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 DG 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/). Organics 2021, 2, 84–97. https://doi.org/10.3390/org2020008 https://www.mdpi.com/journal/organics Organics 2021, 2, FOR PEER REVIEW 2 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 ex- perimental criteria for assigning the mechanism of isomerization to inversion or rotation. However, as shown by our quantum chemical study of quinonimines [7], a mixed isom- erization mechanism including the rotation component in the process of inversion is real- ized 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 sim- ilar mixed isomerization mechanism in other imine derivatives. Moreover, according to [8], electron acceptor substituents determine the inversion mechanism for the isomeriza- tion, 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 spectros- copy [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 pro- cess,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 <can 180° significantly (Figure 1) [6,7].affect Ittheir should chemical be noted proper that,ties: at present,their reactivity there are and no the unambiguous stereochemical ex- consistent with the data of earlier works [9,10]. perimentaloutcome of criteriaenantio- for and assigning diastereoselective the mechanism reactions, of isomerization etc. to inversion or rotation. However, as shown by our quantum chemical study of quinonimines [7], a mixed isom- R1 R2 R2 erization mechanism including the rotation component in the process of inversion is real- N 3 k1 N OR OR3 ized only under certain conditions,1 and is determined mainly by the steric influence of the P R P O 3 O 3 neighboringOR substituents.k-1 One year later,OR Gálvez and Guirado [8] have reported on the sim- ilar mixed isomerization mechanism in other imine derivatives. Moreover, according to [8], electronZ-IP acceptor substituents determE-IP ine the inversion mechanism for the isomeriza- tion, whereas the electron donor groups contribute to the rotational one.