Although kinetic analysis resolved the initial proton transfer step, the subsequent steps could not be determined experimentally due to thermodynamic pre-equilibrium control from the RLPT step. While addition was assumed to occur next, it was unclear if this followed a classical stepwise elimination pathway or was concerted (cSNAr) (Scheme S2). cSNAr is a rapidly growing class of SNAr reactions where strong electron withdrawing and good leaving groups that stabilize the classical Meisenheimer complex are superfluous. Thus, computational studies were undertaken to elucidate the details of the mechanistic final steps. Following DFT calculations, a two-coordinate potential energy surface (PES) scan was performed (Figure ). This was performed to identify saddle point(s) along the PES that could serve as transition state (TS) candidates. This scan identified a single candidate, which was confirmed as the TS (B) for the addition step by intrinsic reaction coordinate (IRC) calculations (Scheme 2). All attempts to locate a ground state σ-complex or a second TS corresponding to a stepwise pathway failed, supporting an asynchronous cSNAr. Additionally, base-mediated and acid-mediated pathways were also calculated, and demonstrated significantly higher barriers (G ‡ ) (see protonation state TS barrier comparison in SI). Consistent with our RPKA, the relatively low barrier (13.2 kcal/mol) for this TS reinforces thermodynamic control of the reaction rate by a proton transfer pre-equilibrium. Our combined mechanistic studies support that PTDI SNAr is unique when compared to traditional SNAr reactions. PTDI capitalizes on the advantages of both nucleophile and electrophile ionization present in disparate SNAr reactions. In theory, other types of appropriately matched nucleophiles and electrophiles could participate in SNAr reactions following a similar mechanism and efforts to uncover such reactions are currently underway. Scheme 2. Proposed reaction mechanism supported by RPKA and computational studies. Substrate Scope. Armed with an understanding of reaction constraints and mechanism, we next leveraged this information to guide substrate scope evaluation. For consistency, MeCN was used as the solvent at temperatures ranging from 23 to 90 °C. While we observed enhanced reaction rates with increasing polarity in polar aprotic solvents, MeCN provided the best combination of reaction rate and ease of product isolation. For isolation, the reactions were either filtered directly or submitted to a basic workup followed by column chromatography (if needed). We first evaluated a range of sulfur-based nucleophiles with 4iodopyridine as the model electrophile (E6) (Scheme 3, left column), which was selected based on its simplicity and availability as a free base. For oxidatively sensitive thiols, sodium thiolate salts were used with 4-bromopyridinium chloride (E7) as an alternative. Across the thiols tested, excellent functional group tolerance was observed (alkyl, alcohol, amino, trifluoromethoxy, ester, thioester, nitro, halogen, thiocyanate, heterocycle). High conversion was consistent for electronically diverse thiophenols and benzeneselenol, generally favoring electron deficiency. This observation contrasts reported base-mediated SNAr reactivity, which typically favors electronically rich nucleophiles based on a rate-limiting addition step. For more electronically rich or sterically encumbered nucleophiles, in general, gentle heating was required (50 °C) and typically lower yields were obtained. Of note, while 4-nitrothiophenol and 2-benzoxazolethione failed in photochemical conditions, these substrates proved successful under these conditions. 2f A handful of sulfur-based nucleophiles were also evaluated. As alluded to in our control experiments (Table ), alkyl thiols are unreactive even at elevated temperatures (80 °C), aside from ethyl thioglycolate due to its increased acidity (pKa ~ 13 vs 17, DMSO) (Scheme S7). 13b Scheme 3. Nucleophile and electrophile substrate scope. PPTS = pyridinium p-toluene sulfonate. a General conditions: N (1.1 equiv), E (1.0 equiv), MeCN (0.5M), 18h. b Dimerization: thioacetic acid (2.0 equiv.), MeCN (0.5M). c Thiolation: thioacetic acid (0.5M); Left column: Nucleophile scope; Right column: Electrophile scope; Inset: Competition experiments between E8 and E5. Some nucleophiles like thiourea and thiocyanate required either increased temperatures (70 °C) or were low yielding, while thiocarboxylic acids worked well at 23 °C. Remarkably, thioacetic acid could be used to produce thioether dimers or free thiols by simply modifying the equivalents used. In the latter case, S -> N acyl transfer is known for thiopyridines and perhaps mediates hydrolysis of an intermediate thioester. This reaction represents a rare traceless thiol installation and provides a valuable alternative to previously described approaches involving multistep sequences using thiol surrogates like the Newman-Kwart rearrangement (for examples, see Scheme S4). For the electrophile scope, a variety of basic halogenated heterocycles were evaluated with methyl 4-mercaptobenzoate (N3) as the standard nucleophile, which was chosen due to excellent reactivity and long-term stability (Scheme 3, right column). Successful reactions were observed for a broad array of heterocycle classes such as pyridine, aminopyridine, pyridone, purine, pyrimidine, pyrazine, quinoline, isoquinoline, napthyridine, imidazopyridine, pyrrolopyrimidine, imidazopyridazine, imidazopyrazine, pyridazinedione and thiazole. Modest reactivity differences were observed by varying the halogen leaving group, best exemplified by P31, which was synthesized starting from each halogenated analog (X = I, Br, Cl, F). As observed in the control experiments (Table , Entry 8), the position of halogenation with respect to the protonation site is important as this impacts protonation ability as well as activation of the ipso site through conjugation. For instance, in pyridine electrophiles, generality was observed for 2-, 4-, and 6-halogenation, while 3-and 5-gave no reaction (Scheme S9). Examples with 2-and 6-halogen substitution require elevated temperatures, which we attribute to their reduced basicity (pKa <2) compared to 4-halogenated pyridines (pKa >3) (vide infra). Suitably basic functionality that resides outside the internal π-system of the heterocycle, for instance as in 5-bromopyridine-2-amine or 5-chloropyrazin-2-amine, show no reaction (Scheme S9). As an extension, halogenation conjugated to the site of protonation through an extended π system, like 5-chloroquinoline or 4-bromophenylpyridine, also do not react (Scheme S9). In general, diverse functionality on the heterocycle was tolerated (amino, alcohol, halogen, ester, carbamate) including challenging functionality for acid-(Boc) or base-(ester) mediated SNAr reactions. Several multi-halogenated substrates were also evaluated and typically displayed complete selectivity favoring the dominant site of reactivity for base-mediated SNAr reactions (Scheme 3, right column). These examples are particularly compelling when compared to TM mediated cross-coupling that can be challenged with positional selectivity and catalyst poisoning on complex targets that contain multiple sites of halogenation or nucleophilic functionality (heterocycles and other nucleophilic functionality). To further explore distinct reactivity differences between traditional base-mediated SNAr and PTDI SNAr, we performed competition experiments between 2-fluoro-5-trifluoromethylpyridine (E8) and 2-amino-4-iodopyridine (E5) under base-mediated (nucleophile ionization) and PTDI conditions (Scheme 3, competition experiments). Unsurprisingly given its high electrophilicity, complete selectivity for the formation of P58 was observed when using sodium methyl-4-mercaptobenzenethiolate (N3-Na) (Reaction 1). 2b Remarkably, when the nucleophile was replaced with N3, the selectivity profile flipped forming P31 exclusively (Reaction 2). Although Reaction 1 showed that E8 is significantly more electrophilic than E5, Reaction 2 demonstrated how proton transfer significantly enhances the electrophilicity of E5 beyond even E8. In summary, our competition experiments alongside nucleophile and electrophile scope showcase the unique reactivity profile of PTDI SNAr.