Attack from the front Biomolecular substitution reactions are widely applied to compounds with carbon-halogen bonds. Typically, an incoming reactive group will attack the carbon from behind its bond with the halogen, causing the halogen to depart in the opposite direction. Zhang et al. now present an asymmetric catalytic substitution reaction that flips the script with an attack on the halogen from the front. Specifically, nitrogen and sulfur nucleophiles stripped bromine from a variety of carbon centers activated by electron-withdrawing groups. A chiral cationic catalyst then directed the carbon fragment back to form a carbon-sulfur or carbon-nitrogen bond enantioselectively. Science, this issue p. 400

Abstract Bimolecular nucleophilic substitution (S N 2) plays a central role in organic chemistry. In the conventionally accepted mechanism, the nucleophile displaces a carbon-bound leaving group X, often a halogen, by attacking the carbon face opposite the C–X bond. A less common variant, the halogenophilic S N 2X reaction, involves initial nucleophilic attack of the X group from the front and as such is less sensitive to backside steric hindrance. Herein, we report an enantioconvergent substitution reaction of activated tertiary bromides by thiocarboxylates or azides that, on the basis of experimental and computational mechanistic studies, appears to proceed via the unusual S N 2X pathway. The proposed electrophilic intermediates, benzoylsulfenyl bromide and bromine azide, were independently synthesized and shown to be effective.

Unimolecular nucleophilic substitution (S N 1) and bimolecular nucleophilic substitution (S N 2) are long-standing textbook reactions in organic chemistry (Fig. 1A). Nonetheless, progress toward enantioconvergent nucleophilic substitutions of racemic tertiary electrophiles has been made only recently. S N 1 reactions generally require substrates that can form stabilized carbocation intermediates. In this regard, Jacobsen and co-workers reported the generation of nonheteroatom-stabilized carbocations for the enantioconvergent allylation of tertiary propargyl acetates (Fig. 1B) (1), whereas Sun and co-workers reported oxygen-stabilized cations for the addition of indoles to racemic tertiary alkyl alcohols (2). S N 2 reactions, on the other hand, are more amenable to kinetic resolution, rather than enantioconvergent synthesis, owing to their stereospecific mechanism (3). Alternatively, enantioconvergent nucleophilic substitutions of racemic tertiary electrophiles can proceed through an S RN 1 (unimolecular radical-nucleophilic substitution) reaction initiated by single-electron transfer (4, 5). The advantage of the S RN 1 mechanism is its insensitivity to steric influences: Fu and co-workers successfully demonstrated the enantioconvergent photoinduced coupling of racemic tertiary alkyl chlorides with amines by using a copper catalyst (Fig. 1B) (6).

Fig. 1 Nucleophilic substitutions. (A) Nucleophilic substitutions: S N 1, S N 2, and S RN 1. SET, single-electron transfer. (B) State-of-the-art enantioconvergent nucleophilic substitution of tertiary electrophiles. TMS, trimethylsilyl; Me, methyl; Et, ethyl; Ph, phenyl; Ar, aryl; tBu, tert-butyl; OTf, triflate; h, Planck’s constant; ν, frequency; LED, light-emitting diode. (C) This work: Pentanidium-catalyzed enantioconvergent halogenophilic nucleophilic substitution (S N 2X).

In the conventionally accepted S N 2 mechanism, the nucleophile displaces the leaving group X, which is typically a halogen, by attacking from behind the C–X bond. Another substitution pathway that has only rarely been reported is the halogenophilic S N 2X mechanism wherein the nucleophile approaches X from the front (7–9). This mechanism has been posited for reactions such as the addition of thiol anions to o-iodonitrobenzene (generating o-nitrophenyl thioethers and nitrobenzene), as well as nucleophilic displacement of halogens on 1-halo-1-alkynes (10, 11). In such S N 2X reactions, the halogen atom (X) of the electrophile interacts with the nucleophile (Nu) to generate a carbanion and a new electrophilic intermediate (Nu–X). The carbanion then displaces X from the Nu–X species to generate the desired substitution product. Such reactions usually occur in cases where nucleophilic substitution at the carbon atom is hampered. For sp3-hybridized carbon centers, bulky substituents may promote halogenophilic attack. As such, they are appealing targets for asymmetric construction of sterically congested tertiary or quaternary stereocenters.

Our interest in S N 2X pathways follows from our previous studies of the role of halogen bonding in catalytic reactions (12, 13). Herein, we report that two different nucleophiles, thiocarboxylates and azides, can formally displace bromide at tertiary stereocenters activated by two electron-withdrawing groups to generate the substitution products with high yields and high enantioselectivities (Fig. 1C). A chiral cationic pentanidium catalyst that our group has developed induces asymmetry (14, 15). Both experimental and computational mechanistic studies support an S N 2X mechanism rather than S N 2 or radical-based S RN 1 reactions.

The activated tertiary bromide 1a was chosen as a model substrate after extensive screening experiments of the enantioconvergent thiocarboxylate substitution reaction (see table S1 for full optimization details). A variety of thiocarboxylate salts were tested in the presence of 5 mole % (mol %) of pentanidium salt as catalyst (Fig. 2A). Potassium thiophenyl thiocarboxylate 2b and pentanidium PN4, bearing 3,5-bis(trifluoromethyl)benzyl groups, were found to produce the best results. Under these optimized conditions, the substrate scope of the reaction was then examined (Fig. 2B). Phenyl, thiophenyl, and furyl thiocarboxylate salts reacted with high yields and high enantiomeric excess (ee) (3a to 3c). 2-Alkyl–substituted methyl 2-bromo-2-cyanoacetates with primary and secondary alkyl groups afforded their respective products in good yields and ee (3d to 3h). The reaction was also effective for substrates bearing allylic (3i to 3k) and propargylic (3l) substituents. For benzyl-substituted substrates, both electron-withdrawing and electron-donating aryl groups were tolerated (3m to 3q). Moreover, both benzyl- and naphthyl-substituted diethyl bromocyanomethylphosphonates reacted with good yields and ee (5a to 5h). Substrates bearing 2-(methyl)furan and 2-(methyl)thiophene groups also produced favorable results, albeit with lower enantioselectivities (5i and 5j).

Fig. 2 Pentanidium-catalyzed enantioconvergent halogenophilic nucleophilic substitution (S N 2X). (A) Optimization of reaction condition. (B) Enantioconvergent thiocarboxylate substitution of tertiary bromides. (C) Enantioconvergent azidation of tertiary bromides. Isolated yields are reported, and ee values were determined using chiral HPLC or gas chromatography. See the supplementary materials for detailed reaction conditions.

The successful preparation of highly enantioenriched tertiary thioesters with our catalyst prompted us to explore the use of other nucleophiles. Organic azides act as valuable building blocks in synthetic chemistry, but the preparation of chiral tertiary azides remains nontrivial. Two examples of the formation of chiral tertiary azides were reported via S N 2 substitution, but these reactions required the use of enantiopure tertiary halide precursors (16, 17). After extensive investigations, we discovered that 3 mol % of PN5 and 2.0 equivalents of NaN 3 , in the presence of a two-phase mixture of diisopropyl ether (iPr 2 O, 1.0 ml) and saturated K 2 CO 3 aqueous solution (0.2 ml), were found to be essential for the enantioconvergent transformation of bulky activated tertiary bromide 6a to tertiary azide 7a smoothly over 3 to 4 days at low temperature (−40°C) with good yield (86%) and ee (94%) (Fig. 2C; see table S2 for full optimization details). The reason for this slow reactivity could be attributed to low solubility of NaN 3 in the two-phase mixed solvent system at very low reaction temperature. 2-Alkyl substituted tert-butyl 2-bromo-2-cyanoacetates, such as methyl- and phenylethyl-substituted bromides, were suitable substrates and provided good results (7b and 7c). For tertiary bromides with bulky substituents, slightly lower yields were obtained, owing to the formation of protonated side products (7d to 7g). Substrates containing alkenyl and alkynyl substituents also afforded their respective products (7h to 7j and 7m) with good yields and ee. When cyclopropyl- and pentenyl-substituted substrates were used as radical probes, substitution products were obtained in desirable yields and ee without formation of any ring-opening or ring-closing products (7e and 7i, respectively). This outcome indicated that free radical species were not likely to be involved in the reactions. Substrates bearing t-butyldimethylsilyl– or acetyl-protected alcohols showed no negative effects on the yields and enantioselectivities (7k and 7l); however, free alcohol groups were not well tolerated because of the formation of a tetrahydrofuran through intramolecular cyclization.

We initially considered S RN 1 as a possible mechanistic pathway for these reactions and were hence intrigued when cyclopropyl- and pentenyl-substitutions on the alkyl cyanoesters were unperturbed by the azidation reaction (Fig. 2C; 7e and 7i). In addition, neither the radical trap TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl] nor the redox trap m-dinitrobenzene substantially affected the substitution reaction (fig. S1). A systematic investigation was then carried out by adding proton donors (MeOH, H 2 O, and PhOH) or hydrogen-atom donors (1,4-cyclohexadiene, fluorene, xanthene, and Et 3 SiH) to the reaction medium containing tertiary bromide 1a and potassium thiophenyl thiocarboxylate 2b (Fig. 3A). Whereas hydrogen-atom donors did not affect the reaction, proton donors facilitated formation of the protonated product 1a-H in good yield. We speculated that if 1a-H was generated via protonation of a carbanion intermediate, we would be able to experimentally observe substituent effects of this carbanion in a Hammett study. Indeed, a linear correlation with a positive slope (ρ = +2.57) was obtained through a Hammett plot (Fig. 3B). This result implicated accumulation of negative charge in the rate-determining transition state, which was stabilized by electron-withdrawing groups. A carbanion-exchange experiment was also conducted to provide experimental evidence for the proposed carbanion intermediate. When a mixture of tertiary bromide 1l (bearing a 4-methylphenyl group) and methyl 2-cyano-3-(4-fluorophenyl)propanoate 1m-H was subjected to the standard reaction conditions, a mixture of tertiary thioester 3n (53% yield, 86% ee) and tertiary thioester 3o (45% yield, 77% ee) (Fig. 3C) was obtained. This result suggested that the initial carbanion generated from 1l had abstracted a proton from 1m-H to generate the corresponding carbanion. Both carbanions reacted with the sulfenyl bromide to generate the mixture of tertiary thioesters 3n and 3o.

Fig. 3 Mechanistic studies. (A) Effects of hydrogen-atom donors and proton donors. (B) Hammett plot of log(k Ar /k Ph ) for the formation of 3m to 3q versus the corresponding σ value (k, reaction rate). (C) Carbanion-exchange experiments. (D) Reactions using the proposed S N 2X intermediates benzoylsulfenyl bromide 8a and BrN 3 . (E) Reactions with enantioenriched tertiary bromides. (F) Proposed S N 2X pathway and side reactions.

At this point, our experimental observations indicated an S N 2X pathway for these reactions. The key feature of S N 2X reactions is the generation of a new electrophilic intermediate (Nu–X) from the attack of the nucleophile (Nu) on the halogen atom (X). To support this pathway, benzoylsulfenyl bromide 8a (18), the proposed new electrophilic intermediate, was prepared and treated with carbanion 1a-A, derived from 1a-H, in the presence of pentanidium PN4 (Fig. 3D). This experiment afforded a mixture of the tertiary bromide 1a (12% yield, 0% ee) and tertiary thioester 3a (66% yield, 82% ee; compare with Fig. 2B, 3a). Similarly, bromine azide (BrN 3 ), the proposed new electrophilic intermediate in the azidation reaction, was prepared via a known procedure with sodium azide and bromine (19). Reaction of BrN 3 with carbanion 6a-A, derived from 6a-H, afforded a mixture of tertiary bromide 6a (32% yield, 0% ee) and tertiary azide 7a (36% yield, 78% ee). These experiments indicate that both benzoylsulfenyl bromide 8a and BrN 3 are plausible intermediates in these reactions. Although the tertiary thioesters or tertiary azides were obtained in high ee, the tertiary bromides were obtained as racemates. This suggests that stereoinduction does not occur through the halogen abstraction step involving the C–Br bond. Next, we separated the two enantiomers of tertiary bromide 1i by using preparative high-performance liquid chromatography (HPLC) and subjected them to enantioconvergent thiocarboxylate substitution separately (Fig. 3E). We found that both enantiomers were transformed to the same enantiomer of thioester, (+)-3k (87% ee), and the recovered 1i was racemized. From these results, we propose that the sulfenyl bromide and BrN 3 are generated through the S N 2X mechanism and are ambident electrophiles. Positing that the C–Br bond cleavage step is reversible (Fig. 3F) explains the racemization of enantioenriched tertiary bromide (Fig. 3E). This mechanism also explains the formation of homocoupled disulfide side products observed in the thiocarboxylate substitution reaction (10). Similar mechanistic studies were conducted for the azidation reaction and support the S N 2X mechanism (fig. S2).

Density functional theory (DFT) calculations were conducted to provide more mechanistic insights and support the experimental studies (vide supra). The modeling involved a simplified pentanidium catalyst, in which phenyl and benzyl groups were truncated into either H or methyl groups, to reduce computational costs. Two possible pathways to achieve the thioester 3d, via S N 2 or halogenophilic S N 2X mechanisms, were modeled (Fig. 4). Our studies revealed that the S N 2 pathway involving rear addition of the thiocarboxylate to the tertiary carbon of 1b via TS-A, required overcoming a relatively high energy barrier of 27.1 kcal/mol. This conclusion is unsurprising, as it is well known that S N 2 reactions are sterically dependent. For the S N 2X pathway, the tertiary bromide 1b is held in place by S–Br intermolecular halogen bonding with the thiocarboxylate, forming int-B (solution Gibbs free energy ΔG sol = 11.2 kcal/mol) (20). The Br possesses a σ hole that is enhanced by the proximity of two covalently bonded electron-withdrawing functional groups (21), namely the cyanide and ester moieties. This intermediate is thus primed for C–Br bond cleavage due to halogen bonding. The calculated S···Br atomic distance in int-B is 3.04 Å, which is well within the reported range for halogen bonds and the C–Br bond of tertiary bromide 1b is slightly elongated to 2.00 Å (Fig. 4). Indeed, mapping of noncovalent interaction surfaces (22, 23) for int-B (fig. S9) showed strong positive interaction between the σ hole of Br and S of the thiocarboxylate. Formation of such intermolecular halogen bonds has been widely established as a strategy to prepare cocrystals in the field of crystal engineering (24), and it has been recently adopted for the rational design of reactions and catalysts (25).

Fig. 4 DFT calculations. DFT was used to calculate relative free energies of the intermediates and transition states of the S N 2 and S N 2X mechanistic pathways. Images of the geometrically optimized structures int-B and int-C, depicting key atomic bond distances, are shown with H atoms omitted for clarity.

From int-B, the most kinetically feasible outcome would be the stepwise Br abstraction by the thiocarboxylate via TS-B (ΔGǂ sol = 20.9 kcal/mol) (26–28). The process through TS-B resulted in the simultaneous formation of the S–Br bond and breakage of the Br–C bond, leading to the sulfenyl bromide/enolate complex int-C (ΔG sol = 17.0 kcal/mol), which is held together by halogen bonding (Br···O atomic distance of 2.55 Å) (Fig. 4). The dissociation of the sulfenyl bromide intermediate from the catalyst, forming a sulfenyl bromide and the catalyst–enolate ion pair separately, is thermodynamically less endergonic (ΔG sol = 7.3 kcal/mol). The experiments, vide supra, revealed that the C–Br bond scission-reformation equilibrium is not enantio-determining, which suggests that the catalytic stereocontrol in orientation and binding of substrates is important for int-D (ΔG sol = 16.0 kcal/mol) to give rise to enantioenriched product. Subsequently, C–S bond formation via TS-D (ΔGǂ sol = 21.3 kcal/mol) leads to the formation of preproduct complex int-E (ΔG sol = 0.3 kcal/mol) and then product complex cat-pdt (ΔG sol = −8.3 kcal/mol). The activation barriers TS-B and TS-D relative to cat-enolate/sulfenyl bromide are nearly isoenergetic, consistent with experimental evidence, suggesting that sulfenyl bromide is an ambident electrophile.

Whereas halogen bonding has been well exploited in the field of supramolecular chemistry and crystal engineering, its role in reaction development and catalysis is still in its infancy. The results presented herein open the door for further exploration along those lines.

Supplementary Materials www.sciencemag.org/content/363/6425/400/suppl/DC1 Materials and Methods Supplementary Text Figs. S1 to S12 Tables S1 to S3 Spectral Data References (29–35)

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Acknowledgments: Funding: We acknowledge support from Nanyang Technological University (M4011663 and M4080946); Ministry of Education, Singapore (MOE2016-T2-1-087); and Singapore University of Technology and Design (T1MOE1706 and IDG31800104) as well as computational resources from National Supercomputing Centre (Singapore). Author contributions: C.-H.T. conceived of the project; C.-H.T., X.Z., and J.R. designed the research; X.Z. carried out the thiocarboxylate substitution; J.R. performed the azidation reaction; R.L. designed the computational studies; and D.T. and S.M.T. conducted the DFT calculations. All authors took part in writing and reviewing the manuscript. Competing interests: The authors declare no competing interests. Data and materials availability: Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC 1845290, 1845291, 1845292, and 1851709. All other data are available in the main text or the supplementary materials.