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Communication

Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide

by
Cui Yu
1,
Yueqian Sang
1,
Yao Li
1,* and
Xiaosong Xue
1,2,*
1
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
2
School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(4), 1669; https://doi.org/10.3390/molecules28041669
Submission received: 8 December 2022 / Revised: 19 January 2023 / Accepted: 1 February 2023 / Published: 9 February 2023
(This article belongs to the Special Issue Insights for Organofluorine Chemistry)
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Abstract

:
That nucleophiles preferentially attack at the less sterically hindered carbon of epoxides under neutral and basic conditions has been generally accepted as a fundamental rule for predicting the regioselectivity of this type of reaction. However, this rule does not hold for perfluorinated epoxides, such as hexafluoropropylene oxide (HFPO), in which nucleophiles were found to attack at the more hindered CF3 substituted β-C rather than the fluorine substituted α-C. In this contribution, we aim to shed light on the nature of this intriguing regioselectivity by density functional theory methods. Our calculations well reproduced the observed abnormal regioselectivities and revealed that the unusual regiochemical preference for the sterically hindered β-C of HFPO mainly arises from the lower destabilizing distortion energy needed to reach the corresponding ring-opening transition state. The higher distortion energy required for the attack of the less sterically hindered α-C results from a significant strengthening of the C(α)-O bond by the negative hyperconjugation between the lone pair of epoxide O atom and the antibonding C-F orbital.

1. Introduction

Epoxides play an essential role in the fields of pharmaceuticals [1], materials [2,3], and organic syntheses [4,5,6,7,8] owing to their unique biological and chemical activities. Due to the large ring strain of epoxides compared to linear aliphatic ethers, the epoxide carbon atoms can be attacked by nucleophiles to release the ring strain [9]. When the epoxide is unsymmetric, one of the two epoxide C atoms will be attacked selectively [10]. It has been well established that the less hindered carbon atom of the epoxide will be preferentially attacked under neutral and basic conditions [10,11].
Intriguingly, this rule does not apply to perfluorinated epoxides, such as hexafluoropropylene oxide (HFPO, 1) [12]. As an important raw material for the synthesis of perfluoropolyether [13], reactions of HFPO with various nucleophiles under neutral and basic conditions have been widely investigated (Scheme 1), including ring-opening (Scheme 1a,b) [12,14,15,16], rearrangement (Scheme 1c) [14] and anion polymerization reactions (Scheme 1d) [13,17,18]. In these reactions, the nucleophile selectively attacks at the more sterically hindered CF3 substituted β-C instead of the fluorine substituted α-C.
Several explanations have been proposed for the anomalous ring-opening regioselectivity of HFPO. Sianesi et al. [14] hypothesized that nucleophiles preferentially attack at the more hindered CF3 substituted β-C atom due to its higher electrophilicity endowed by the strong electron-withdrawing trifluoromethyl group. Besides the increased electrophilicity of the β-C atom by the trifluoromethyl group, Eleuterio [13] proposed that the lone pair repulsion between fluorine on the α-C atom and the incoming nucleophiles also contributes to the observed abnormal regioselectivity. Jiang et al. [19,20] attributed the abnormal regioselectivity to the strengthening of the C(α)-O bond by the α-fluorine effect [21,22]. Lemal and Sudharsanam [23] put forward that negative hyperconjugation [24,25,26,27,28,29,30] of the developing oxyanion stabilizing the ring-opening transition state was at least one cause.
To date, the origin of abnormal ring-opening regioselectivity of HFPO remains unclear. As a continuation of our research efforts on the structure−reactivity relationship and mechanism of fluorination/fluoroalkylation reagents [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48], we investigated the mechanism of the ring-opening reaction of HFPO by density function theory (DFT) calculations and performed distortion/interaction activation strain analysis [49,50,51] and Natural Bond Orbital (NBO) [52,53] analysis to explore the determinant of the abnormal regioselectivity.

2. Results and Discussion

The ring-opening reactions of HFPO (1) and propylene oxide (PO, 2) by fluoride were employed as the model reactions (Scheme 2). The computed Gibbs free energy profiles for the two ring-opening reactions are shown in Figure 1. In the reaction of 1 (Figure 1a), nucleophilic attack at the more sterically encumbered CF3 substituted β-C (β-attack) by fluoride has an activation free energy barrier of only 7.6 kcal/mol via TS1β to give Int1β. This process is highly exergonic and irreversible. Then, the release of fluoride from the Int1β gives perfluoropropionic acid fluoride P1β. Nucleophilic attack at the α-C (α-attack) has a higher barrier of 11.5 kcal/mol, leading to hexafluoroacetone P1α after the exclusion of fluoride. Accordingly, the attack at the more sterically hindered CF3 substituted β-C is preferred over the attack at the α-C by 3.9 kcal/mol in the ring-opening reaction of 1. Conversely, nucleophilic attack at the α-C (TS2α) is favored over the β-C (TS2β) by 2.9 kcal/mol in the ring-opening reaction of 2 (Figure 1b). Substantially higher barriers are required for ring-opening reaction of 2 than of 1. Overall, the predicted regioselectivities and reactivities are consistent with the experimental results [12].
To reveal the physical factors determining the distinct regioselectivity, we performed distortion/interaction activation strain analysis (DIAS) for the two model reactions (Figure 2a,b). DIAS analysis revealed that the preferred nucleophilic attack at the more sterically hindered CF3 substituted β-C of 1 originates mainly from the lower destabilizing distortion energy (Figure 2a). The stabilizing interaction energy for β-attack is slightly weaker than for α-attack.
The lower destabilizing distortion energy for β-attack in the ring-opening of 1 can be attributed to the weaker C(β)-O bond strength relative to C(α)-O bond as indicated by their bond lengths (C(α)-O bond length: 1.374 Å vs. C(β)-O bond length: 1.415 Å) [54]. Substitution of all H-atoms in 2 with F enhances the strength of both C(β)-O and C(α)-O bonds (C(α/β)-O: 1.431/1.432 Å in 2 vs. 1.374/1.415 Å in 1). We noted, however, that the C(α)-O bond was strengthened even more. This can be mainly ascribed to the stronger negative hyperconjugation (Figure 2c) between the lone pair of O atom and the antibonding C-F orbital compared to the antibonding C-CF3 orbital (n(O) → σ*C-F is at least 9.2 kcal/mol more stable than n(O) → σ*C- CF3) [24,25,26,27,28,29,30], owing to the former is a better electron-acceptor (the electron-acceptor capability: σ*C-F > σ*C- CF3/σ*C-H). The n(O) → σ*C-F negative hyperconjugation strengthens the C-O bond and weakens the C-F bond. Notably, as the negative charge on the O atom accumulates during the ring-opening, the stabilizing stereo-electronic interactions between oxygen lone pairs and antibonding C-F orbitals become even stronger in the transition states, thus causing an even larger difference in distortion energy around the transition state zone of the ring-opening of 1 (Figure 2a and Figure S1 from Supplemetary Materials).
The calculated electrophilicity indexes [55,56] indicate that the β-C is more electrophilic than the α-C in 1 (Figure 2d and Figure S2 from Supplementary Materials). Moreover, the antibonding C(β)-O orbital is lower in energy than the antibonding C(α)-O orbital (Figure 2e and Figure S3b from Supplementary Materials). Irrespective of steric repulsion, β-attack in the ring-opening of 1 should exhibit stronger interaction energy (electrostatic and orbital interactions). Thus, the observed slightly weaker interaction energy for β-attack must result from a more significant destabilizing steric repulsion between the incoming fluoride and the trifluoromethyl group (Figure 2f) that overrides the stabilizing electrostatic and orbital interactions. Indeed, due to the destabilizing steric repulsion, the F−···β-C distance is longer in TS1β than in TS1α, leading to a loss of stabilizing orbital and electrostatic interactions.
Consistent with the previous report of Hamlin, Bickelhaupt, and coworkers [57], the α-C regioselectivity of 2 is controlled by interaction energy (Figure 2b) that mainly originates from the lower steric repulsion (Figure 2f). The lower steric repulsion of α-C allows the development of stronger stabilizing orbital and electrostatic interaction between the incoming nucleophile and this position. The α-C is more electrophilic than β-C in 2 (Figure 2d and Figure S2 from Supplementary Materials), and the antibonding C(α)-O orbital is lower in energy than the antibonding C(β)-O orbital (Figure 2e and Figure S3a from Supplementary Materials), owing to the electron-donating of the methyl group. The strengths of C(β)-O and C(α)-O bonds are nearly identical (C(α)-O bond length: 1.431 Å vs. C(β)-O bond length: 1.432 Å), and thus the destabilizing distortion energies are similar in magnitude for β- and α-attack.
The higher ring-opening reactivity of 1 can be attributed to (1) the effective stabilizing of the developing negative charges on the O atom in transition structure by negative hyperconjugation (n(O) → σ*C-F) and strong electron-withdrawing capability of F/CF3 and (2) the enhanced HOMO (F−)-LUMO (substrate) orbital interaction as a result of the LUMO lowering after fluorine substitution.

3. Computational Details

DFT calculations were performed with the Gaussian 16 programs [58]. Geometry optimization and frequency calculations were carried out at the ꞷB97X-D/6-31+G(d,p)-SMD-(ethyl ether) level of theory [59,60,61,62,63,64,65,66]. All the transition states have only one imaginary frequency, while the stationary points do not. Intrinsic reaction coordinates (IRC) calculations at the same level verified the connectivity of located intermediates and transition states. Single-point energy was calculated at the level of ꞷB97X-D/6-311++G(2df,2p)-SMD-(ethyl ether) [67]. Non-covalent interaction (NCI) analysis was performed by NCIplot 3.0 [68]. Wavefunctions analysis and reactivity descriptors calculation were performed by Multiwfn 3.8 [69,70], for which substrates were reoptimized at the ꞷB97X-D/6-31G(d,p)-SMD-(ethyl ether) level. Distortion/interaction activation strain analysis (DIAS) was realized by a python tool named autoDIAS [71]. Figures of NCI and orbital isosurfaces were plotted with PyMOL 2.0.4 [72]. The 3D plots for the molecules were created with CYLview 20 [73].
Distortion/interaction activation strain analysis is a popular model [49,50,51] developed to investigate the determinant of chemical reactivity. In this model, the total energy increased along the reaction pathway is decomposed into the distortion energy of substrates and the interaction energy between the two reactants (1).
Δ E t o t a l = Δ E i n t e r a c t i o n + Δ E d i s t o r t i o n
The distortion energy describes the energy needed to deform the substrate from the equilibrium structure to deformed structure along the reaction coordinate (2). The interaction energy refers to the energy all the interaction between the two deformed reactants (3).
Δ E d i s t o r t i o n = Δ E d i s t o r e d − s t r u c t u r e − Δ E e q u i l i b r i u m − s t r u c t u r e  
Δ E i n t e r a c t i o n = Δ E t o t a l − Δ E d i s t o r t i o n  

4. Conclusions

In conclusion, we revealed that the abnormal regioselectivity of the ring-opening reaction of HFPO originates from a significant strengthening of C-O bond by the negative hyperconjugation between the lone pair of epoxide O atom and the antibonding C-F orbital, which leads to the higher destabilizing distortion energy needed to reach the ring-opening transition state for attacking at the less sterically hindered carbon. Our results provide strong support for Jiang’s [20] and Lemal’s [23] hypotheses. We expected that the insights from this study would enrich our understanding of unique fluorine effects in organic reactions [25,74,75,76,77,78] and should be helpful for the design of new regioselective ring-opening reactions of epoxides by regulating the electronic properties of the substituents.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28041669/s1. Figure S1: The key donor–acceptor orbital interactions of TS1α (a) and TS1β (b) by NBO analysis; Figure S2: The reactivity descriptors of epoxide carbon atoms of 1 and 2, respectively; Figure S3: The key NBOs isosurfaces of 2 (a) and 1 (b); References [79,80,81,82,83,84] are cited in supplementary materials.

Author Contributions

Conceptualization, C.Y. and X.X.; writing—original draft preparation, C.Y. and Y.S.; writing—review and editing, Y.L. and X.X.; visualization, C.Y., Y.L. and Y.S.; supervision, X.X.; project administration, X.X.; funding acquisition, X.X. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Technology of China, grant number 2021YFF0701700, and the Natural Science Foundation of China, grant numbers 22122104, 21933004, 21772098.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are grateful for the support from the Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

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Molecules 28 01669 sch001 550
Scheme 1. Typical reactions of hexafluoropropylene oxide (HFPO, 1). (a,b) Ring-opening reactions; (c) rearrangement reaction; (d) anion polymerization reaction of HFPO.
Scheme 1. Typical reactions of hexafluoropropylene oxide (HFPO, 1). (a,b) Ring-opening reactions; (c) rearrangement reaction; (d) anion polymerization reaction of HFPO.
Molecules 28 01669 sch001
Molecules 28 01669 sch002 550
Scheme 2. The model reactions studied computationally. (a) ring-opening reaction of 1; (b) ring-opening reaction of 2.
Scheme 2. The model reactions studied computationally. (a) ring-opening reaction of 1; (b) ring-opening reaction of 2.
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Molecules 28 01669 g001 550
Figure 1. Gibbs free energy profiles for the ring-opening reaction of 1 (a) and 2 (b). The bond distances are given in angstroms.
Figure 1. Gibbs free energy profiles for the ring-opening reaction of 1 (a) and 2 (b). The bond distances are given in angstroms.
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Molecules 28 01669 g002 550
Figure 2. DIAS analysis for the ring-opening reaction of 1 (a) and 2 (b). The electronic energy values are projected on the distance between the breaking C-O bond (positions of TS indicated with a dot). There is only one curve showing the distortion energy for the case where F− is not distorted along the reaction coordinate; (c) The key donor-acceptor orbital interactions of 1 obtained by NBO analysis at the ωB97X-D/6-31G(d,p)-SMD-(ethyl ether) level; (d) The condensed local electrophilicity indexes of the epoxide carbon atoms; (e) The lowest unoccupied molecular orbital (LUMO) isosurfaces of 1 and 2; (f) NCI analysis for the four transition states.
Figure 2. DIAS analysis for the ring-opening reaction of 1 (a) and 2 (b). The electronic energy values are projected on the distance between the breaking C-O bond (positions of TS indicated with a dot). There is only one curve showing the distortion energy for the case where F− is not distorted along the reaction coordinate; (c) The key donor-acceptor orbital interactions of 1 obtained by NBO analysis at the ωB97X-D/6-31G(d,p)-SMD-(ethyl ether) level; (d) The condensed local electrophilicity indexes of the epoxide carbon atoms; (e) The lowest unoccupied molecular orbital (LUMO) isosurfaces of 1 and 2; (f) NCI analysis for the four transition states.
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Yu, C.; Sang, Y.; Li, Y.; Xue, X. Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide. Molecules 2023, 28, 1669. https://doi.org/10.3390/molecules28041669

AMA Style

Yu C, Sang Y, Li Y, Xue X. Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide. Molecules. 2023; 28(4):1669. https://doi.org/10.3390/molecules28041669

Chicago/Turabian Style

Yu, Cui, Yueqian Sang, Yao Li, and Xiaosong Xue. 2023. "Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide" Molecules 28, no. 4: 1669. https://doi.org/10.3390/molecules28041669

APA Style

Yu, C., Sang, Y., Li, Y., & Xue, X. (2023). Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide. Molecules, 28(4), 1669. https://doi.org/10.3390/molecules28041669

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