Unraveling the α-effect in α-fluorinated carbanionic nucleophiles: origins and synthetic implications

Abstract

The α-effect refers to the dramatically enhanced reactivity of α-nucleophiles bearing a heteroatom with an adjacent lone-pair (R–Y–X:⁻) compared to normal nucleophiles (R–X:⁻), as predicted by Brønsted-type correlation. Despite extensive research, the underlying mechanisms of this phenomenon remain debated, and previous studies have predominantly focused on O-, N-, and S-based nucleophiles, leaving carbanions—key intermediates in organic synthesis—comparatively underexplored. Here, we present an in-depth computational investigation into the intriguing influence of α-fluorine substitution on carbanion nucleophilicity. Despite fluorine's strong electron-withdrawing capability, our results reveal that α-fluorocarbanions could exhibit the α-effect when they satisfy Hamlin's two criteria originally proposed for heteroatom-based anionic α-nucleophiles. This study extends the scope of the α-effect from heteroatom-based nucleophiles to carbanionic nucleophiles, offering new insights into this fundamental chemical phenomenon.

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Introduction

The α-effect in organic chemistry is a fundamental phenomenon that describes the significantly enhanced reactivity of nucleophiles possessing adjacent heteroatoms with lone pairs.¹ Coined by Pearson and Edwards² in 1962, the term refers to the downward deviation from the expected Brønsted-type correlation for normal nucleophiles (Fig. 1a, left column). The α-effect has been observed in numerous reactions, with its magnitude highly dependent on both the class of reaction and the type of α-nucleophiles involved.³ The origin of the α-effect has been a long-standing debate and remains a subject of controversy. Several explanations have been proposed regarding the origin of the α-effect, including ground state destabilization, transition state stabilization, thermodynamic product stability, and external solvent effects.^3g,4 Recently, Hamlin et al.⁵ identified two key criteria that α-nucleophiles need to fulfill to exhibit the α-effect (Fig. 1a, right column): (1) a small HOMO lobe on the nucleophilic center to minimize Pauli repulsion with the substrate and (2) a sufficiently high-energy HOMO to engage in strong orbital interactions with the substrate. These criteria have been proposed for heteroatom-based anionic nucleophiles, including O- and N-based α-nucleophiles. However, to the best of our knowledge, their implications for carbanions—fundamental intermediates in organic synthesis—remain notably underexplored.

Fig. 1 (a) Definition and criteria (proposed by Hamlin et al.) for the α-effect. (b) Variable effects of α-fluorine on carbanions.

Fluorocarbon anions play a crucial role in nucleophilic fluoroalkylations.⁶ As Schlosser's seminal review highlights,⁷ “fluorine as a substituent always good for a surprise, but often completely unpredictable”. Variable effects of α-fluorine substitution on the thermal stability,⁸ Brønsted basicity,⁹ and nucleophilicity¹⁰ of carbanions have been observed (Fig. 1b). For instance, while the fluoromalonate anion was traditionally perceived as a weaker nucleophile compared to malonate in reactions with alkyl bromides,¹¹ Shibata and colleagues¹² highlighted that fluorodi(benzenesulfonyl)methane (FBSM: (PhSO₂)₂CFH)¹³ participates smoothly in palladium-catalyzed allylic methylation reactions, achieving remarkable enantioselectivity and excellent yields, contrasting sharply with the trace yields obtained with di(benzenesulfonyl)methane (BSM: (PhSO₂)₂CH₂). Furthermore, recent studies by Hu and colleagues¹⁴ demonstrated that FBSM reacts with enones significantly faster than BSM. They also found that the nucleophilic addition of (PhSO₂)₂CFLi to benzaldehyde produces the corresponding alcohol in high yields, whereas BSM or (PhSO₂)₂CClLi yields no adducts under similar conditions. Moreover, the conventional view that α-fluorine generally diminishes carbanion nucleophilicity due to its strong electron-withdrawing effects has been challenged by studies from Prakash and Mayr,^10a which suggest that α-fluorine substitution can, in fact, enhance the nucleophilicity of certain carbanions.

In this study, we present an in-depth computational investigation into the intriguing effects of α-fluorine substitution on the nucleophilicity of carbanions,^10a aiming to elucidate why it can enhance the nucleophilicity of specific carbanions. The results not only extend the scope of the α-effect from heteroatom-containing nucleophiles to carbanionic nucleophiles but also provide valuable insights into the intriguing role of α-fluorine substitution in nucleophilic fluoroalkylation.

Results and discussion

According to the nucleophilicity measurement experiment adopted by Mayr and Prakash et al.,^10a the nucleophilic addition of a series of K[(PhSO₂)₂CY] to quinone was employed as a model reaction to investigate whether there is an α-effect of fluorocarbanions (Fig. 2a). The α-group Y can be divided into two series: one series bears lone pairs such as –F, –OMe, and –NHMe; the corresponding carbanions belong to “α-nucleophiles”. The other series has no lone-pair in the α-atom, and the corresponding carbanions are “normal nucleophiles”. Fig. 2a presents a Brønsted-type correlation analysis for the nucleophilic additions, showing a strong correlation between the free energy barriers and the basicity of normal nucleophiles (R² = 0.94). α-Nucleophiles with substituents Y = OMe and NHMe still roughly follow the Brønsted-type correlation. However, the α-F-substituted carbanion a-F⁻ exhibits a higher reactivity than that predicted based on its basicity despite the strong electron-withdrawing capability of fluorine. This results in a downward deviation from the expected Brønsted correlation, thus demonstrating the α-effect. Similar observations were made using nucleophilic S_N2 reaction models (Fig. 2b),⁵ although varying degrees of the α-effect were observed when changing the carbanions (see Fig. S1 in the ESI,† for b-Y⁻ [(PhSO₂)(EtOOC)CY⁻] and c-Y⁻ [(EtOOC)₂CY⁻]).

Fig. 2 (a) Reaction between a nucleophilic reagent and quinone methide and its computational reaction model, and Brønsted-type correlation between free energy barrier (ΔG^‡_calc.) and basicity (ΔG⁰, the larger the value of ΔG⁰, the stronger the basicity). (b) Computational reaction model of S_N2 reactions of carbanions and Brønsted-type correlation between free energy barrier and basicity. Energies in kcal mol⁻¹.

The α-effect observed for fluorocarbanion a-F⁻ is consistent with Hamlin's two criteria.⁵ As shown in Fig. 3a, the HOMO of a-F⁻ exhibits higher energy and a smaller lobe on the nucleophilic center compared to that of the corresponding normal nucleophile a-H⁻. The higher HOMO energy and smaller lobe on the nucleophilic center of a-F⁻ make it more reactive than normal nucleophiles due to two main factors: (1) the higher HOMO energy can lead to a small HOMO_Nu:–LUMO_substrate orbital energy gap, thus enhancing the orbital interaction and (2) the smaller lobe on the nucleophilic center reduces the repulsive occupied–occupied orbital overlap between the nucleophile and substrate. Indeed, energy decomposition analysis¹⁵ performed using sobEDA¹⁶ along the intrinsic reaction coordinate (IRC) of S_N2 reaction¹⁷ reveals that the Pauli repulsion between a-F⁻ and CH₃Cl (Fig. 3b, the reaction coordinate defined in this case as the IRC projection onto the C1⋯C2 distance) is always smaller than that for a-H⁻. In contrast, (steric) Pauli repulsion values for a-OMe⁻ and a-NHMe⁻ are significantly larger than those for a-H⁻. Thus, Hamlin's criteria for the α-effect can apply to carbanions.

Fig. 3 (a) Isosurfaces (isovalues = 0.05), energies, and volumes (isovalues = 0.05) of the HOMO in a-H⁻ and α-nucleophiles a-Y⁻. (b) Pauli repulsion energy (ΔE_rep) between the carbanion and CH₃Cl along the IRC projected on the C1⋯C2 distance (d_C1–C2). The carbanion moiety of TS-S_N2-a-Y is defined as Fragment 1 (F1) and the remaining moiety is defined as Fragment 2 (F2).

The applicability of Hamlin's α-effect criteria for carbanions has significant implications for predicting their nucleophilicity. While the HOMO energy is a key parameter influencing the nucleophilicity, it alone cannot fully reflect the nucleophilicity of BSM anions, as indicated by the poor correlation between the barrier of nucleophilic addition and HOMO energy (Fig. 4a). Given that the HOMO of BSM anions is contributed not only from the carbanionic center but also from the α-group Y (for examples in Fig. 3a), we hypothesized that the degree of localization of the HOMO, which is influenced by the composition of each atom and can be quantitatively estimated by the orbital delocalization index (ODI: Fig. 4b),¹⁸ could also affect the nucleophilicity of the BSM anion. Indeed, a strong correlation was observed between DFT-predicted barriers and those predicted using a binary linear equation that combines both E_HOMO and ODI_HOMO (R² = 0.97, Fig. 4c, and also see Fig. S2† for the cases of b-Y⁻ and c-Y⁻). Notably, ODI_HOMO alone could not adequately reflect the nucleophilicity either (Fig. S3 in the ESI†). This further corroborates that both the energy and shape of the HOMO influence the reactivity of nucleophiles. In addition, other α-fluorocarbanions with higher E_HOMO or ODI_HOMO also have stronger nucleophilicity (Table S4 in the ESI†), while for methyl anions, neither E_HOMO nor ODI_HOMO of CH₂F⁻ is higher than that of CH₃⁻, causing weaker nucleophilicity.

Fig. 4 (a) Relationship between the free energy barrier (ΔG^‡) of the S_N2 reaction and E_HOMO of carbanions a-Y⁻. (b) Illustration for the significance of the orbital delocalization index (ODI), and ODI_HOMO of carbanions a-Y⁻ (isovalues = 0.05 for isosurfaces, the composition of atoms below 10% is omitted for clarity). (c) The plot of computed vs. predicted free energy barrier of the S_N2 reaction between a-Y⁻ and CH₃Cl using the multivariate linear regression model. Energies in kcal mol⁻¹.

Natural bond orbital (NBO)¹⁹ analyses offer additional insights into the effects of α-fluorine on the carbanion nucleophilicity (Fig. 5). For α-fluorocarbanions with stronger nucleophilicity like a-F⁻, there is a significant lone-pair repulsion between the carbanionic center and α-fluorine, causing a higher E_HOMO and/or a more pyramidal structure of α-fluorocarbanions (meaning higher ODI_HOMO). In contrast, for α-fluorocarbanions with weaker nucleophilicity like CH₂F⁻, the lone-pair repulsion between α-fluorine and the carbanionic center could largely be avoided due to the already highly pyramidal structure of the carbanionic center. As a result, CH₂F⁻ has both lower energy and localization degree of the HOMO than CH₃⁻.

Fig. 5 Comparison of E_HOMO and ODI_HOMO among fluorocarbanions and hydrocarbanions, and NBO (isovalues = 0.08) analyses for selected carbanions. The isosurfaces of NBOs are the lone-pair (LP) orbitals for the carbanionic center and F atom, φ(C⁻) represents the pyramidalization angle around the carbanion center.

The α-effect in fluorocarbanion a-F⁻ can effectively rationalize the previously observed intriguing outcomes in monofluoromethylation reactions shown in Fig. 1b. For the palladium-catalyzed enantioselective allylic fluoromethylation reaction, the key step is nucleophilic attack by carbanions to the allylpalladium complex via the transition state TSB-Y (Fig. 6a, and see Fig. S4† for overall mechanistic information). Due to the stronger nucleophilicity of fluorocarbanion a-F⁻, the barrier corresponding to TSB-F is 2.4 kcal mol⁻¹ lower than that of TSB-H. For LiHMDS intermediated monofluoromethylation of FBSM on benzaldehyde, as shown in Fig. 6b, the barrier of nucleophilic addition by (PhSO₂)₂CCl⁻ and (PhSO₂)₂CH⁻ is much higher than that of (PhSO₂)₂CF⁻, and the formation of products C2-Cl and C2-H is significantly endergonic, explaining why these products were not obtained. The stronger nucleophilicity and the corresponding bonding ability of fluorocarbanion a-F⁻ are further supported by distortion/interaction activation strain (DIAS)²⁰ analysis for nucleophilic attack along the IRC path (Fig. 6c and d, the reaction coordinate defined in this case as the IRC projection onto the C1⋯C2 distance). For both reactions, it is the more favorable interaction between two fragments, rather than distortion, that governs the reactivity. The absolute value of E_int follows the order of Y = F > Y = H (>Y = Cl), which is consistent with the order of nucleophilicity of carbanions.

Fig. 6 Calculated free energy profiles for nucleophilic addition of [(PhSO₂)₂CY]⁻ in the palladium-catalyzed allylic methylation reaction (a) and in LiHMDS intermediated methylation of benzaldehyde (b). DIAS analysis for nucleophilic attack in palladium-catalyzed allylic methylation (c) and LiHMDS intermediated methylation of benzaldehyde (d) along the IRC projected on the C1⋯C2 distance (d_C1–C2). The carbanion moiety of TSB-Y or TSC-Y is defined as Fragment 1 (F1) and the remaining moiety is defined as Fragment 2 (F2). E_tot = [E_dist(F1) + E_dist(F2)] + E_int.

Conclusions

In conclusion, this study sheds light on the intriguing influence of α-fluorine substitution on the nucleophilicity of carbanions, a class of intermediates fundamentally important in organic synthesis. Through computational analysis, we demonstrated that the α-effect, previously observed in O- and N-based nucleophiles, also applies to carbanions when Hamlin's criteria are met. The enhancement in nucleophilicity upon α-fluorination arises from the elevation of HOMO energy and reduction in the orbital lobe size at the nucleophilic center, thereby facilitating efficient orbital interactions and reducing repulsive overlaps with substrates. These insights may inspire further exploration of the effects of other substituents on nucleophilicity and facilitate the design of more efficient and selective synthetic strategies in organic chemistry.

Computational details

All the quantum chemical calculations were carried out using the Gaussian 16²¹ package. Optimizations of the geometries of minima and transition states (TSs) were carried out at the PBE0-D3(BJ)^22,23/6-31G(d,p)²⁴-SDD(Pd, Cs)²⁵ level of theory. The PCM²⁶ implicit solvation model was used to account for the solvation effects of DMSO or dichloromethane (DCM), which were used in the corresponding experiments. Frequency calculations were performed at the same level to ensure their nature as minima (no imaginary frequency) or transition states (only one imaginary frequency). Intrinsic reaction coordinate (IRC) calculations at the same level verified the connectivity of located intermediates and transition states. The single point energy calculations were performed at the PBE0-D3(BJ)/6-311++G(d,p)-SDD(Pd, Cs) level of theory with the SMD²⁷ solvation model to obtain more accurate electronic energies. Grimme's quasi-RRHO correction²⁸ for the frequencies that are below 100 cm⁻¹ and concentration correction from 1 atm to 1 mol L⁻¹ were implemented using GoodVibes 3.2.²⁹ The wavefunction analyses were performed using Multiwfn 3.8(dev),¹⁸ including the orbital delocalization index (ODI) and the volume of isosurfaces. Energy decomposition analysis was performed using sobEDA.¹⁶ Distortion/interaction activation strain (DIAS) analysis was realized using a Python tool named autoDIAS.³⁰ The images of the orbital isosurfaces were created using VMD³¹ combined with Multiwfn 3.8(dev).

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its ESI,† including computed energy and thermal corrections, and optimized Cartesian coordinates for all the stationary points.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 22122104, 22193012 and 21933004), the CAS Project for Young Scientists in Basic Research (grant numbers YSBR-095 and YSBR-052), and the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB0590000).

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Footnote

† Electronic supplementary information (ESI) available: Supplementary computational results (PDF) and Cartesian coordinates for all the stationary points (XYZ). See DOI: https://doi.org/10.1039/d5qo00292c

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