The mechanism of the phosphine-catalyzed oxa-Michael reaction: A DFT investigation

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K. Bansal This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5179889/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jan, 2025 Read the published version in Structural Chemistry → Version 1 posted 7 You are reading this latest preprint version Abstract The model reactions of phenol and methanol with acrolein catalyzed by trimethylphosphine were computed in the gas phase at the B3LYP/6–31 + G(d) level. The reaction is found to occur in four steps. It is initiated by the combination of the oxa-compound with trimethylphosphine to generate successively the reactant complex and the phenoxide/methoxide anion. The latter reacts with acrolein to produce the enolate anion, which accepts a proton from the protonated trimethylphosphonium cation to generate enol intermediate. Finally, 1,3-prototropic shift occurs via trimethylphosphine molecule to afford the final product. Acetonitrile is found to lower activation energies in all the four steps. DFT calculations Oxa-Michael reaction mechanism trimethylphosphine-catalyzed acrolein phenol methanol Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The Michael addition, also known as conjugate addition or 1,4-addition, though discovered about 140 years ago [ 1 ], continues to entice researchers to extend its applications in newer directions. Over the years, its connotation and scope broadened dramatically; though originally it implied the base catalyzed conjugate addition of a nucleophile such as enolate anion (Michael donor) to an activated α,β-unsaturated carbonyl compound (Michael acceptor), soon its different versions, such as aza-Michael [ 2 ], oxa-Michael [ 3 ], sulfa-Michael [ 4 ], phospha-Michael [ 5 ] additions could be developed. Furthermore, asymmetric versions of the Michael additions made it possible to synthesize a variety of highly useful enantio-enriched products [ 6 – 8 ]. In fact, oxa-version of the Michael addition was reported by Loydl [ 9 ] in 1878, earlier than the actual Michael addition. This reaction received much attention due to its ability to make a variety of valuable intermediates in organic synthesis accessible [ 10 ]. Many natural products incorporate oxygen-containing heterocyclic rings, such as tetrahydropyrans, chromenes or xanthones which can be constructed through oxa-Michael reactions [ 11 ]. There are, however, some inherent challenges in the case of oxa-Michael reactions, which need to be taken care of. Firstly, oxa-Michael donor, alcohol or phenol, is comparatively a weaker nucleophile and secondly, its reaction with Michael acceptor is reversible. In view of this, these reactions are carried out in the presence of a catalyst. In recent years, organocatalysts, such as secondary amines [ 12 ], phosphines [ 13 ], and N-heterocyclic carbenes (NHC) [ 14 ] have been frequently used in the Domino reactions involving Michael addition [13a, 15]. In this context, it is noteworthy that in contrast to the use of alcohols as Michael donors, the reports concerning the reaction of phenols are rather scant. Gunnoe and co-workers [ 16 ] carried out Michael addition of ethanol and phenol with acrylonitrile in the presence of NHC-Cu(I) as catalyst when remarkable difference was observed in the reaction conditions in the two cases- the reaction with ethanol was complete at room temperature (RT) in 20 hr, whereas the reaction with phenol required refluxing at 80°C for 40 hrs. Similarly, Al-Awadi and co-workers [ 17 ] accomplished the Michael addition of phenol with acrylonitrile by using dimethylbenzylacetylammonium hydroxide as the catalyst under refluxing for 20 hrs. Iida and Takahashi carried out the same reaction under microwave irradiation using benzyltrimethylammonium hydroxide or aqueous tetramethylammonium hydroxide as the catalyst. It was found that the reaction proceeded more smoothly in the presence of 4-dimethylaminopyridine [ 18 ]. Scheidt and co-workers achieved asymmetric synthesis of flavanones and chromanones from intramolecular Michael addition of α-hydroxyphenyl substituted chalcones catalyzed by chiral thioureas [ 19 ]. The mechanism of the phosphine-catalyzed Michael addition of an alcohol to acrolein reported earlier [13b] is reproduced in Scheme 1 . In this connection, possibility of an alternative mechanism involving trimethylphosphine as a base (p Ka = 9) was also mentioned, but it was ruled out by the fact that no product was obtained on using triethylamine (p Ka = 11) in place of trimethylphosphine as a catalyst [13b]. A third possibility of acting phosphine oxide, formed in situ from the oxidation of trimethylphosphine, as catalyst was also considered improbable as no product was formed in the presence of trimethylphosphine oxide [13b]. The mechanism shown in Scheme 1 is, however, not compatible with the experimental results wherein Michael addition of alcohol occurs much faster than that of phenol and milder reaction conditions are required for the former [ 16 ]. In the second step, alcohol donates its O-H proton; phenol is expected to be a much stronger proton donor due to its acidic nature. Thus, as per this mechanism, Michael addition of phenol should occur faster than that of alcohol which is not the case. The development of the DFT calculations based on the Hohenberg–Kohn theorems and later on the Kohn–Sham approximation turned out to be watershed in computational chemistry as it made it possible to study the progress of organic reactions with manageable computational costs [ 20 , 21 ]. Subsequently, “Conceptual DFT”, a subfield of DFT was developed by Parr and co-worker [ 22 ] which allows to calculate various reactivity descriptors, such as electrochemical potential, electrophilicity and nucleophilicity indices, global hardness, electronegativity, etc. The concept of hard–soft acid–base (HSAB) was used to explain the reactivity of the organic molecules towards electrophilic and nucleophilic reagents [ 23 ]. Thus, the reactivity at a particular site in a molecule was rationalized by using a quantitative descriptor, the Fukui function (f(r)), arising from finite difference approximation. The Fukui function was defined as ƒ + (r) = ρ N+1 (r) – ρ N (r) for nucleophilic attack (1) ƒ −( r) = ρ N (r) – ρ N−1 (r) for electrophilic attack (2) where ρN + 1(r), ρN(r) and ρN-1(r) are the electron densities at a point r in the system with (N + 1), N and (N-1) electrons respectively, all in the ground state geometry of N electrons system. It was concluded that the center with a large Fukui function is chemically softer than the one where Fukui function is small. Thus by invoking the HSAB principle, behavior of different sites with respect to hard or soft reagents can be predicted [ 23 ]. Yang and Mortier [ 24 ] suggested the use of the gross charge (qr) at a particular atom r in a molecule obtainable from Mulliken population analysis (MPA) for calculating Fukui function (ƒ(r)) at that atom. The condensed Fukui function using MPA often has negative values and in this context, the use of Hirshfeld population analysis (HPA) based on the Stock-Holder idea was recommended [ 25 , 26 ]. Yoshizawa et al. [ 27 ] while studying the reaction pathway for the direct benzene hydroxylation with FeO + species theoretically, reported the existence of the reactant-complex and the product- complex, which alter the energy profile of the reaction. In some other cases also, involvement of these species has been established [ 28 – 30 ]. We reported earlier participation of the reactant-, transition structure-, and the product-complexes in the reaction of benzylamine with DMAD [ 31 ]. This motivated us to investigate the mechanism of the oxa-Michael addition theoretically at the DFT (B3LYP/6–31 + G(d)) level; the results are presented herein. Results and discussion As shown in Scheme 1 , the first step in the proposed mechanism involves combination of trimethylphosphine with acrolein to generate the intermediate zwitterion. In view of this, an attempt was made to optimize the geometry of the zwitterion at the DFT (B3LYP/6–31 + G (d)) level, but surprisingly, the two molecules went apart and no global minimum of the intermediate or the reactant complex could be obtained (Scheme 2 ). Thus, formation of the zwitterion from the reaction of trimethylphsphine with acrolein can be ruled out. Non-formation of the intermediate or the reactant complex can be rationalized on the basis of the HSAB principle; a soft nucleophile phosphine does not combine with a hard electrophilic acrolein. The Fukui functions of the phosphorus atom in trimethylphosphine for the electrophilic attack and C3 atom of acrolein for the nucleophilic attack are given in Table 1 . Table 1 Fukui functions of trimethylphosphine and acrolein calculated at the B3LYP/6–31 + G(d) level. Trimethylphosphine Acrolein Fukui function ( f − (r)) for the electrophilic attack Fukui function ( f + (r)) for the nucleophilic attack Mulliken Hirshfeld -0.432 -0.418 -0.387 -0.396 It may be noted that values of the Fukui functions obtained from the MPA and HPA do not differ significantly and show the same pattern, i.e. by ignoring the negative sign, Fukui function of acrolein is smaller than that of trimethylphosphine indicating their hard and soft characters respectively. On the basis of the reaction profile, it can be perceived to occur in the following four steps which were computed at the B3LYP/6–31 + G(d) level. Step 1 The hydroxyl compound ( 1 ) combines with triphenylphosphine ( 2 ) to generate phenoxide/methoxide ion via a reactant complex 1 a,b and transition structure TS1a,b (Scheme 3 ). The geometries of these species optimized at the B3LYP/6–31 + G(d) level and the free energy profile of this step are given in Fig. 1. The phenol and methanol molecules first combine with a molecule of trimethylphosphine to form the respective reactant complex molecules 1a and 1 b .The process is endergonic, the increase in the free energy (ΔG°) being 3.58 kcal mol -1 and 4.31 kcal mol -1 respectvely. The activation free energy barrier for the reaction of methanol with trimethylphosphine (ΔG # = 35.63 kcal mol -1 ) is greater than that for phenol (ΔG # = 25.93 kcal mol -1 ), which is in accordance with the weaker acidic character of the hydroxy proton in methanol than in phenol. It may be noted that formation of the intermediate Int.1 is also endergonic, the standard free energy (ΔG ° ) being ca 20 kcal mol -1 . Step 2 It may be noted that the intermediates, 1a,b are pentacoordinate phosphorus species, i.e. phosphoranes and have the expected trigonal bipyramidal molecular geometries. The generation of the corresponding phenoxide/methoxide ion from these intermediates is expected to involve the corresponding transition structures; however, in spite of our repeated attempts the respective transition structures could not be located. The next step involves nucleophilic attack of the generated RO - ion ( 3 )on the electrophilic center C3 of acrolein ( 4 ) via transition structure TS2 to produce the intermediate ( Int.2 ) as depicted in Scheme 4. This step is expected to be the rate-differentiating step in the reaction of phenol/methanol with acrolein in the presence of trimethylphosphine. As mentioned earlier, Michael addition of alcohol is much faster than that of phenol. However, our repeated attempts to locate a transition structure in the reaction of MeO - with acrolein at the B3LYP/6-31+G(d) level failed . The geometries of the species shown above optimized at the B3LYP/6-31+G(d) level and the energy profile for the reaction of the PhO - with acrolein are given in Figure 2. The activation free energy (ΔG # ) for the reaction of phenoxide ion with acrolein is 10.55 kcal mol -1 only. The reaction leads to the formation of the intermediate Int.2a . Formation of the latter is endergonic, ΔG ° being 9.28 kcal mol -1 . As mentioned earlier, the corresponding transition structure involved in the reaction of methoxide ion with acrolein, for which activation free energy barrier is expected to be comparatively smaller, could not be located. It is, however, possible to establish greater nucleophilicity of MeO - as compared to that of PhO - on the basis of the shapes of their highest occupied molecular orbitals (HOMO) and reactivity descriptors derived from conceptual DFT calculations. The HOMOs of the phenoxide and methoxide anions and LUMO of acrolein are shown in Figure 3. It is noteworthy that while HOMO of the phenoxide ion is diffused with a small coefficient of the p orbital on the oxygen atom, HOMO of the methoxide ion is concentrated on the oxygen atom with a large coefficient of the p orbital. In view of this, methoxide ion is expected to be a much stronger nucleophile than the phenoxide ion. It is further supported by the reactivity descriptors discussed later. It is noteworthy that LUMO of acrolein is a π * orbital centered on C2-C3 atoms. Energies of the frontier molecular orbitals (FMOs) and the reactivity indices of different species are given in Table 2. Table 2 . Energies of the FMOs and reactivity indices of different species computed at the B3LYP/6-31+G(d) level. Species E HOMO (eV) E LUMO (eV) Electrochemical potential µ (eV) Electrophilicity index ω (eV) x 10 2 Nucleophilicity index Ǹ* (eV) x 10 2 PhO - -0.009 0.130 0.060 - 33.6 MeO - 0.039 0.174 0.107 - 38.5 Acrolein -0.271 -0.081 -0.176 16.3 - *With respect to Tetracynoethylene (TCNE) = E HOMO= -0.346 [Ref 32] The electronic chemical potential (μ) is a useful descriptor that reveals efficacy of charge transfer from the species of higher chemical potential to a species with lower chemical potential [33]. The reactivities of two substrates A and B with the same reagent C can be compared on the basis of the relative values of ΔμAC and ΔμBC; the greater the value of Δμ is, faster will be the reaction. It may be noted that the ΔμMeO - - acrolein (0.283 eV) is greater than ΔμPhO - - acrolein (0.236 eV) and hence MeO - is expected to be a stronger electron donor than PhO - . A similar conclusion can be drawn on the basis of the nucleophilicity indices of the two species. Step 3 The next step involves transfer of a proton from the species HP + Me 3 to the intermediate Int.2 to generate enol Int. Comp.3 (Scheme 5). The geometries of the species shown above optimized at the B3LYP/6-31+G(d) level and the energy profile for the reaction of the Int.2 with HP + Me 3 are given in Figure 4. It is noteworthy that the 3 rd step involving transfer of a proton from HP + Me 3 to the enolate ion Int.2 is a barrierless process, the energy level of TS3 being lower than that of the reacting species in both cases. The TS3 leads to the formation of the Int.Comp.3 , which subsequently splits off PMe 3 molecule to generate enol species, Int.3 . Step 4 This is the final step involving change of the enolic form ( Int.3 ) to the keto form through 1,3-prototropic shift. On computation, a direct 1,3-prototropic shift was found to be a high energy path, ΔG # = ~55 kcal mol -1 . However, when HP + Me 3 positions itself between C2 and OH acting as a bridge, on the one hand, it transfers its proton to C2 and on the other hand, it takes up proton of the enolic OH making it a low energy path (Scheme 6). The optimized geometries of TS4 and the products and the energy profile computed at the B3LYP/6-31+G(d) are given in Figure 5. It may be noted that this step has low activation free energy barrier and reaction is exergonic, the standard free energy being ca 11 kcal mol -1 . A critical analysis reveals that in this reaction, trimethylphosphine acts as a base, first accepting a proton from the hydroxyl compound and transferring this proton in the last step. It is contrary to the observation reported earlier, when triethylamine was not found to catalyze oxa-Michael reaction of alcohol to acrolein [13b]. We tried to investigate reason of this observation theoretically and attempted to locate a transition structure TS3’ by using Et 3 N in place of Me 3 P in Step 3, but it failed, i.e. HN + Et 3 is not able to transfer its proton to the enolate intermediate. This can be rationalized on the basis of the principle that conjugate acid of a stronger base is weaker. Triethyamine (p Ka =11) is a much stronger base than trimethylphosphine (p Ka =9), and hence conjugate acid of the former is expected to be much weaker than that of the latter. Consequently, in contrast to HP + Me 3 , HN + Et 3 is not able to transfer its proton to the intermediate enolate ion and the third step does not proceed. Solvent effect Effect of the solvent, namely acetonitrile on the activation energies of different steps was investigated by computing single-point energies of different species at the B3LYP/6-311++G(d,p) level using self-consistent reaction field (SCRF) [34,35] and polarizable continuum model (PCM) [36-38]. The activation energy profiles of different steps in the gas and solvent phases are given in Figure 6. It is noteworthy that solvent (acetonitrile) causes lowering of activation energies in all steps, the most remarkable being in the step 2. As reaction follows an ionic mechanism, lowering of the activation energies can be expected in the presence of a polar solvent such as acetonitrile. Computational methods All calculations were done using Gaussian 16 suite of programs [39]. The geometries were optimized by using a hybrid of Becke3 and LYP correlation functional [40, 41]. Frequency calculations were done at the same level to determine zero-point corrections and to characterize energy minimum or saddle point with no imaginary frequency or one imaginary frequency respectively. The total enthalpies of different species were obtained by adding thermal correction to the sum of electronic and thermal enthalpies calculated at the same level. The free energy was calculated by using the formula ΔG = ΔH – TΔS ΔH, Enthalpy; T = 298.5 K; ΔS, Entropy in kcal mol -1 K -1 The total energy of a species in solvent was obtained by adding zero-point correction of the gas phase to the single-point energy calculated in the solvent phase at the B3LYP/6-311++G(d,p) level. Conclusion The oxa-Michael reaction to acrolein catalyzed by trimethylphosphine is not initiated by interaction of trimethylphosphine with acrolein, instead the first step involves combination of the hydroxyl compound with phosphine to produce reactant complex which subsequently generates the phenoxide or alkoxide ion. The latter then reacts with acrolein to generate enolate anion; it is the rate-determining step. It is followed by the transfer of a proton from HP + Me 3 to enolate to generate enol. Finally, the latter changes into the product through 1,3-prototropic shift mediated by trimethylphosphine. As expected, the activation energy barriers in all steps are lowered in the presence of acetonitrile. Declarations Supporting Information The Cartesian coordinates of the geometries of all species optimized at the B3LYP/6-31+G(d) level are given. Acknowledgements Authors acknowledge gratefully the research facilities provided by the IIS (deemed to be University), Jaipur (India). Disclosure statement Authors declare to have no financial or non-financial competing interest. ORCID Priyanka Suthar: https://orcid.org/0009-0004-7611-4570 Ruchi Singh: https://orcid.org/0000-0001-8138-1842 Raj K. Bansal https://orcid.org/0000-0002-8154-9817 Ethical Approval This declaration is “not applicable” Funding No funding Availability of data and materials This declaration is “not applicable” References Michael A (1886). J Prakt Chem 35:349 (a)Enders D, Wang C, Liebich J X ( 2009). Chem Eur J 15 :11058 (b) Song Y, Du D (2021). Adv Synth Catal 363 :4667 (c) Sharma P, Gupta R, Bansal R K (2021). 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Supplementary Files GraphicalAbstract.docx SupportingInformation.docx Scheme1.png Scheme2.png Scheme3.png Scheme4.png Scheme5.png Scheme6.png Cite Share Download PDF Status: Published Journal Publication published 03 Jan, 2025 Read the published version in Structural Chemistry → Version 1 posted Editorial decision: Revision requested 09 Oct, 2024 Reviews received at journal 09 Oct, 2024 Reviewers agreed at journal 06 Oct, 2024 Reviewers invited by journal 06 Oct, 2024 Editor assigned by journal 02 Oct, 2024 Submission checks completed at journal 02 Oct, 2024 First submitted to journal 30 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5179889","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":364288512,"identity":"f59cd460-7d5c-43e8-9935-fed6daf71f62","order_by":0,"name":"Priyanka Suthar","email":"","orcid":"","institution":"The IIS (deemed to be University)","correspondingAuthor":false,"prefix":"","firstName":"Priyanka","middleName":"","lastName":"Suthar","suffix":""},{"id":364288513,"identity":"2f0b20ad-4ed7-43cd-82e7-975dfe795412","order_by":1,"name":"Ruchi Singh","email":"","orcid":"","institution":"The IIS (deemed to be University)","correspondingAuthor":false,"prefix":"","firstName":"Ruchi","middleName":"","lastName":"Singh","suffix":""},{"id":364288514,"identity":"6dade740-6137-40bd-a10e-a55c082bc234","order_by":2,"name":"R. 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Bansal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYBACAzBZ8E+OH0QnFBCtxeCAsWQDSIsBCVoSDQ4guPiBOfvZwx9+GNxJMD6/OvHDAwMGeX6xA/i1WPbkpUn2GDzLM7vxdrME0GGGM2cnEHDYgRwzBh4D5mKzG2c3gLQkGNwmpOX8G+OPfwyYEzfPOLv5B3FabuQYSPMYHE7cwN+7jThbLGe8MZOWMUgzlrjBu80iwUCCsF/M+XOMP76psJHj7z+7+eaPCht5fmkCWhBAAqxSgljlIMB/gBTVo2AUjIJRMJIAAGvpRefHUQSvAAAAAElFTkSuQmCC","orcid":"","institution":"The IIS (deemed to be University)","correspondingAuthor":true,"prefix":"","firstName":"R.","middleName":"K.","lastName":"Bansal","suffix":""}],"badges":[],"createdAt":"2024-09-30 10:08:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5179889/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5179889/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11224-024-02431-0","type":"published","date":"2025-01-03T15:57:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69370422,"identity":"b2bdd0c0-b297-405a-a252-a541a08c1e2e","added_by":"auto","created_at":"2024-11-19 16:06:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":212275,"visible":true,"origin":"","legend":"\u003cp\u003eGeometries of different species and energy profile of Step 1 computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e\n\u003cp\u003eNote: The relative energies of phenol/methanol and trimethylphosphine were taken as zero.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/446fa898c21fb59cdeee7fbd.png"},{"id":69369214,"identity":"d7bec25d-2be6-4dae-aa52-e462f943ea61","added_by":"auto","created_at":"2024-11-19 15:50:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":59605,"visible":true,"origin":"","legend":"\u003cp\u003eGeometries of different species and energy profile of step 2 computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/6a850a6b86cb9b431b0a7861.png"},{"id":69370421,"identity":"553c3538-cc4c-4f16-9b39-e519b493b4d8","added_by":"auto","created_at":"2024-11-19 16:06:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82343,"visible":true,"origin":"","legend":"\u003cp\u003eKohn-Sham\u003cstrong\u003e \u003c/strong\u003eorbitals of phenoxide and methoxide anions and acrolein computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/7114d2ed3340aa59487dd0e8.png"},{"id":69371781,"identity":"e93fa2e0-b4fc-4f8b-8a4d-39db1a077805","added_by":"auto","created_at":"2024-11-19 16:22:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114746,"visible":true,"origin":"","legend":"\u003cp\u003eGeometries of different species and energy profile of Step 3 computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/5464d9dcece9f590b1f62e17.png"},{"id":69371594,"identity":"8cc3f401-5969-4563-a987-8be6d5e2ec35","added_by":"auto","created_at":"2024-11-19 16:14:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":117740,"visible":true,"origin":"","legend":"\u003cp\u003eThe optimized geometries of \u003cstrong\u003eTS4 \u003c/strong\u003eand the products and the energy profile of Step 4 computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/141c70a387f3985f5d55da7d.png"},{"id":69369228,"identity":"a6687e83-3e97-42b9-8319-e07da965fd47","added_by":"auto","created_at":"2024-11-19 15:50:37","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":65068,"visible":true,"origin":"","legend":"\u003cp\u003eThe activation energy profiles of different steps in the gas and solvent (acetonitrile) phases.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/dae7848364d59a6b63efcb3e.png"},{"id":73093565,"identity":"bcd83984-1376-4eb1-851b-c2ba4bc236ad","added_by":"auto","created_at":"2025-01-06 16:21:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1099659,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/60e0ffef-91ae-428d-9e60-d0e9b9ccac42.pdf"},{"id":69370093,"identity":"de3eeb11-5c45-45f2-b533-c2c929d09ca8","added_by":"auto","created_at":"2024-11-19 15:58:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":190636,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.docx","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/231fcddb46c659c0b1a014cc.docx"},{"id":69370425,"identity":"faec3dd6-91ec-44f1-b16a-9e4efdd312c0","added_by":"auto","created_at":"2024-11-19 16:06:37","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":24996,"visible":true,"origin":"","legend":"","description":"","filename":"SupportingInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/ebea15eed6e63d811fac8422.docx"},{"id":69370085,"identity":"bdc235be-29f4-41ec-9289-c207c2738454","added_by":"auto","created_at":"2024-11-19 15:58:36","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19766,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/08a74faa30f083f010aa3c03.png"},{"id":69371592,"identity":"85326364-74f9-42b5-9391-53177f208acd","added_by":"auto","created_at":"2024-11-19 16:14:36","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":12503,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme2.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/8f685b3169d6ee554f91c2a6.png"},{"id":69370088,"identity":"c1122949-9853-49fa-a4d9-5351a9167a38","added_by":"auto","created_at":"2024-11-19 15:58:37","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":8982,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme3.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/697109e75e8fc7a2afd10064.png"},{"id":69369217,"identity":"a765056c-067b-47ab-bebb-8d6a43defabe","added_by":"auto","created_at":"2024-11-19 15:50:37","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":8089,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme4.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/8312ca308031e88332845db1.png"},{"id":69370426,"identity":"56ab55b2-a970-408e-b453-e7fb9b8b9b8d","added_by":"auto","created_at":"2024-11-19 16:06:37","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":15572,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme5.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/e5280dd4885896a34b639486.png"},{"id":69369225,"identity":"931db6ce-6c5f-4db1-b7bf-6d716a0b3a65","added_by":"auto","created_at":"2024-11-19 15:50:37","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":12793,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme6.png","url":"https://assets-eu.researchsquare.com/files/rs-5179889/v1/a376b21ba73c5da6aa5c3f07.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"The mechanism of the phosphine-catalyzed oxa-Michael reaction: A DFT investigation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Michael addition, also known as conjugate addition or 1,4-addition, though discovered about 140 years ago [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], continues to entice researchers to extend its applications in newer directions. Over the years, its connotation and scope broadened dramatically; though originally it implied the base catalyzed conjugate addition of a nucleophile such as enolate anion (Michael donor) to an activated α,β-unsaturated carbonyl compound (Michael acceptor), soon its different versions, such as aza-Michael [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], oxa-Michael [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], sulfa-Michael [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], phospha-Michael [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] additions could be developed. Furthermore, asymmetric versions of the Michael additions made it possible to synthesize a variety of highly useful enantio-enriched products [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In fact, oxa-version of the Michael addition was reported by Loydl [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] in 1878, earlier than the actual Michael addition. This reaction received much attention due to its ability to make a variety of valuable intermediates in organic synthesis accessible [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Many natural products incorporate oxygen-containing heterocyclic rings, such as tetrahydropyrans, chromenes or xanthones which can be constructed through oxa-Michael reactions [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. There are, however, some inherent challenges in the case of oxa-Michael reactions, which need to be taken care of. Firstly, oxa-Michael donor, alcohol or phenol, is comparatively a weaker nucleophile and secondly, its reaction with Michael acceptor is reversible. In view of this, these reactions are carried out in the presence of a catalyst. In recent years, organocatalysts, such as secondary amines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], phosphines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and N-heterocyclic carbenes (NHC) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] have been frequently used in the Domino reactions involving Michael addition [13a, 15]. In this context, it is noteworthy that in contrast to the use of alcohols as Michael donors, the reports concerning the reaction of phenols are rather scant. Gunnoe and co-workers [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] carried out Michael addition of ethanol and phenol with acrylonitrile in the presence of NHC-Cu(I) as catalyst when remarkable difference was observed in the reaction conditions in the two cases- the reaction with ethanol was complete at room temperature (RT) in 20 hr, whereas the reaction with phenol required refluxing at 80\u0026deg;C for 40 hrs. Similarly, Al-Awadi and co-workers [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] accomplished the Michael addition of phenol with acrylonitrile by using dimethylbenzylacetylammonium hydroxide as the catalyst under refluxing for 20 hrs. Iida and Takahashi carried out the same reaction under microwave irradiation using benzyltrimethylammonium hydroxide or aqueous tetramethylammonium hydroxide as the catalyst. It was found that the reaction proceeded more smoothly in the presence of 4-dimethylaminopyridine [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Scheidt and co-workers achieved asymmetric synthesis of flavanones and chromanones from intramolecular Michael addition of α-hydroxyphenyl substituted chalcones catalyzed by chiral thioureas [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanism of the phosphine-catalyzed Michael addition of an alcohol to acrolein reported earlier [13b] is reproduced in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn this connection, possibility of an alternative mechanism involving trimethylphosphine as a base (p\u003cem\u003eKa\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9) was also mentioned, but it was ruled out by the fact that no product was obtained on using triethylamine (p\u003cem\u003eKa\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11) in place of trimethylphosphine as a catalyst [13b]. A third possibility of acting phosphine oxide, formed in situ from the oxidation of trimethylphosphine, as catalyst was also considered improbable as no product was formed in the presence of trimethylphosphine oxide [13b].\u003c/p\u003e \u003cp\u003eThe mechanism shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e is, however, not compatible with the experimental results wherein Michael addition of alcohol occurs much faster than that of phenol and milder reaction conditions are required for the former [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the second step, alcohol donates its O-H proton; phenol is expected to be a much stronger proton donor due to its acidic nature. Thus, as per this mechanism, Michael addition of phenol should occur faster than that of alcohol which is not the case.\u003c/p\u003e \u003cp\u003eThe development of the DFT calculations based on the Hohenberg\u0026ndash;Kohn theorems and later on the Kohn\u0026ndash;Sham approximation turned out to be watershed in computational chemistry as it made it possible to study the progress of organic reactions with manageable computational costs [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Subsequently, \u0026ldquo;Conceptual DFT\u0026rdquo;, a subfield of DFT was developed by Parr and co-worker [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] which allows to calculate various reactivity descriptors, such as electrochemical potential, electrophilicity and nucleophilicity indices, global hardness, electronegativity, etc. The concept of hard\u0026ndash;soft acid\u0026ndash;base (HSAB) was used to explain the reactivity of the organic molecules towards electrophilic and nucleophilic reagents [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Thus, the reactivity at a particular site in a molecule was rationalized by using a quantitative descriptor, the Fukui function (f(r)), arising from finite difference approximation. The Fukui function was defined as\u003c/p\u003e \u003cp\u003eƒ\u003csup\u003e+\u003c/sup\u003e(r) = ρ\u003csub\u003eN+1\u003c/sub\u003e(r) \u0026ndash; ρ\u003csub\u003eN\u003c/sub\u003e(r) for nucleophilic attack (1)\u003c/p\u003e \u003cp\u003eƒ\u003csup\u003e\u0026minus;(\u003c/sup\u003er) = ρ\u003csub\u003eN\u003c/sub\u003e(r) \u0026ndash; ρ\u003csub\u003eN\u0026minus;1\u003c/sub\u003e(r) for electrophilic attack (2)\u003c/p\u003e \u003cp\u003ewhere ρN\u0026thinsp;+\u0026thinsp;1(r), ρN(r) and ρN-1(r) are the electron densities at a point r in the system with (N\u0026thinsp;+\u0026thinsp;1), N and (N-1) electrons respectively, all in the ground state geometry of N electrons system.\u003c/p\u003e \u003cp\u003eIt was concluded that the center with a large Fukui function is chemically softer than the one where Fukui function is small. Thus by invoking the HSAB principle, behavior of different sites with respect to hard or soft reagents can be predicted [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eYang and Mortier [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] suggested the use of the gross charge (qr) at a particular atom r in a molecule obtainable from Mulliken population analysis (MPA) for calculating Fukui function (ƒ(r)) at that atom. The condensed Fukui function using MPA often has negative values and in this context, the use of Hirshfeld population analysis (HPA) based on the Stock-Holder idea was recommended [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eYoshizawa et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] while studying the reaction pathway for the direct benzene hydroxylation with FeO\u003csup\u003e+\u003c/sup\u003e species theoretically, reported the existence of the reactant-complex and the product- complex, which alter the energy profile of the reaction. In some other cases also, involvement of these species has been established [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. We reported earlier participation of the reactant-, transition structure-, and the product-complexes in the reaction of benzylamine with DMAD [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis motivated us to investigate the mechanism of the oxa-Michael addition theoretically at the DFT (B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G(d)) level; the results are presented herein.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eAs shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the first step in the proposed mechanism involves combination of trimethylphosphine with acrolein to generate the intermediate zwitterion. In view of this, an attempt was made to optimize the geometry of the zwitterion at the DFT (B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G (d)) level, but surprisingly, the two molecules went apart and no global minimum of the intermediate or the reactant complex could be obtained (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThus, formation of the zwitterion from the reaction of trimethylphsphine with acrolein can be ruled out. Non-formation of the intermediate or the reactant complex can be rationalized on the basis of the HSAB principle; a soft nucleophile phosphine does not combine with a hard electrophilic acrolein. The Fukui functions of the phosphorus atom in trimethylphosphine for the electrophilic attack and C3 atom of acrolein for the nucleophilic attack are given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFukui functions of trimethylphosphine and acrolein calculated at the B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G(d) level.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrimethylphosphine\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAcrolein\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFukui function (\u003cem\u003ef\u003c/em\u003e \u003csup\u003e\u0026minus;\u003c/sup\u003e(r)) for the electrophilic attack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFukui function (\u003cem\u003ef\u003c/em\u003e \u003csup\u003e+\u003c/sup\u003e(r)) for the nucleophilic attack\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMulliken\u003c/p\u003e \u003cp\u003eHirshfeld\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.432\u003c/p\u003e \u003cp\u003e-0.418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.387\u003c/p\u003e \u003cp\u003e-0.396\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIt may be noted that values of the Fukui functions obtained from the MPA and HPA do not differ significantly and show the same pattern, i.e. by ignoring the negative sign, Fukui function of acrolein is smaller than that of trimethylphosphine indicating their hard and soft characters respectively.\u003c/p\u003e \u003cp\u003eOn the basis of the reaction profile, it can be perceived to occur in the following four steps which were computed at the B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G(d) level.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStep 1\u003c/h2\u003e \u003cp\u003eThe hydroxyl compound (\u003cb\u003e1\u003c/b\u003e) combines with triphenylphosphine (\u003cb\u003e2\u003c/b\u003e) to generate phenoxide/methoxide ion via a reactant complex 1\u003cb\u003ea,b\u003c/b\u003e and transition structure \u003cb\u003eTS1a,b\u003c/b\u003e (Scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe geometries of these species optimized at the B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G(d) level and the free energy profile of this step are given in Fig.\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003cp\u003eThe phenol and methanol molecules first combine with a molecule of trimethylphosphine to form the respective reactant complex molecules \u003cstrong\u003e1a\u0026nbsp;\u003c/strong\u003eand 1\u003cstrong\u003eb\u003c/strong\u003e.The process is endergonic, the increase in the free energy (\u0026Delta;G\u0026deg;) being 3.58 kcal mol\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003eand 4.31 kcal mol\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003erespectvely. The activation free energy barrier for the reaction of methanol with trimethylphosphine (\u0026Delta;G\u003csup\u003e#\u0026nbsp;\u003c/sup\u003e= 35.63 kcal mol\u003csup\u003e-1\u003c/sup\u003e) is greater than that for phenol (\u0026Delta;G\u003csup\u003e#\u0026nbsp;\u003c/sup\u003e= 25.93 kcal mol\u003csup\u003e-1\u003c/sup\u003e), which is in accordance with the weaker acidic character of the hydroxy proton in methanol than in phenol. It may be noted that formation of the intermediate \u003cstrong\u003eInt.1\u003c/strong\u003e is also endergonic, the standard free energy (\u0026Delta;G\u003csup\u003e\u0026deg;\u003c/sup\u003e) being ca 20 kcal mol\u003csup\u003e-1\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStep 2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt may be noted that the intermediates, \u003cstrong\u003e1a,b\u0026nbsp;\u003c/strong\u003eare pentacoordinate phosphorus species, i.e. phosphoranes and have the expected trigonal bipyramidal molecular geometries. The generation of the corresponding phenoxide/methoxide ion from these intermediates is expected to involve the corresponding transition structures; however, in spite of our repeated attempts the respective transition structures could not be located.\u003c/p\u003e\n\u003cp\u003eThe next step involves nucleophilic attack of the generated RO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003eion (\u003cstrong\u003e3\u003c/strong\u003e)on the electrophilic center C3 of acrolein (\u003cstrong\u003e4\u003c/strong\u003e) via transition structure \u003cstrong\u003eTS2\u003c/strong\u003e to produce the intermediate (\u003cstrong\u003eInt.2\u003c/strong\u003e) as depicted in Scheme 4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis step is expected to be the rate-differentiating step in the reaction of phenol/methanol with acrolein in the presence of trimethylphosphine. As mentioned earlier, Michael addition of alcohol is much faster than that of phenol. However, our repeated attempts to locate a transition structure in the reaction of MeO\u003cstrong\u003e\u003csup\u003e-\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003ewith acrolein at the B3LYP/6-31+G(d) level failed\u003cem\u003e.\u003c/em\u003e The geometries of the species shown above optimized at the B3LYP/6-31+G(d) level and the energy profile for the reaction of the PhO\u003csup\u003e-\u0026nbsp;\u003c/sup\u003ewith acrolein are given in Figure 2.\u003c/p\u003e\n\u003cp\u003eThe activation free energy (\u0026Delta;G\u003csup\u003e#\u003c/sup\u003e) for the reaction of phenoxide ion with acrolein is 10.55 kcal \u0026nbsp; \u0026nbsp; mol\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003eonly. The reaction leads to the formation of the intermediate \u003cstrong\u003eInt.2a\u003c/strong\u003e. Formation of the latter is endergonic, \u0026Delta;G\u003csup\u003e\u0026deg;\u0026nbsp;\u003c/sup\u003ebeing 9.28 kcal mol\u003csup\u003e-1\u003c/sup\u003e. As mentioned earlier, the corresponding transition structure involved in the reaction of methoxide ion with acrolein, for which activation free energy barrier is expected to be comparatively smaller, could not be located. It is, however, possible to establish greater nucleophilicity of MeO\u003cstrong\u003e\u003csup\u003e-\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003eas compared to that of PhO\u003cstrong\u003e\u003csup\u003e-\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003eon the basis of the shapes of their highest occupied molecular orbitals (HOMO) and reactivity descriptors derived from conceptual DFT calculations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe HOMOs of the phenoxide and methoxide anions and LUMO of acrolein are shown in Figure 3.\u003c/p\u003e\n\u003cp\u003eIt is noteworthy that while HOMO of the phenoxide ion is diffused with a small coefficient of the \u003cem\u003ep\u0026nbsp;\u003c/em\u003eorbital on the oxygen atom, HOMO of the methoxide ion is concentrated on the oxygen atom with a large coefficient of the \u003cem\u003ep\u0026nbsp;\u003c/em\u003eorbital. In view of this, methoxide ion is expected to be a much stronger nucleophile than the phenoxide ion. It is further supported by the reactivity descriptors discussed later. It is noteworthy that LUMO of acrolein is a \u0026pi;\u003csup\u003e*\u0026nbsp;\u003c/sup\u003eorbital centered on C2-C3 atoms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEnergies of the frontier molecular orbitals (FMOs) and the reactivity indices of different species are given in Table 2. \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. \u0026nbsp;Energies of the FMOs and reactivity indices of different species computed at the B3LYP/6-31+G(d) level.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.2349%;\"\u003e\n \u003cp\u003eSpecies\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003eE\u003csub\u003eHOMO\u0026nbsp;\u003c/sub\u003e(eV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003eE\u003csub\u003eLUMO\u0026nbsp;\u003c/sub\u003e(eV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.9021%;\"\u003e\n \u003cp\u003eElectrochemical potential \u0026micro; (eV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003eElectrophilicity index \u0026omega; (eV) x 10\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003eNucleophilicity index Ǹ* (eV) x 10\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.2349%;\"\u003e\n \u003cp\u003ePhO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e-0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e0.130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.9021%;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e33.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.2349%;\"\u003e\n \u003cp\u003eMeO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.9021%;\"\u003e\n \u003cp\u003e0.107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e38.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12.2349%;\"\u003e\n \u003cp\u003eAcrolein\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e-0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.3344%;\"\u003e\n \u003cp\u003e-0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.9021%;\"\u003e\n \u003cp\u003e-0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.5971%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*With respect to Tetracynoethylene (TCNE) = E HOMO= -0.346 [Ref 32]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe electronic chemical potential (\u0026mu;) is a useful descriptor that reveals efficacy of charge transfer from the species of higher chemical potential to a species with lower chemical potential [33].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThe \u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003ereactivities of two substrates A and B with the same reagent C can be compared on the basis of the relative values of \u0026Delta;\u0026mu;AC and \u0026Delta;\u0026mu;BC; the greater the value of \u0026Delta;\u0026mu; is, faster will be the reaction. It may be noted that the \u0026Delta;\u0026mu;MeO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e-\u0026nbsp;acrolein (0.283 eV) is greater than \u0026Delta;\u0026mu;PhO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e-\u0026nbsp;acrolein (0.236 eV) and hence MeO\u003cstrong\u003e\u003csup\u003e-\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003eis expected to be a stronger electron donor than PhO\u003cstrong\u003e\u003csup\u003e-\u003c/sup\u003e\u003c/strong\u003e. A similar conclusion can be drawn on the basis of the nucleophilicity indices of the two species.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStep 3\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe next step involves transfer of a proton from the species HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eto the intermediate \u003cstrong\u003eInt.2\u0026nbsp;\u003c/strong\u003eto generate enol \u003cstrong\u003eInt. Comp.3\u003c/strong\u003e (Scheme 5).\u003c/p\u003e\n\u003cp\u003eThe geometries of the species shown above optimized at the B3LYP/6-31+G(d) level and the energy profile for the reaction of the Int.2 with HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u003c/sub\u003e are given in Figure 4.\u003c/p\u003e\n\u003cp\u003eIt is noteworthy that the 3\u003csup\u003erd\u003c/sup\u003e step involving transfer of a proton from HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u0026nbsp;\u003c/sub\u003eto the enolate ion \u003cstrong\u003eInt.2\u0026nbsp;\u003c/strong\u003eis a barrierless process, the energy level of \u003cstrong\u003eTS3\u0026nbsp;\u003c/strong\u003ebeing lower than that of the reacting species in both cases. The \u003cstrong\u003eTS3\u0026nbsp;\u003c/strong\u003eleads to the formation of the \u003cstrong\u003eInt.Comp.3\u003c/strong\u003e, which subsequently splits off PMe\u003csub\u003e3\u0026nbsp;\u003c/sub\u003emolecule to generate enol species, \u003cstrong\u003eInt.3\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStep 4\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the final step involving change of the enolic form (\u003cstrong\u003eInt.3\u003c/strong\u003e) to the keto form through 1,3-prototropic shift. On computation, a direct 1,3-prototropic shift was found to be a high energy path, \u0026Delta;G\u003csup\u003e#\u003c/sup\u003e = ~55 kcal mol\u003csup\u003e-1\u003c/sup\u003e. However, when HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u0026nbsp;\u003c/sub\u003epositions itself between C2 and OH acting as a bridge, on the one hand, it transfers its proton to C2 and on the other hand, it takes up proton of the enolic OH making it a low energy path (Scheme 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe optimized geometries of \u003cstrong\u003eTS4\u0026nbsp;\u003c/strong\u003eand the products and the energy profile computed at the B3LYP/6-31+G(d) are given in Figure 5.\u003c/p\u003e\n\u003cp\u003eIt may be noted that this step has low activation free energy barrier and reaction is exergonic, the standard free energy being ca 11 kcal mol\u003csup\u003e-1\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eA critical analysis reveals that in this reaction, trimethylphosphine acts as a base, first accepting a proton from the hydroxyl compound and transferring this proton in the last step. It is contrary to the observation reported earlier, when triethylamine was not found to catalyze oxa-Michael reaction of alcohol to acrolein [13b].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eWe tried to investigate reason of this observation theoretically and attempted to locate a transition structure \u003cstrong\u003eTS3\u0026rsquo;\u0026nbsp;\u003c/strong\u003eby using Et\u003csub\u003e3\u003c/sub\u003eN in place of Me\u003csub\u003e3\u003c/sub\u003eP in Step 3, but it failed, i.e. HN\u003csup\u003e+\u003c/sup\u003eEt\u003csub\u003e3\u003c/sub\u003e is not able to transfer its proton to the enolate intermediate. This can be rationalized on the basis of the principle that conjugate acid of a stronger base is weaker. Triethyamine (p\u003cem\u003eKa\u003c/em\u003e=11) is a much stronger base than trimethylphosphine (p\u003cem\u003eKa\u003c/em\u003e=9), and hence conjugate acid of the former is expected to be much weaker than that of the latter. Consequently, in contrast to HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u003c/sub\u003e, HN\u003csup\u003e+\u003c/sup\u003eEt\u003csub\u003e3\u003c/sub\u003e is not able to transfer its proton to the intermediate enolate ion and the third step does not proceed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSolvent effect\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEffect of the solvent, namely acetonitrile on the activation energies of different steps was investigated by computing single-point energies of different species at the B3LYP/6-311++G(d,p) level using self-consistent reaction field (SCRF)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[34,35]\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand polarizable continuum model (PCM) [36-38].\u003csup\u003e\u0026nbsp;\u003c/sup\u003e The activation energy profiles of different steps in the gas and solvent phases are given in Figure 6.\u003c/p\u003e\n\u003cp\u003eIt is noteworthy that solvent (acetonitrile) causes lowering of activation energies in all steps, the most remarkable being in the step 2. As reaction follows an ionic mechanism, lowering of the activation energies can be expected in the presence of a polar solvent such as acetonitrile.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComputational methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll calculations were done using Gaussian 16 suite of programs [39].\u003c/p\u003e\n\u003cp\u003eThe geometries were optimized by using a hybrid of Becke3 and LYP correlation functional [40, 41].\u003c/p\u003e\n\u003cp\u003eFrequency calculations were done at the same level to determine zero-point corrections and to characterize energy minimum or saddle point with no imaginary frequency or one imaginary frequency respectively. The total enthalpies of different species were obtained by adding thermal correction to the sum of electronic and thermal enthalpies calculated at the same level. The free energy was calculated by using the formula\u003c/p\u003e\n\u003cp\u003e\u0026Delta;G = \u0026Delta;H \u0026ndash; T\u0026Delta;S\u003c/p\u003e\n\u003cp\u003e\u0026Delta;H, Enthalpy; T = 298.5 K; \u0026Delta;S, Entropy in kcal mol\u003csup\u003e-1\u0026nbsp;\u003c/sup\u003eK\u003csup\u003e-1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe total energy of a species in solvent was obtained by adding zero-point correction of the gas phase to the single-point energy calculated in the solvent phase at the B3LYP/6-311++G(d,p) level.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe oxa-Michael reaction to acrolein catalyzed by trimethylphosphine is not initiated by interaction of trimethylphosphine with acrolein, instead the first step involves combination of the hydroxyl compound with phosphine to produce reactant complex which subsequently generates the phenoxide or alkoxide ion. The latter then reacts with acrolein to generate enolate anion; it is the rate-determining step. It is followed by the transfer of a proton from HP\u003csup\u003e+\u003c/sup\u003eMe\u003csub\u003e3\u003c/sub\u003e to enolate to generate enol. Finally, the latter changes into the product through 1,3-prototropic shift mediated by trimethylphosphine. As expected, the activation energy barriers in all steps are lowered in the presence of acetonitrile.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Cartesian coordinates of the geometries of all species optimized at the B3LYP/6-31+G(d) level are given.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors acknowledge gratefully the research facilities provided by the IIS (deemed to be University), Jaipur (India).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare to have no financial or non-financial competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePriyanka Suthar: \u0026nbsp;https://orcid.org/0009-0004-7611-4570\u003c/p\u003e\n\u003cp\u003eRuchi Singh: https://orcid.org/0000-0001-8138-1842\u003c/p\u003e\n\u003cp\u003eRaj K. Bansal https://orcid.org/0000-0002-8154-9817\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis declaration is \u0026ldquo;not applicable\u0026rdquo;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis declaration is \u0026ldquo;not applicable\u0026rdquo;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMichael A (1886). 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Phys Rev B Condens Matter 37:785\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"structural-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stuc","sideBox":"Learn more about [Structural Chemistry](https://www.springer.com/journal/11224)","snPcode":"11224","submissionUrl":"https://submission.nature.com/new-submission/11224/3","title":"Structural Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"DFT calculations, Oxa-Michael reaction mechanism, trimethylphosphine-catalyzed, acrolein, phenol, methanol","lastPublishedDoi":"10.21203/rs.3.rs-5179889/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5179889/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe model reactions of phenol and methanol with acrolein catalyzed by trimethylphosphine were computed in the gas phase at the B3LYP/6\u0026ndash;31\u0026thinsp;+\u0026thinsp;G(d) level. The reaction is found to occur in four steps. It is initiated by the combination of the oxa-compound with trimethylphosphine to generate successively the reactant complex and the phenoxide/methoxide anion. The latter reacts with acrolein to produce the enolate anion, which accepts a proton from the protonated trimethylphosphonium cation to generate enol intermediate. Finally, 1,3-prototropic shift occurs via trimethylphosphine molecule to afford the final product. Acetonitrile is found to lower activation energies in all the four steps.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"The mechanism of the phosphine-catalyzed oxa-Michael reaction: A DFT investigation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 15:50:32","doi":"10.21203/rs.3.rs-5179889/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-09T21:08:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-09T13:25:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73774185801318554658092401962132647696","date":"2024-10-07T02:17:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-07T01:52:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-02T13:38:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-02T09:41:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Structural Chemistry","date":"2024-09-30T10:06:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"structural-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"stuc","sideBox":"Learn more about [Structural Chemistry](https://www.springer.com/journal/11224)","snPcode":"11224","submissionUrl":"https://submission.nature.com/new-submission/11224/3","title":"Structural Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dda9bd61-16b6-4963-85eb-eb84e2762c63","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:05:33+00:00","versionOfRecord":{"articleIdentity":"rs-5179889","link":"https://doi.org/10.1007/s11224-024-02431-0","journal":{"identity":"structural-chemistry","isVorOnly":false,"title":"Structural Chemistry"},"publishedOn":"2025-01-03 15:57:29","publishedOnDateReadable":"January 3rd, 2025"},"versionCreatedAt":"2024-11-19 15:50:32","video":"","vorDoi":"10.1007/s11224-024-02431-0","vorDoiUrl":"https://doi.org/10.1007/s11224-024-02431-0","workflowStages":[]},"version":"v1","identity":"rs-5179889","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5179889","identity":"rs-5179889","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}