SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates

Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the ex situ generation of trifluoromethanesulfonyl fluoride (CF3SO2F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the SVI–F connector with a S 
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Created by potrace 1.16, written by Peter Selinger 2001-2019
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 O → SNR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H2O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols vs. amine groups, a phenomenon best explained—using ab initio metadynamics simulations—by a hydrogen bonded termolecular transition state for the CF3SO2F triflylation of amines.


Introduction
Recent interest in high-valent sulfur species has brought about an increasing number of S VI -F bond-containing connective hubs. In the framework of Sulfur(VI)-Fluoride Exchange (SuFEx) chemistry-an umbrella term for substitution events replacing uoride at the electrophilic sulfur center-these 'molecular plugins' allow selective and efficient installation of linkages around the S VI core. Especially in the last seven years, various research groups have demonstrated the potential of SuFEx hubs such as sulfonyl uorides (R-SO 2 F), 1 sulfuryl uoride (SO 2 F 2 ), 2 thionyl tetrauoride (SOF 4 ), 3 ethenesulfonyl uoride (ESF, CH 2 ]CH-SO 2 F), 2a,4 and others. 5 The chemoselective and straightforward nature of SuFEx chemistry has enabled a range of applications in synthesis and materials. 6 A particularly intriguing aspect of SuFEx chemistry is its ability to activate oxygen nucleophiles. Various OH-containing materials of different acidities and nucleophilicities have been shown to react cleanly at the sulfur center, and subsequently transform them into useful electrophiles for further derivatization. For example, through SO 2 F-containing reagents, aliphatic alcohols have been converted into alkyl uorides 7 or alkylating agents, 8 carboxylic acids into acyl uorides, 9 and silyl ethers into sulfonate esters 10 (Scheme 1B). A unique role in this collection is reserved for aromatic alcohols, which in reaction with SO 2 F 2 selectively form the valuable aryl uorosulfates in the presence of various other nucleophiles. 2a,11 By far, the most commonly employed category of O-based pseudohalides consists of aryl triates. 12 Even though a number of ways to prepare aryl triates exist, 13,14,15,16,17 a broadly applicable protocol that uses an inexpensive and atom-economic [CF 3 SO 2 ] precursor in a chromatography-free and water-tolerable fashion is still missing from the toolbox.
Herein, we set out to investigate whether SuFEx chemistry can provide this general way of [CF 3 SO 2 ] transfer onto complex organic molecules. Building on our previous work on sulfuryl uoride, 2b we propose triuoromethanesulfonyl uoride gas, CF 3 SO 2 F (b.p. À22 C), as a new electrophilic SuFEx hub, easily generated via two-chamber reactor technology and which reacts efficiently with phenols. Other nucleophiles such as carboxylic acids and amines reacted smoothly with the gas under dry conditions, identifying water as a key additive to obtain complete chemoselectivity for aromatic alcohols (Scheme 1C). Moreover, to shed some light on the mechanistic origins of this chemoselectivity, we relied on ab initio metadynamics simulations to gain fundamental insight into the key SuFEx transition state. Finally, we report a general synthesis of aryl tri-uoromethanesulfonimidate (triimidate) esters: the rarely reported aza analogs of the ArOTf scaffold. Triimidoyl uorides show potential as weakly electrophilic SuFEx hubs, which could have unexplored applications as covalent warheads.

Results and discussion
Triyl uoride gas was rst reported in 1956 by Gramstad for the synthesis of triuoromethanesulfonic acid derivatives. 18 This smallest peruoroalkanesulfonyl uoride is gaseous above À22 C, and its atmospheric chemistry is relatively innocuous. 19 The most relevant industrial preparation consists of the electrolytic uorination of methanesulfonic acid or methanesulfonyl uoride, and the resulting gas serves as the precursor to all other [CF 3 SO 2 ]-containing bulk chemicals such as TfOH or Tf 2 O. 20 Other authors have prepared triyl uoride on a semibulk scale, by reacting CF 3 SO 2 Cl 19,21 or Tf 2 O 22 with a uoride source. 23 Recently, Pees and co-workers have developed CF 3 SO 2 18 F as a carrier gas for nucleophilic [ 18 F]-uoride, evolving it from PhNTf 2 as a precursor. 24 We envisaged the generation of CF 3 SO 2 F in a two-chamber reactor as the most convenient way to employ this gas safely on lab scale. 25 Even though a higher-MW precursor adds to the process mass intensity of this procedure, the results obtained with ex situ CF 3 SO 2 F gas remain true on larger scales in which case the precursor would be abandoned for direct use of gas bottles. Inspired by the aforementioned results, we set out to develop a CF 3 SO 2 F gas generation method using PhNTf 2 as a bench-stable and easily handled solid precursor (for optimization, see ESI Section 3 †). To our delight, the nal reaction conditions allowed conversion of the model substrate 4-uoro-4 0 -hydroxybiphenyl into product 1 in 85% yield aer 4 hours at room temperature (Scheme 2A). With optimized conditions of method A in hand, a variety of readily accessible phenol derivates was examined to further explore the scope of this methodology (Scheme 2). First, monosubstituted electron-rich and decient phenols were successfully transformed into their corresponding triates (2-8). Sterically hindered triates 8, 12 and 27 were also formed efficiently. Although 19 F NMR monitoring of catechols showed a high degree of ditriation at the reaction onset, they nevertheless converged to the mono-triates (14 and 16) aer longer reaction times, most likely due to subsequent hydrolysis (see ESI Section 5.1 †). With a few experimental adaptations and shorter reaction times, however, it was possible to get the less stable ditriates 15 and 17 in a fair isolated yield. The triation of two L-tyrosine derivatives not only offered corresponding products in excellent yields (24 and 25), but also without loss of enantiopurity (25). When it comes to naturally occurring phenols, all afforded the corresponding monotriates in good to excellent yields (4, 9, 10, 19, 20, 26, 27 and 29). In addition, three heteroaryl triates were obtained in good to excellent yields (21, 22 and 23). It is worth pointing out that in many cases, the two-chamber reactor method afforded the triates in sufficiently pure form aer extractive work-up, without the need for column chromatography.
[a] Isolated yield after aqueous work-up.
[b] 2.5 equiv. of DIPEA were used in the reaction chamber. [c] 3 mL MeCN was used in the reaction chamber as solvent, and the crude reaction mixture was purified on silica directly without aqueous work-up. [d] 2.5 equiv. of PhNTf 2 and 1.67 equivalents of KHF 2 were used in the generation chamber.
[e] The reaction was set under Argon atmosphere. [f] Et 3 N (3.5 equiv.) and DMSO (0.25 M, 4.0 mL) were used in the reaction chamber.
[g] The corresponding boronic acid was used as the starting material, and protected afterwards with pinacol.
[h] Yield corresponds to product isolated as an HCl salt.
[i] The assay yield is reported (average over two runs), defined by dividing the [M + 132] peak area by the total AUC of the HPLC-MS TIC chromatogram.
In parallel to this method, a different set of conditions was developed using Tf 2 O as the gas precursor, 22 a less expensive and commonly available chemical (method B). Even though good results were obtained for simple phenols (1), the unpleasant nature of this fuming and sensitive liquid, and the reduced yields for more complex phenols (3, 8, 9 and 18) make this method less ideal. Next, in order to further assess the validity of CF 3 SO 2 F as a triating agent, our method was benchmarked against other known triation methods (for details, see ESI Section 4.1.3 †). Four representative phenols were treated according to three literature triation protocols: adding Tf 2 O to a solution of phenol and organic base (method C); 26 adding Tf 2 O under Frantz' aqueous conditions (method D) 27 and using the PhNTf 2 reagent directly (method E). 28 Even though the gasfree methods required a shorter reaction time, the corresponding triates were almost universally obtained in lower yield than with CF 3 SO 2 F. Not only did the literature methods require more careful temperature control or moisture exclusion, also the chemoselectivity was usually inferior when the phenol starting materials contained indoles (19), aliphatic amines (24 and 28), carboxylic acids (25) or aliphatic alcohols (27). Moreover, amine 28 did not show any trace of sulfonamide formation, even with 2.5 equivalents of gas (see ESI Section 5.2.1 †). To sum up, our CF 3 SO 2 F gas-based two-chamber system allowed triation to proceed in a stable, productive and chemoselective fashion.
During the development of this work, it was observed that the aryl triate synthesis was relatively insensitive towards the choice of solvent or base. To further showcase the versatility of this SuFEx reaction, a series of solvent-base combinations was explored (Scheme 2G). While maintaining the original gas generation using PhNTf 2 , a set of 7 bases (organic and inorganic) was screened against a set of 6 commonly used reaction solvents. In almost all cases, the reactions had reached >50% conversion aer 20 h, and the majority even >80% under unoptimized conditions. While some of the stronger bases were more prone to cause product degradation, nevertheless this broad compatibility enables a subsequent reaction step without intermediate ArOTf isolation.
Given the variety of allowed solvent/base combinations, we wondered whether the triation method can reach further synthetic utility in a one-pot Suzuki-Miyaura cross-coupling reaction. Based on a literature protocol, 29 we found that the (hetero)aryl triates underwent efficient cross-coupling by transferring the reaction mixture to a vial with the (hetero)aryl boronic acid, palladium(II) acetate and tricyclohexylphosphine (Scheme 3A). With this protocol, biaryls 33-37 were synthesized under mild conditions with good to near-quantitative isolated yield over two steps. The more challenging bipyridine 35 was prepared in a 1,4-dioxane/H 2 O mixture in 63% yield, which was higher than the 42% yield reported in literature. 30 In addition, this Suzuki cross-coupling afforded 2-methyl-5-(3-uoro phenyl) pyridine 36, the pharmacophore of vorapaxar 31 in 80% yield without purifying the intermediate triate.
Another class of oxygen nucleophiles that was subjected to CF 3 SO 2 F-enabled post-transformations, consists of carboxylic acids. In line with Moses' 9c and Qin's 9b work on SuFEx-mediated carboxylic acid activation, we aimed to develop a new method based on generating acyl uoride intermediates via CF 3 SO 2 F gas (Scheme 3B). Without isolating the acyl uorides, they were reacted immediately to build amides with various degrees of steric congestion. Where the biphasic conditions developed in Scheme 2A le carboxylic acids untouched (products 7 and 25), simply shiing to a pure organic solvent led to smooth deoxo-uorination. To explore the substrate scope and functional group tolerance of the amidation process, a variety of aromatic and aliphatic carboxylic acids were examined for coupling with different kinds of amines, including anilines, primary and secondary alkylamines and azoles. All coupling reactions proceeded in fair to excellent yields (Scheme 3, [38][39][40][41][42][43][44]. This work Scheme 3 One-pot reactions enabled by CF 3 SO 2 F gas generation. (A) One-pot, two-step method of aryl triflate generation followed by Suzuki-Miyaura cross-coupling. (B) Amide synthesis with in situ generated acyl fluorides. The yield corresponds in all cases to the isolated yield after column chromatography without isolation of the intermediates; the enantiomeric excess (ee) was determined by HPLC analysis.
could be extended to peptide formation, and dipeptide 45 was obtained in 98% isolated yield, while retaining 84% diastereomeric ratio. Especially noteworthy is the procedure's tolerance of bulky coupling partners, a known feature of acyl uorides. 32 Aer investigating the chemistry of CF 3 SO 2 F with oxygen nucleophiles, we were curious to see whether S]N analogs uphold the same substitution reactions. By replacing a single oxo-group with a substituted nitrogen in the S VI -F hub, tri-uoromethanesulfonimidoyl (triimidoyl) uorides are obtained. These chiral molecules are characterized by a milder electrophilicity compared to CF 3 SO 2 F, due to the increased electron density around the sulfur atom. Since the rst description of triimidoyl uorides in 2002, 33 the recent report by Oehlrich and co-workers is the only example of triimidoyl uorides reacting with phenols to form tri-uoromethanesulfonimidate (triimidate) esters. 34 Given that only two examples were made under strongly basic conditions, we surmised that an improved synthesis under mild SuFEx conditions should be possible. 3b, 35 We synthesized three different triimidoyl uoride compounds containing N-aryl or N-alkyl substituents (for preparation, see ESI Section 4.5 †). These electrophiles were engaged in SuFEx reactions with various phenols to generate a small library of triimidate esters. The N-aryl substituted triimidoyl uorides reacted efficiently under mild conditions to afford the corresponding products in moderate to excellent yields (Scheme 4, 46-51). The N-alkyl counterparts, which are less electrophilic, 3b,36 required DBU as a stronger base and an elevated reaction temperature of 50 C. Naturally occurring phenols such as vanillin (47), eugenol (50), L-tyrosine methyl ester (53), raspberry ketone (54), as well as sterically hindered 2-bromophenol (51) and thiophen-2-ol (48) were all well tolerated (Scheme 4).
Aer the transformation of various oxygen nucleophiles into reactive handles with CF 3 SO 2 F, we also wanted to investigate nitrogen nucleophiles. To this end, a range of aliphatic amines, anilines and azoles was engaged in a triylating reaction to form the triuoromethanesulfonamides (triamides) (Scheme 5). Based on a literature SuFEx reaction between SO 2 F 2 and secondary amines, 2a we selected DMAP as a stoichiometric base, although we found later that Et 3 N furnishes the same products in equal reaction times and yields with the dry MeCN served as the solvent.
[b] 1.2 equiv. of ArOH used, reaction time was 3 h. [c] Reaction was carried out at a 2.0 mmol scale.
Scheme 5 Synthesis of triflamides by reaction of CF 3 SO 2 F with amines and azoles. Reaction was carried out on 1.0 mmol scale and reported yields are after column chromatography unless noted otherwise. Between brackets is given the 19 F NMR yield using PhCF 3 as internal standard, between parentheses the reaction time.
[a] Isolated yield of pure material after aqueous work-up. [b] 3.0 equiv. of base was used.
[c] 2.5 equiv. of CF 3 SO 2 F gas was used. [d] 3.5 equiv. of base was used.
[e] 2.0 equiv. of CF 3 SO 2 F was generated. [f] K 2 CO 3 was used as the base.
[g] 2.5 equiv. of base was used. monosubstituted triamides, an interesting contrast with monosubstituted sulfamoyl uorides, which cannot be formed under basic conditions. 2a Finally, except for a few unsuccessful substrates (see ESI Section 7.7 †), various N-triyl heterocycles were prepared in the same manner in fair to good yields (66-70). It is worth noting that the N,O-bis(triuoromethanesulfonyl) compound 60 was formed in high yield using 2.5 equivalents of the generated gas. This stands in contrast to the reaction leading to 28, where no trace of N-triyl product was observed. The same discrepancy was observed for 70 vs. 19. It was also veried that N-triyl compounds 60 and 70 were not hydrolysed by water (see ESI Section 5.3 and 5.4 †). Since the only difference between these reaction conditions is the presence or absence of water, it seems that water inuences the mechanism in such a way that it plays a decisive role in the reaction outcome. Ultimately, a direct reactivity comparison of phenol and amine groups in compound 60 was evaluated using only 1.0 equiv. of CF 3 SO 2 F gas. Regardless of choice of base, the product mixtures resulting from triuoromethanesulfonation in anhydrous MeCN invariably lacked N-SO 2 CF 3 monotriylated product, indicating highest reactivity for the phenol group (see ESI Section 5.2.2 †).
Having established a robust procedure for installing a triyl group through our CF 3 SO 2 F SuFEx hub, we turned towards the mechanism of this reaction. More specically, we investigated the base-mediated triylation of secondary amines, aiming to elucidate the reaction pathway and the specic role of the base. As a result, we hope to shed light on the observed chemoselectivity, by comparing our simulations for secondary amines with the better-studied mechanism of phenol SuFEx reactions. 35,37 To achieve this goal, we use ab initio metadynamics (AIMtD) to retrieve the mechanism as well as quantify the associated activation barriers. 38 In contrast to static DFT computations, AIMtD usually includes all molecules in the simulation box, meaning explicit interactions between reactants and additives or solvents are accurately modelled, with the trade-off of a signicant increase in computational workload (for theoretical background, see ESI Section 8.1 †). We, among others, have previously shown the ability of AIMtD to elucidate reaction mechanisms, quantify reaction barriers and unveil solvation effects. 39 Here, piperidine served as a case study for the computationally modelled CF 3 SO 2 F triylation reaction (Fig. 1A). In parallel, a series of experimental studies was performed, to complement the in silico ndings (Fig. 1B). 40 Initially, three different systems were considered. A single CF 3 SO 2 F and one piperidine molecule were placed in the simulation box together with explicit acetonitrile (I), or with DMAP (II) or Et 3 N (III) included as a base (Fig. 1A). All simulations in this study followed the Born-Oppenheimer molecular dynamics scheme at the DFT level of theory, with the GGA PBE functional and DZVP-MOLOPT-GTH plane wave basis set. 41 Additionally, the description of long-range dispersion interactions was improved by Grimme's D3 dispersion correction. 42 The CP2K code (version 6.1) was used together with the Quickstep implementation (for full computational details see ESI Section 8.1 †). 43 From analysing the trajectory obtained for the non-activated CF 3 SO 2 F-triylation of piperidine (I), a concerted bimolecular reaction mechanism was observed, akin to an S N 2-type pathway (see ESI Movie †). Indeed, bond length analysis shows a simultaneous S-F bond breaking and S-N pip bond formation (see ESI Section 8.1 †) and the free energy surface displays a reactant and product phase, without an additional intermediate basin (Fig. 1A, I). Notably, without a base, the piperidine nucleophile attacks the sulfur-center from the frontside, which for most S N 2 reactions would be less favourable compared to the corresponding backside pathway. 44 Herein, frontside attack allows F À to directly scavenge the amine hydrogen of piperidine.
While this mechanism coincides with the ndings of Luy and Tonner, the AIMtD simulations result in a Helmholtz free energy of activation (DF ‡ ) of 29 AE 4 kcal mol À1 , which exceeds a barrier that can readily be crossed at ambient conditions. 37 As the non-activated triylation of 55 yielded 49% of product at room temperature aer 18 hours (Fig. 1B, entry 1), the obtained high activation barrier raises questions on the validity of this mechanism. When adding a base such as DMAP (A, II) or Et 3 N (A, III) to the simulation box, a signicantly reduced DF ‡ is observed (13 AE 1 kcal mol À1 and 22.1 AE 0.05 kcal mol À1 , respectively, Fig. 1A). These activation barriers are reasonable, given the high experimental yields obtained for the basemediated triylation of 55 (entries 2-3). Mechanistically, the reaction occurs concertedly when DMAP or Et 3 N are used, similar to the non-activated CF 3 SO 2 F-triylation of piperidine (see ESI Section 8.1 and Movie †). Moreover, the trajectory indicates that the base forms a Lewis adduct with piperidine through a hydrogen bond, enhancing the nucleophilicity of N pip . Collectively, these observations indicate that the transition state has a termolecular nature, meaning the reaction follows an S N 3-type pathway. While initially these ndings might seem surprising, such S N 3 pathways have previously been proposed as mechanisms for substitution reactions on sulfonyl substrates. 45 Moreover, when the reaction is activated by DMAP or Et 3 N, backside attack of the nucleophile is preferred.
Another intriguing observation was the difference between DF ‡ of the DMAP and Et 3 N activated triylation. One would expect that a stronger base would activate the nucleophile more efficiently and thus further decrease the activation barrier. Nevertheless, our AIMtD simulations resulted in a value for DF ‡ of 13 AE 1 kcal mol À1 and 21.9 AE 0.5 kcal mol À1 for DMAP and Et 3 N, respectively. In other words, the activating role of Et 3 N is signicantly less effective compared to DMAP, notwithstanding Et 3 N is the stronger base. To further study the differences between the DMAP-mediated and Et 3 N-mediated triylation of piperidine, NCI analyses were performed on their transition states (for theoretical background, see ESI Section 8.2 †). 46 Remarkably, the 3D NCI isosurface of the DMAP-mediated transition state and bond length analysis reveals an attractive non-classical CH/O hydrogen bond connecting DMAP with CF 3 SO 2 F (Fig. 1C, purple arrow and ESI Section 8.1 †). The synergy between this CH/O hydrogen bond and Lewis adduct formation between DMAP and piperidine favourably align both reactants in the transition state. Furthermore, the isosurface of the Et 3 Nmediated transition state is characterized by larger repulsive (red) surfaces compared to the DMAP-mediated transition state, especially between Et 3 N and CF 3 SO 2 F. From the number of peaks present in the plot of s against r sign(l 2 ), it can also be inferred that the Et 3 N-mediated transition state contains considerably more noncovalent interactions (Fig. 1C). Based on these results, we believe that the activating role of the base in the CF 3 SO 2 F-triylation of piperidine transcends beyond deprotonation of the amine. Clearly, intricate non-covalent interactions such as hydrogen bonding or steric repulsion due to the bulkiness of all reactants involved play an important role in the stability of the termolecular transition state.
Aer establishing plausible reaction pathways for the activated triylation of piperidine, we reconsidered the mechanism for the non-activated reaction (A, I). We reasoned that, besides acting as the nucleophile, a second equivalent of piperidine could activate the reaction, similar to an added base. Such a mechanistic picture would also coincide with the nonactivating triylation of 55 yielding 49% of product (Fig. 1B  entry 1). Indeed, a maximum of 50% would be expected when the substrate acts as its own base. To our delight, we obtained Fig. 1 (A) Transition states obtained through metadynamics simulations for: (I) the non-activated CF 3 SO 2 F-triflylation of piperidine in acetonitrile, (II) the DMAP-activated CF 3 SO 2 F-triflylation of piperidine in acetonitrile, (III) the Et 3 N-activated CF 3 SO 2 F-triflylation of piperidine in acetonitrile and (IV) the non-activated CF 3 SO 2 F-triflylation of piperidine in acetonitrile including two molecules of piperidine. In all cases, electron displacement is schematically illustrated using green arrows. During the simulations, Gaussian shaped potentials were placed along two coordination numbers, resulting in a free energy surface and Helmholtz free energy of activation (DF ‡ ). Simulations were performed in triplicate. (B) Triflylation of phenylpiperazine as model reaction varying the base, solvent and relative amounts of substrate and CF 3 SO 2 F. Isolated yields are provided unless stated otherwise.
[a] 19 F NMR yield relative to int. std. after 72 h reaction time. (C) NCI analyses were performed on the transition states of the DMAP-mediated CF 3 SO 2 F triflylation (II, green) and Et 3 N-mediated CF 3 SO 2 F triflylation (III, red). Analyses were performed in absence of the solvent to focus on the noncovalent interactions present in and between the reactive species. Top; 3D NCI isosurfaces (s ¼ 0.5) visualized for both reactive systems. An RGB-scale is used to differentiate between repulsive (red) and attractive (green) interactions, set from À0.005 a.u. to 0.005 a.u. For the DMAP-mediated triflylation, a non-classical CH/O hydrogen bond is observed as an attractive blue surface, which connects DMAP with CF 3 SO 2 F (purple arrow). Bottom; an overlay plot of s against r sign(l 2 ) is presented for both NCI analyses.
an energetically more reasonable mechanism for the nonactivated triylation of piperidine when a second piperidine molecule was added to the simulation box, resulting in a DF ‡ of 18 AE 4 kcal mol À1 (A, IV). In this mechanism, a second equivalent of piperidine forms a Lewis adduct with the piperidine nucleophile and a termolecular transition state is observed. A notable difference with the activated pathways (A, II and III), is that herein substitution preferably proceeds through frontside attack of the nucleophile. To further strengthen our hypothesis, the relative amount of phenylpiperazine with respect to CF 3 SO 2 F was increased (2 : 1 ratio). As expected, the experimental yield of the reaction increased to 79% (entry 4), suggesting that indeed a second equivalent of piperidine plays an active part in the reaction. Intriguingly, when the water content is gradually increased, as little as 1.5 equivalent shuts down the reaction completely (entries 5-7).
Based on these mechanistic insights, we propose an explanation for the observed chemoselectivity when comparing the tri-ylation of amines and phenols. When performing the reaction in MeCN : H 2 O (3 : 1), phenols are selectively triylated, while amines remain unaffected (compounds 19 and 28). On the other hand, in dry MeCN (0.33 M), both phenols and amines are converted (compounds 60 and 70). We believe that the inuence of H 2 O on chemoselectivity can be explained through the difference in mechanism. A trialkylamine (pK aH $11) will partially deprotonate the phenol (pK aH $10) towards the phenolate, which is likely to undergo triylation via a bimolecular S N 2 type mechanism, as shown by Zuilhof and co-workers. 35 In contrast, our simulations showed that under the same conditions, amines would undergo an S N 3 type mechanism, in which a hydrogen bond driven Lewis adduct between the nucleophile and the base is formed (Scheme 6). We assume H 2 O to disrupt these essential hydrogen bonds, explaining why the reaction in MeCN : H 2 O is selective towards phenols, while in dry MeCN both phenols and amines showcase a high reactivity towards triylation.

Conclusions
To summarize, we designed a two-chamber procedure for the safe and efficient ex situ handling of triyl uoride gas (CF 3 SO 2 F) as a new type of SuFEx connector. Herewith, a diverse library of triates and triamides was built straightforwardly, oen without the need for further purication. Comparing with literature triation methods, CF 3 SO 2 F consistently furnished higher yields and selectivities. A particularly interesting nding was the lack of reactivity of carboxylic acids and amines in the presence of water, allowing a completely chemoselective triation of phenolic nucleophiles. In a more in-depth study of this phenomenon, ab initio metadynamics (AIMtD) simulations offered insight into the reactivity of the CF 3 SO 2 F triylation with secondary amine nucleophiles. In contrast to phenolates reacting in a bimolecular fashion, the simulations for amines suggested a formal S N 3 mechanism with a termolecular transition state that relies on hydrogen bond formation between base and nucleophile. Due to the absence of such H-bonds in aqueous media, we believe this mechanism explains the observed difference in reaction outcome. The formation of aryl triates proved amenable to peptide functionalization and reaction telescoping into one-pot Suzuki-Miyaura cross-coupling. In addition, the sulfonylation chemistry developed for triyl uoride CF 3 SO 2 F was found to be fully translatable to triimidoyl uorides CF 3 -SO(NR)F. These aza-analogous SuFEx hubs provided an efficient route to aryl triimidate esters, a barely reported class of compounds with three-dimensional, potentially chiral character and unknown biological properties. Overall, we believe that the ex situ gas generation method will lead to increased use of CF 3 SO 2 F in chemoselective, lab-scale synthesis of valuable aryl triates and triamides. Also, process chemistry may benet from the clean reaction proles demonstrated here, when using gaseous CF 3 SO 2 F directly as a low-MW progenitor to current standard Tf 2 O. Ultimately, we believe the insights derived from high-quality ab initio calculations form the next step in understanding the fundamental interactions during S VI -F chemistry, and provide a better-informed basis for future applications.

Data availability
All experimental data, procedures for data analysis and pertinent data sets are provided in the ESI. †

Conflicts of interest
There are no conicts to declare.