1, and 7), the the 3-E isomer inversion barriersproved increased to be more sharply stable ( 3-Ethan→ 3-Zthe correspondingΔG 102.0 kJ mol 3-Z−1, structureΔG’ 3-Z→ by3-E 4.6 97.4 kJ kJmol −1, and the mol−1). The onlyinversion important barriers difference increased in the sharply charge (distribution3-E→3-Z ΔG in 102.0 the molecule, kJ mol−1 ,compared ΔG’ 3-Z→ 3-E 97.4 kJ to 1, is the lackmol of− 1a). positive The only charge important on the difference carbon atom in the of charthe methylge distribution group, which in the replacesmolecule, compared the CF3 groupto (Figure1, is the 5).lack The of aclose positive proximity charge of on the the similarly carbon atom charged of the carbon methyl atoms group, in 3Ewhich replaces Organics 2021, 2 89 should destabilizethe CF the3 group more (Figure stable E-structur5). The closee compared proximity with of the the similarly Z-isomer. charged Thus, the carbon dif- atoms in 3E ferent chargeshould distributions destabilize in 1 the and more 3 that stable influence E-structur the Coulombe compared interactions with the Z-isomer. in the iso- Thus, the dif- meric structuresferent cannot charge serve distributions as a suitable in 1explanation and 3 that influencefor the configurational the Coulomb stabilityinteractions in in the iso- the series of mericinterest.isomeric structures structures cannot cannot serve serve as a as suitable a suitable explanation explanation for forthe the configurational conﬁgurational stability stability in thein the series series of interest. of interest.

Figure 7. Optimized structures of Z- and E-isomers (3-Z and 3-E, respectively) and the transition → state of the isomerizationFigureFigure 7. 7. OptimizedOptimized reaction 3-Zstructures structures 3-Е (of3-TS of Z- Z- ).and and E-isomers E-isomers (3-Z (3-Z andand 3-E3-E, respectively), respectively) and and the the transition transition statestate of of the the isomerization isomerization reaction reaction 3-Z → 3-3-EЕ ((3-TS3-TS).). The replacement of C- and N-methyl groups in 3 by phenyl substituents (Figure 8, structures 4-Z andTheThe 4-E replacement replacement) decreases the of of C-advantage C- and and N-methyl N-methyl for the groups4-E groups-isomer in in 33 tobyby 1.7 phenyl phenyl kJ mol substituents substituents−1. There- (Figure (Figure 88,, −1 fore, the theoreticallystructuresstructures and4-Z andexperimentally 4-E) decreases found the advantageadvantagestabilization forfor of thethe the 4-E4-E Z-isomers-isomer-isomer toto in 1.71.7 com- kJkJ molmol−1.. There- There- pounds 1,2 isfore,fore, mainly the the antheoretically theoretically effect of the and and trifluoromet experimentally experimentallyhyl group. fo foundund The stabilization stabilization values of theof of theactivation the Z-isomers Z-isomers in in com- com- energy for thepoundspounds isomerization 1,21,2 isis mainly processes an effect E→ ofZ the(ΔG) triﬂuoromethyltrifluoromet and Z→E hyl(ΔG’) group. for compound The values 4 ofare the activation lower than thoseenergyenergy found for for the for isomerization 1: 62.1 and 60.4 processes processes kJ mol− 1EE, →→respectivelyZZ ((Δ∆G)G) and and (Table Z→EE S1).((Δ∆G’)G’) The for for lower compound 44 are −1 activation barrierslowerlower can than probably thosethose foundfound be referred for for1 :1 62.1: 62.1to andan and additional 60.4 60.4 kJ molkJ stabilizationmol,− respectively1, respectively of the (Table 4-TS(Table S1). tran- S1). The The lower lower acti- sition state byactivationvation conjugation barriers barriers effects. can can probably probably be referred be referred to an to additional an additional stabilization stabilization of the of4-TS the 4-TStransition tran- sitionstate bystate conjugation by conjugation effects. effects.

Figure 8. OptimizedFigure 8. structures Optimized of Z-structures and E-isomers of Z- and (4-Z E-isomersand 4-E, respectively)(4-Z and 4-E, and respectively) the transition and statethe transition of the isomerization → reaction 4-Z →state4-E of(4-TS the ).isomerizationFigure 8. Optimized reaction 4-Zstructures 4-Е (of4-TS Z- ).and E-isomers (4-Z and 4-E, respectively) and the transition state of the isomerization reaction 4-Z → 4-Е (4-TS). Previously [9], we investigated the process of Z/E-isomerization in N-aryltrifluoroacetimidoyl phosphonates by dynamic NMR on 19F nuclei, and we calculated the rate constant of the isomerization process and its thermodynamic parameters using the Eyring equation. The activation barriers for the transformation were found to be quite low, such that it proceeds even at room temperature [9]. For model 5 (Figure9), our calculations predict

conformational isomerism for the structures corresponding both to the local energy minima

and to TS structures. As our calculations show, it is possible to localize for 5 two different energy minima for the E-forms, 5-E and 50-E (50-E is 6.2 kJ mol−1 more stable than 5-E), and the geometry of the corresponding Z-isomers, 5-Z and 50-Z differs, too (5-Z is 5.7 kJ mol−1 more stable than 50-Z and 9.2 kJ mol−1 more stable than 50-E). The structure of 5-Z seems to be stabilized due to CH,π-interactions: the distance from one of the hydrogen atoms of the P-methoxy group to the carbon atoms of the Ph ring is almost identical, 2.8–2.9 Å, while for the conformation 50-Z CPhH···O=P, hydrogen bonding was found. For these two types of conformational isomers, two different paths of Z,E-transformation and correspondingly, Organics 2021, 2 90

two transition state structures (5-TS and 50-TS) can be located. Interestingly, despite almost identical calculated total energies (the difference in ∆G values is only ca. 0.2 kJ mol−1 in favor of 50-TS), the structures themselves differ signiﬁcantly. In the case of 5-TS, it is easy to recognize an iminium-type structure, in which the plane of the Ph moiety and the plane of the C = N π-system are almost orthogonal to each other (the corresponding dihedral angle in the optimized TS structure is ~65◦), which minimizes steric interactions. The alternative (and somewhat more advantageous) structure of 50-TS is of the quinone imine type: the two π-systems are in the same plane, and the structure is stabilized by two hydrogen bonds, F···H (2.78 Å) and O···H (2.96 Å). Therefore, the isomerization of 5 can proceed via two different reaction pathways, as the isomeric local minima for the Organics 2021, 2, FOR PEER REVIEW 0 0 9 most favorable 5 -E and 5-Z structures can easily undergo transformations to 5-E and 5 -Z, respectively, with much lower activation energies (not studied here in detail).

FigureFigure 9.9. Optimized structures of the Z- andand E-isomersE-isomers ofof compoundcompound 55 ((5-Z5-Z,, 550′-Z-Z andand 5-E5-E,, 550′-E-E,, respectively),respectively), andand thethe structuresstructures correspondingcorresponding toto thethe transitiontransition statesstates ofof thethe isomerizationisomerization reactionreaction( 5-TS(5-TSand and5 50′-TS-TS).).

As we have shown previously [9], the introduction of the electron acceptor substituent (CN) in the para-position of the aromatic moiety signiﬁcantly accelerates the isomerization process, i.e., it reduces the activation energy of the inversion around the nitrogen atom. The DFT calculations evidence that the substitution character in the aromatic ring affects the structure of the ground and transition states (Figure 10): the only located TS structure 6-TS involving the acceptor nitrile group mimics structure 5-TS (Scheme2), whereas the donor methoxy group promotes the formation of the planar transition state 7-TS, which is similar to 50-TS discussed above. The different polar structures predicted for 6-TS, involving the imino-nitrogen lone pair in direct conjugation with the π-acceptor nitrile group, and 7-TS with the delocalization of electron density from the π-donor methoxy oxygen onto the acceptor CF3 and phosphonic groups (Scheme2) is reﬂected in their geometry: the CF 3C-N bond is slightly shorter in 6-TS (1.228 Å) than in 7-TS (1.237 Å), and the interatomic distances C–P and C-CF3 in 6-TS (1.858 and 1.541 Å, respectively) are still slightly longer than those predicted for 7-TS (1.842 and 1.534 Å, respectively).

Figure 10. Optimized structures of the Z- and E-isomers of compounds 6 and 7 (6-Z, 7-Z and 6-E, 7-E, respectively), and the structures corresponding to the transition states of the isomerization reaction (6-TS and 7-TS).

O OMe O OMe P P OMe OMe N C N N C N CF3 CF3

O OMe O OMe O OMe Me P Me P Me P OMe OMe OMe O N O N O N CF3 CF3 CF3 Scheme 2. Different substituent effects of electron delocalization in compounds 6 and 7, stabilizing the transition state structure for the Z,E-isomerization reaction.

Organics 2021, 2, FOR PEER REVIEW 9 Organics 2021, 2, FOR PEER REVIEW 9

Organics 2021, 2 91 Figure 9. Optimized structures of the Z- and E-isomers of compound 5 (5-Z, 5′-Z and 5-E, 5′-E, respectively), and the structuresFigure 9. Optimizedcorresponding structures to the transitionof the Z- statesand E-isomers of the isomerization of compound reaction 5 (5-Z (5-TS, 5′-Z and and 5 ′5-E-TS, ).5 ′-E, respectively), and the structures corresponding to the transition states of the isomerization reaction (5-TS and 5′-TS).

FigureFigure 10. Optimized structures ofof thethe Z-Z- and and E-isomers E-isomers of of compounds compounds6 and6 and7 (76-Z (6-Z, 7-Z, 7-Zand and6-E 6-E, 7-E, 7-E, respectively),, respectively), and and the Figure 10. Optimized structures of the Z- and E-isomers of compounds 6 and 7 (6-Z, 7-Z and 6-E, 7-E, respectively), and thestructures structures corresponding corresponding to the to the transition transiti stateson states of the of isomerizationthe isomerization reaction reaction (6-TS (6-TSand and7-TS 7-TS). ). the structures corresponding to the transition states of the isomerization reaction (6-TS and 7-TS). O OMe O OMe OP OMe O P OMe P OMe P OMe N C N OMe N C N OMe N C N N C N CF3 CF3 CF3 CF3

O OMe O OMe O OMe Me OP OMe Me O P OMe Me O P OMe Me P OMe Me P OMe Me P OMe O N OMe O N OMe O N OMe O N O N O N CF3 CF3 CF3 CF3 CF3 CF3 Scheme 2. Different substituent effects of electron delocalization in compounds 6 and 7, stabilizing the transition state structureScheme 2.for Different the Z,E-isomerization substituent effects reaction. of electron delocalization in compounds 6 and 7, stabilizing the transitiontransition state structure for the Z,E-isomerization reaction. structure for the Z,E-isomerization reaction.

It was found by a dynamic NMR study that the activation barriers of Z→E isomer- 6= −1 ization in toluene-d8 increase in the order 6 < 5 < 7 (∆G 298 64.6, 67.1 and 73.4 kJ mol , respectively) [9]. However, the gas phase DFT calculations failed to reproduce the experi-

mental trend of activation energies. In particular, the activation energy calculated for Z→E isomerization in the 4-CN-substituted compound 6 (∆G 68.3 kJ mol−1) is even slightly higher than the value predicted for the 4-methoxy derivative 7 (∆G 66.5 kJ mol−1). Finally, the highest activation barrier in the studied series was predicted for phenyl derivative 5 (∆G 73.5 kJ mol−1). Such discrepancies were observed despite the use of the DFT functional (M06-2X), which is known to reproduce well the thermochemistry of chemical reactions and, in particular, the values of activation barriers [15,16]. As could be expected, taking into account the solvent effects for the low-polar toluene using empirical PCM and CPCM methods did not improve the compliance with the experiment (see Table S3). In particular, while some qualitative agreement was found for 5–7 between the experimentally found Z/E-isomeric ratio and the calculated differences in the Gibbs free energy values, corrected for solvent effects (Table1, Table S3), predicting the lowest advantage of Z-isomer for 7, the predicted stability of 2-Z was obviously too low. Thus, the stability of Z-isomers seems to be overestimated for structures 5–7, and—at the chosen approximation level—we cannot expect any general correlation between the calculated and experimental data. However, the application of a more superior RI-SCS-MP2 level of approximation [33] in combination with the larger Dunning cc-pVTZ basis sets [34] and DFT corrections to ∆G values (Table S2) to some extent lowers the advantage of Z-isomers for structures 5, 6 and 7 (3.3, 13.0 and Organics 2021, 2, FOR PEER REVIEW 10

It was found by a dynamic NMR study that the activation barriers of Z→E isomeri- ≠ zation in toluene-d8 increase in the order 6 < 5 < 7 (ΔG 298 64.6, 67.1 and 73.4 kJ mol−1, respectively) [9]. However, the gas phase DFT calculations failed to reproduce the experimental trend of activation energies. In particular, the activation energy calculated for Z→E isomerization in the 4-CN-substituted compound 6 (ΔG 68.3 kJ mol−1) is even slightly higher than the value predicted for the 4-methoxy derivative 7 (ΔG 66.5 kJ mol−1). Finally, the highest activation barrier in the studied series was predicted for phenyl derivative 5 (ΔG 73.5 kJ mol−1). Such discrepancies were observed despite the use of the DFT functional (M06-2X), which is known to reproduce well the thermochemistry of chemical reactions and, in particular, the values of activation barriers [15,16]. As could be expected, taking into account the solvent effects for the low-polar toluene using empirical PCM and CPCM methods did not improve the compliance with the experiment (see Table S3). In particular, while some qualitative agreement was found for 5–7 between the experimentally found Z/E-isomeric ratio and the calculated differences in the Gibbs free energy values, corrected for solvent effects (Table 1, Table S3), predicting the lowest advantage of Z-isomer for 7, the predicted stability of 2-Z was obviously too low. Thus, the stability of Z-isomers seems to be overestimated for structures 5–7, and—at the chosen approximation level—we cannot expect any general correlation between the calculated and experimental data. How- Organics 2021, 2 92 ever, the application of a more superior RI-SCS-MP2 level of approximation [33] in combination with the larger Dunning cc-pVTZ basis sets [34] and DFT corrections to ΔG values (Table S2) to some extent lowers the advantage of Z-isomers for structures 5, 6 and 7 5.3(3.3, kJ 13.0 mol −and1, respectively), 5.3 kJ mol−1, respectively), and establishes and the establishes correct ratio the of correct activation ratio energies of activation for these en- modelergies structuresfor these model (see Discussion). structures (see Discussion). TheThe replacementreplacement ofof thethe substituentsubstituent atat thethe nitrogennitrogen atomatom byby hydrogenhydrogen (Scheme(Scheme3 )3) shouldshould additionally additionally stabilize stabilize the the Z-isomers Z-isomers compared compared to to the the E-structures E-structures due due to to a a probableprobable formationformation ofof N-HN-H····O=P····O=P hydrogen bonds (Figures(Figures 1111 andand 1212).). TheThe calculatedcalculated valuesvalues ofof activationactivation energiesenergies ∆ΔGG relatedrelated toto thethe moremore stablestable Z-isomersZ-isomers 8-Z8-Z andand 9-Z9-Z(Table (Table S1, S1, 107.2 107.2 −1 andand 119.7119.7 kJkJ mol mol−1,, respectively) are thethe highesthighest forfor thethe studiedstudied seriesseries ofof IPs.IPs. AA suitable suitable explanationexplanation for such high high barriers, barriers, in in addition addition to tohydrogen hydrogen bonding bonding stabilizing stabilizing the theZ-con- Z- conﬁguration,figuration, is the is the small small values values of ofthe the ∠HNC∠HNC valence valence angle angle (Table (Table S1, S1, 109.9 109.9 and and 110.7 110.7 for for 8- 8-ZZ andand 9-Z9-Z, ,respectively), respectively), which which are are much much smaller smaller than the corresponding ∠∠CNCCNC angleangle of of ◦ 122.0122.0°found found forfor thethe1-Z 1-Zstructure structure(the (thestructure structurewith withthe thelarger larger XNC XNC bond bond angle angle is is closer closer toto thethe transitiontransition statestate structurestructure andand requiresrequires lessless activationactivation energyenergy forfor thethe inversioninversion atat nitrogennitrogen [[7]).7]).

H H N O N O C P C P OMe OMe F C OMe C OMe F F F F F 8-E 8-Z

H H N O N O C P C P OMe OMe Ph Ph OMe OMe Organics 2021, 2, FOR PEER REVIEW 11 Organics 2021, 2, FOR PEER REVIEW 9-E 9-Z 11

SchemeScheme 3.3.Isomerization Isomerization ofof8 8and and9 9..

FigureFigure 11. 11. OptimizedOptimized structuresstructures ofof the the Z- Z- and and E-isomers E-isomers of of compound compound 88 (((8-Z8-Z andand 8-E8-E,,, respectively), respectively), and andand the thethe structure structurestructure corresponding to the transition state of the isomerization reaction (8-TS). correspondingcorresponding toto thethe transitiontransition statestate ofof thethe isomerizationisomerization reactionreaction ((8-TS8-TS).).

FigureFigure 12. 12. OptimizedOptimized structuresstructures ofof the the Z- Z- and and E-isomers E-isomers of of compound compound 99 (((9-Z9-Z andand 9-E9-E,,, respectively), respectively), and andand the thethe structure structurestructure correspondingcorrespondingcorresponding to to the the transitiontransition statstatestatee ofof thethe isomerizationisomerization reactionreaction ((9-TS9-TS).).

AsAs evidenceevidence forfor thisthis assumption,assumption, thethe replacementreplacement ofof thethe methylmethyl groupgroup inin 11 byby aa tri-trimethylsilylmethylsilyl substituentsubstituent (Scheme(Scheme 4,4, structuresstructures 1010)) destabilizesdestabilizes thethe groundground statesstates forfor bothboth thethe E-E- andand Z-isomersZ-isomers (Figure(Figure 13)13) duedue toto thethe ininfluencefluence ofof stericsteric factors.factors. TheThe correspondingcorresponding ∠ ∠SiNCSiNC bondbond anglesangles (138.0(138.0 andand 136.2°,136.2°, respecrespectively)tively) significantlysignificantly exceedexceed thethe correspond-correspond- inging valuesvalues inin 1-E1-E andand 1-Z1-Z (122.8(122.8 andand 122.0°),122.0°), andand areare muchmuch closercloser toto thethe geometrygeometry ofof thethe 10-TS10-TS (Figure(Figure 13).13). ThisThis facilitatesfacilitates thethe Z,E-isomZ,E-isomerizationerization reactionreaction [7],[7], andand determinesdetermines thethe → Δ → Δ lowestlowest activationactivation energiesenergies forfor thethe 10-E10-E→10-Z10-Z ((ΔG)G) andand 10-Z10-Z→10-E10-E ((ΔG’)G’) isomerizationisomerization −1 processesprocesses inin thethe studiedstudied seriesseries ofof IPsIPs (9.8(9.8 andand 25.925.9 kJkJ molmol−1,, respectively).respectively). DueDue toto thethe sig-sig- Δ −1 nificantnificant differencedifference inin energyenergy inin favorfavor ofof 10-Z10-Z ((ΔGG −−16.116.1 kJkJ molmol−1),), IPIP 1010 willwill existexist inin aa rapidrapid dynamicdynamic equilibriumequilibrium betweenbetween ththee E-E- andand Z-forms,Z-forms, stronglystrongly shiftedshifted towardstowards thethe Z-isomer.Z-isomer.

SiMe3 SiMe3 N O N O MeMe3SiSi N O N O 3 C P C P OMe C P OMeOMe F C P OMe C OMe F C F C OMe FF C OMeOMe F FF F FF F 10-E 10-Z 10-E 10-Z SchemeScheme 4.4. IsomerizationIsomerization ofof 1010..

Organics 2021, 2, FOR PEER REVIEW 11

Figure 11. Optimized structures of the Z- and E-isomers of compound 8 (8-Z and 8-E, respectively), and the structure corresponding to the transition state of the isomerization reaction (8-TS).

Organics 2021, 2 93 Figure 12. Optimized structures of the Z- and E-isomers of compound 9 (9-Z and 9-E, respectively), and the structure corresponding to the transition state of the isomerization reaction (9-TS).

AsAs evidenceevidence for this assumption, assumption, the the replacement replacement of of the the methyl methyl group group in in1 by1 bya tri- a trimethylsilylmethylsilyl substituent substituent (Scheme (Scheme 4,4, structures structures 1010)) destabilizes destabilizes the ground statesstates forfor bothboth thethe E-E- andand Z-isomersZ-isomers (Figure(Figure 13 13)) duedue toto the the influence influence of of steric steric factors. factors. TheThe correspondingcorresponding ◦ ∠∠SiNCSiNC bondbond angles angles (138.0 (138.0 and and 136.2 136.2°,, respectively) respectively) significantly significantly exceed exceed the the corresponding correspond- ◦ valuesing values in 1-E inand 1-E 1-Zand(122.8 1-Z (122.8 and 122.0 and 122.0°),), and are and much are much closer closer to the geometryto the geometry of the 10-TS of the (Figure10-TS (Figure 13). This 13). facilitates This facilitates the Z,E-isomerization the Z,E-isomerization reaction reaction [7], and [7], determines and determines the lowest the activationlowest activation energies energies for the 10-E for→ the10-Z 10-E(∆→G)10-Z and (10-ZΔG)→ and10-E 10-Z(∆G’)→10-E isomerization (ΔG’) isomerization processes −1 inprocesses the studied in the series studied of IPs series (9.8 of and IPs 25.9 (9.8 kJand mol 25.9, kJ respectively). mol−1, respectively). Due to theDue significant to the sig- 10-Z − −1 10 differencenificant difference in energy in inenergy favor in of favor of( ∆10-ZG (16.1ΔG − kJ16.1 mol kJ mol),− IP1), IP 10will will exist exist in in a a rapid rapid dynamicdynamic equilibriumequilibrium betweenbetween thethe E-E- andand Z-forms,Z-forms, stronglystrongly shiftedshifted towardstowards thethe Z-isomer.Z-isomer.

SiMe3 O N Me3Si N O C P C P OMe OMe F C OMe F C OMe F F F F 10-Z Organics 2021, 2, FOR PEER REVIEW 10-E 12

SchemeScheme 4.4. IsomerizationIsomerization ofof10 10..

Figure 13. Optimized structures of the Z- and E-isomers of compound 10 (10-Z and 10-E, respectively), and the structure corresponding to the transition statesstates of the isomerization reactionreaction ((10-TS10-TS).).

The replacement of of the di diakylphosphonicakylphosphonic group group in in 99 and 10 by the ester moiety (Scheme 55,, compoundscompounds 11 and 12,, respectively) respectively) does not not significantly signiﬁcantly affect the activation energies of the Z,E-isomerization process. process. The The most most stable stable are are E-isomers E-isomers 11-E11-E andand 12-E12-E,, which in in their their structure structure and and the the position position of of their their substituents substituents are are similar similar to to 9-Z9-Z andand 10-Z10- isomers.Z isomers. The The structure structure 11-E11-E (Figure(Figure 14), 14which), which is perfectly is perfectly planar planar (symmetry (symmetry Cs), is C obvi-s), is ouslyobviously stabilized stabilized due to due the to hydrogen the hydrogen bond bondN–H····O=C, N–H···· asO=C, evidenced as evidenced by its short by its H····O short distanceH····O distance (2.238 Å). (2.238 Structure Å). Structure 11-E is 35.911-E kJis mol 35.9−1 kJ more mol −stable1 more than stable 11-Z than, and11-Z the, value and the of thevalue activation of the activation energy of energy the process of the processof Z,E-isomerization of Z,E-isomerization is 101.3 is kJ 101.3 mol kJ−1 mol(relative−1 (relative to the moreto the stable more stableisomer isomer 11-E). 11-ETherefore,). Therefore, the presence the presence of both of bothisomers isomers with with a significant a signiﬁcant ad- vantageadvantage of 11-E of 11-E shouldshould be expected be expected both both in the in thegas gasphase phase and andin solutions in solutions (see (seeTable Table S3), andS3), andrapid rapid isomerization isomerization will willnot notoccur occur even even at elevated at elevated temperatures. temperatures. In contrast—as In contrast—as in thein the case case of compound of compound 10—for10—for the trimethylsilyl the trimethylsilyl derivative derivative 12 (Figure12 (Figure 15), the 15 value), the of value the −1 activationof the activation barrier barriercalculated calculated at the DFT at the approximation DFT approximation level is only level 24.3 is onlykJ mol 24.3−1 in kJ relation mol toin the relation isomer to the12-E isomer, which—according12-E, which—according to the results to of the calculations—is results of calculations—is more stable morethan −1 12-Zstable by than 13.412-Z kJ molby 13.4−1. This kJ mol agrees. This with agrees the large with predicted the large predictedvalue of the value ∠CNSi of the valence∠CNSi ◦ anglesvalence (137.5 angles and (137.5 134.4°, and respectively, 134.4 , respectively, vide supravide). supra).

Figure 14. Optimized structures of the Z- and E-isomers of compound 11 (11-Z and 11-E, respectively), and the structure corresponding to the transition states of the isomerization reaction (11- TS).

H H N O N O C C C C C OMe F C OMe F F F F F

11-Z 11-E

SiMe3 Me3Si N O N O C C C C C OMe F F F F C OMe F F 12-Z 12-E Scheme 5. Isomerization of 11 and 12.

Organics 2021, 2, FOR PEER REVIEW 12

Figure 13. Optimized structures of the Z- and E-isomers of compound 10 (10-Z and 10-E, respectively), and the structure corresponding to the transition states of the isomerization reaction (10-TS).

The replacement of the diakylphosphonic group in 9 and 10 by the ester moiety (Scheme 5, compounds 11 and 12, respectively) does not significantly affect the activation energies of the Z,E-isomerization process. The most stable are E-isomers 11-E and 12-E, which in their structure and the position of their substituents are similar to 9-Z and 10-Z isomers. The structure 11-E (Figure 14), which is perfectly planar (symmetry Cs), is obviously stabilized due to the hydrogen bond N–H····O=C, as evidenced by its short H····O distance (2.238 Å). Structure 11-E is 35.9 kJ mol−1 more stable than 11-Z, and the value of the activation energy of the process of Z,E-isomerization is 101.3 kJ mol−1 (relative to the more stable isomer 11-E). Therefore, the presence of both isomers with a significant ad- Organics 2021, 2, FOR PEER REVIEW 12 vantage of 11-E should be expected both in the gas phase and in solutions (see Table S3), and rapid isomerization will not occur even at elevated temperatures. In contrast—as in the case of compound 10—for the trimethylsilyl derivative 12 (Figure 15), the value of the activation barrier calculated at the DFT approximation level is only 24.3 kJ mol−1 in relation to the isomer 12-E, which—according to the results of calculations—is more stable than 12-Z by 13.4 kJ mol−1. This agrees with the large predicted value of the ∠CNSi valence angles (137.5 and 134.4°, respectively, vide supra).

Figure 13. Optimized structures of the Z- and E-isomers of compound 10 (10-Z and 10-E, respectively), and the structure corresponding to the transition states of the isomerization reaction (10-TS).

Organics 2021, 2 FigureThe 14. replacement Optimized structures of the di ofakylphosphonic the Z- and E-isomers group of compound in 9 and 1110 ( 11-Zby theand ester11-E, respec-moiety94 (Schemetively), and 5, compounds the structure 11correspon and 12,ding respectively) to the transition does statesnot significantly of the isomerization affect the reaction activation (11- energiesTS). of the Z,E-isomerization process. The most stable are E-isomers 11-E and 12-E, which in their structure and the position of their substituents are similar to 9-Z and 10-Z H isomers.H N TheO structure 11-E (FigureN O 14), which is perfectly planar (symmetry Cs), is obviously stabilizedC C due to the hydrogenC C bond N–H····O=C, as evidenced by its short H····O OMe C F C OMe −1 distanceF (2.238F Å). Structure 11-E is 35.9 kJ mol more stable than 11-Z, and the value of F F F the activation energy of the process of Z,E-isomerization is 101.3 kJ mol−1 (relative to the more stable11-Z isomer 11-E). Therefore,11-E the presence of both isomers with a significant advantage of 11-E should be expected both in the gas phase and in solutions (see Table S3), SiMe3 andMe3 SirapidN isomerizationO willN not Ooccur even at elevated temperatures. In contrast—as in the case ofC compoundC 10—for CtheC trimethylsilyl derivative 12 (Figure 15), the value of the C OMe F activationF Fbarrier calculatedF atC the OMeDFT approximation level is only 24.3 kJ mol−1 in relation F F to the isomer 12-E, which—according to the results of calculations—is more stable than 12-Z 12-E 12-Z by 13.4 kJ mol−1. This agrees with the large predicted value of the ∠CNSi valence anglesSchemeScheme (137.5 5. 5.Isomerization Isomerization and 134.4°, of of respectively,11 11and and12 12. . vide supra).

Organics 2021, 2, FOR PEER REVIEW 13 Figure 14. Optimized structuresstructures ofof the the Z- Z- and and E-isomers E-isomers of of compound compound11 11(11-Z (11-Zand and11-E 11-E, respectively),, respectively),and the and structure the structure corresponding correspon toding the transition to the transition states of states the isomerization of the isomerization reaction reaction (11-TS). (11- TS).

H H N O N O C C C C C OMe F C OMe F F F F F

11-Z 11-E

SiMe3 Me3Si N O N O C C C C C OMe F F F F C OMe F F 12-Z 12-E FigureFigure 15. 15. OptimizedOptimized structures structuresScheme of of the the 5. IsomerizationZ- Z- and and E-isomers E-isomers of 11 of of and compound compound 12. 1212 ((12-Z12-Z andand 12-E12-E,, respectively), respectively), and and the the structure structure correspondingcorresponding to to the the transition stat stateses of the isomerization reaction (12-TS).

4.4. Discussion Discussion The experimentally found specific effect of the trifluoromethyl group stabilizing the The experimentally found specific effect of the trifluoromethyl group stabilizing the stericallysterically less-favorable Z-formZ-form ofof IPs IPs is is reproduced reproduced well well by by quantum quantum chemical chemical calculations. calculations.However, However, the key the factor key causingfactor causing the stabilization the stabilization cannot cannot be easily be identified: easily identified: the driving the drivingrole of hydrogenrole of hydrogen bonding bonding (HB) in (HB) the Z-isomer in the Z-isomer of 1-Z cannotof 1-Z canno be confirmedt be confirmed by HB energyby HB energyestimation. estimation. In addition, In addition, the AIM the methodAIM method unexpectedly unexpectedly indicates indicates the presence the presence of bond of bondCPs betweenCPs between fluorine fluorine and oxygenand oxygen atoms atoms (Figure (Figure4, left, 4, critical left, critical points points 3 and 3 4), and as 4), well as ⋅⋅⋅⋅ wellas in as some in some other other CF 3CF-substituted3-substituted IPs IPs (see (see Figure Figure S2). S2). The The calculated calculated O O····F interatomic distancesdistances (2.89 (2.89 and and 2.92 2.92 Å) Å) are are even even slightly slightly shorter shorter than than the the sum sum of of the the van van der der Waals Waals radiiradii of of oxygen oxygen and and fluorine fluorine (2.99 (2.99 Å) [33]. [33]. The The found found O⋅⋅⋅⋅····FF interactions interactions cannot cannot be be referred referred toto the the well-known well-known ‘halogen ‘halogen bond’ bond’ [42–46], [42–46], whic whichh withal withal is is very very rarely rarely observed for for the fluorine–oxygenfluorine–oxygen pair pair [47]: [47]: the the predicted predicted C-F-O C-F-O bond bond angle angle is is far far away away from from the the favored valuevalue of of 180°, 180◦, which which is is typical typical for for halogen halogen bonding. bonding. Generally, Generally, the the presence presence of of CPs CPs cannot cannot bebe considered considered as as evidence evidence of of bonding bonding [48,49]. [48,49]. Thus, Thus, the the found found CPs CPs could could be be considered considered as as anan artifacts, artifacts, not not manifesting manifesting true true bonding bonding betw betweeneen fluorine fluorine and and oxygen oxygen atoms. atoms. In In this this case, case, a steric compression of the O⋅⋅⋅⋅F interatomic distances is unfavorable, and more likely resulted from the effect of other factors stabilizing the equilibrium conformations. This is confirmed by the NCI method [38], indicating repulsion between the fluorine and oxygen atoms (Figure S3). It was shown that the isomerization of compounds 5–7 can pass through two different but close-in-energy TSs, having the iminium and quinone imine structures (Scheme 2). The structure of TS is determined by the nature of the substituent in the aromatic moiety. The discrepancies observed for the calculated values of the activation energies using the DFT functional (M06-2X) were overcome by performing single-point energy calculations at the more superior RI-SCS-MP2 level of approximation [33] in combination with the larger Dunning cc-pVTZ basis sets [34]. The corrections to ΔG values calculated at the DFT level of theory established the correct ratio of activation energies between 5, 6 and 7 (ΔG(MP2) 73.2, 75.8 and 75.9 kJ mol−1, respectively). The activation barrier predicted for the 5-TS transition state is now definitely lower than that expected for the alternative reaction pathway via the 5′-TS transition state (ΔΔG(MP2) -5.4 kJ mol−1). Therefore, the complete 5′-E to 5-Z transformation proceeds can be formulated as 5′-E → 5-E → 5-TS → 5-Z, where the conformational equilibrium in the first stage requires much less activation energy than the nitrogen inversion. In conclusion, the structure of IPs is determined by a combination of factors such as HB, electronic and electrostatic interactions, and steric factors. In general, the advantage of Z- or E-isomers found in the experiment is well reproduced at the DFT level of theory. For the modeling of subtle substituent effects, the use of the more superior MP2 level of approximation is necessary. At the same time, the value of the activation energies is determined primarily by steric factors: the smaller the valence angle on the nominal nitrogen

Organics 2021, 2 95

a steric compression of the O····F interatomic distances is unfavorable, and more likely resulted from the effect of other factors stabilizing the equilibrium conformations. This is confirmed by the NCI method [38], indicating repulsion between the fluorine and oxygen atoms (Figure S3). It was shown that the isomerization of compounds 5–7 can pass through two different but close-in-energy TSs, having the iminium and quinone imine structures (Scheme2). The structure of TS is determined by the nature of the substituent in the aromatic moiety. The discrepancies observed for the calculated values of the activation energies using the DFT functional (M06-2X) were overcome by performing single-point energy calculations at the more superior RI-SCS-MP2 level of approximation [33] in combination with the larger Dunning cc-pVTZ basis sets [34]. The corrections to ∆G values calculated at the DFT level of theory established the correct ratio of activation energies between 5, 6 and 7 (∆G(MP2) 73.2, 75.8 and 75.9 kJ mol−1, respectively). The activation barrier predicted for the 5-TS transition state is now definitely lower than that expected for the alternative reaction pathway via the 50-TS transition state (∆∆G(MP2) -5.4 kJ mol−1). Therefore, the complete 50-E to 5-Z transformation proceeds can be formulated as 50-E → 5-E → 5-TS → 5-Z, where the conformational equilibrium in the first stage requires much less activation energy than the nitrogen inversion. In conclusion, the structure of IPs is determined by a combination of factors such as HB, electronic and electrostatic interactions, and steric factors. In general, the advantage of Z- or E-isomers found in the experiment is well reproduced at the DFT level of theory. For the modeling of subtle substituent effects, the use of the more superior MP2 level of approximation is necessary. At the same time, the value of the activation energies is determined primarily by steric factors: the smaller the valence angle on the nominal nitrogen atom in the ground state of the compound, the higher the activation barrier for the inversion at nitrogen. Within the studied series, the values of the activation energy range from 10 to 110 kJ mol−1, which corresponds to the isomerization freely proceeding at room temperature, or the simultaneous presence of both isomers in solution in the absence of rapid exchange at the temperature limit of the standard NMR probe head (~120 ◦C).

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/org2020008/s1, Table S1: Calculated (M062X/6–311+G**) total energy values (E), zero-point energy correction (ZPE), thermal correction to Gibbs free energy (TCGFE), corrected energy values (E+ZPE and E+TCGFE), relative energy values (∆E and ∆G) and the lowest vibration. Table S2: Calculated (RI-MP2/cc-pVTZ) total energy values (E(MP2)), zero point energy correction (ZPE, M062X/6–311+G**), thermal correction to Gibbs free energy (TCGFE, M062X/6–311+G**), corrected energy values (E+ZPE and E+TCGFE, without scaling), relative energy values (∆E and ∆G), and the lowest vibration (M062X/6–311+G**). Table S3: Calculated (M062X/6–311+G**) total energy values, taking into account solvent effects (PCM and CPCM methods), zero-point energy correction (ZPE, M062X/6–311+G**), corrected energy values (E+ZPE, without scaling), and relative energy values (∆E). Figure S1: An illustration of weak C–F ···H–C attraction (green) (left) and bond critical points of type (3, −1) and (3, +1) (CPs) (right) for 2-TS structure. Figure S2: Bond-critical points of type (3, −1) and (3, +1) (CPs) for E- and Z-isomers of 1–3. Figure S3: An illustration of non-covalent interactions for compound 1-Z. The gradient isosurfaces (s = 0.5 a.u.) are colored on a blue-green-red scale according to the character of interaction, where blue indicates attractive interactions and red indicates strong repulsive interactions. Cartesian coordinates for equilibrium (M062X/6–311+G**) structures. Author Contributions: Conceptualization, A.B.R., Y.V.R., V.V.T. and P.P.O.; methodology, A.B.R. and A.A.K.; software, A.B.R., A.A.K. and J.L.; validation, A.B.R., J.L. and P.P.O.; formal analysis, V.V.P., V.V.T., Y.V.R. and P.P.O.; investigation, A.A.K., V.V.P. and Y.O.L.; resources, A.B.R. and J.L.; data curation, A.B.R. and P.P.O.; writing—original draft preparation, A.B.R. and P.P.O.; writing—review and editing, A.B.R., J.L. and P.P.O.; visualization, A.B.R. and A.A.K.; supervision, A.B.R., Y.V.R. and P.P.O.; project administration, A.B.R., Y.V.R. and P.P.O.; funding acquisition, A.B.R. and P.P.O. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Organics 2021, 2 96

Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The Supplementary Materials are available online. Acknowledgments: The authors thank Benjamin Pharr, Director of the Mississippi Center for Super- computing Research for the computational resources and technical support for the calculations. A.R. thanks the Alexander von Humboldt foundation for purchasing the license for the TURBOMOLE program set. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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