Catalyst Activation, Chemoselectivity, and Reaction Rate Controlled

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Research Article Cite This: ACS Catal. 2018, 8, 7889−7897

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Catalyst Activation, Chemoselectivity, and Reaction Rate Controlled by the Counterion in the Cu(I)-Catalyzed Cycloaddition between Azide and Terminal or 1‑Iodoalkynes Ryan Chung,† Anh Vo,‡ Valery V. Fokin,*,§ and Jason E. Hein*,†,‡ †

Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada Department of Chemistry and Chemical Biology, University of California, Merced, Merced, California 95343, United States § Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States Downloaded via UNIV OF SUSSEX on August 2, 2018 at 10:27:42 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

‡

S Supporting Information *

ABSTRACT: A comprehensive mechanistic analysis of the coppercatalyzed azide−alkyne cycloaddition to form 5-protio-1,2,3-triazoles (from terminal alkynes) or 5-iodo-1,2,3-triazoles (from 1-iodoalkynes) is presented. Through various mechanistic probes, we elucidate several salient features of this well-known reaction that have yet to be fully articulated in the literature: Kinetic evidence is provided that supports (i) the copper-catalyzed cycloadditions to form 5-protiotriazoles and 5-iodotriazoles are mechanistically distinct, (ii) the catalyst counterion has a linchpin role in facilitating the chemoselective generation of 5-iodotriazoles from 1-iodoalkynes in the presence of terminal alkynes, (iii) “activation” of the requisite catalyst for protiotriazole synthesis is highly influenced by the nature of the catalyst counterion, and last (iv) a more nuanced interpretation of the role of copper acetylides in triazole synthesis is required. An expanded reaction manifold is offered to provide the most comprehensive image to date of the different copper-catalyzed processes active during triazole synthesis, which are obscured behind what appears to be a simple catalytic system. Ultimately, mechanistic and kinetic insight is provided that can be utilized in the development of chemoselective methods where 1-iodoalkynes and terminal alkynes are simultaneously present. KEYWORDS: copper, azide−alkyne cycloaddition, triazole synthesis, counterion effects, chemoselectivity, reaction progress kinetic analysis, mechanism

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triazoles,2−4 the CuI-mediated azide−iodoalkyne cycloaddition provided easy access to a diverse array of triazoles directly amenable to further functionalization via the halogen substituent. Although applications incorporating iodotriazoles are at early stages, they already have prominent roles in multicomponent synthetic methods,1,5−7 halogen-bonding and ion-recognition, 8−13 materials fabrication, 14,15 and biomedical research.16−19 The limited number of uses of iodotriazoles compared to their 5-protio counterparts might be due to the small number of robust methods for iodotriazole synthesis and can be attributed, in part, to poorly understood mechanistic details and catalyst scope of the reaction. Despite the time elapsed since our original report, mechanistic studies on copper-mediated iodotriazole formation remain incomplete. We initially posited two mechanisms for iodotriazole formation, favoring a pathway in which the iodoalkyne Csp−I bond was not severed during catalysis. The alternative pathway, where a copper acetylide intermediate resulting from copper insertion into the C−I bond of the iodoalkyne, was

INTRODUCTION In 2009, Hein, Fokin, and co-workers disclosed a general and regiospecific means to obtain 5-iodo-1,4,5-trisubstituted-1,2,3triazoles from 1-iodoalkynes and organic azides (Scheme 1A). Scheme 1. Copper-Mediated Azide−Alkyne Cycloaddition

This transformation, mediated by CuI and a tris(triazolylmethyl)amine accelerating ligand, was the first efficient method to access these halogenated heterocycles under mild conditions.1 As an extension of the well-known Copper-catalyzed Azide-(terminal) Alkyne Cycloaddition (“CuAAC”, Scheme 1B) that exclusively affords 5-protio-1,2,3© XXXX American Chemical Society

Received: April 5, 2018 Revised: June 18, 2018 Published: July 17, 2018 7889

DOI: 10.1021/acscatal.8b01342 ACS Catal. 2018, 8, 7889−7897

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Scheme 2. Competition Reaction Involving Benzyl Azide (1, 0.1 M), (Iodoethynyl)benzene (2, 0.05 M), and Phenylacetylene (3, 0.05 M)a

a

TCPTA = tris((1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl)amine.

progress kinetic analysis (RPKA).30−32 The experiments were monitored heat-flow calorimetry, offering direct access to the reaction rate.30−33 Figure 1a gives the rate profile for the individual reaction of benzyl azide (1, 0.10 M) and terminal alkyne 3 (0.10 M) under standard conditions (Scheme 2). Upon initiation, the system is subject to an induction process wherein the rate increases until a maximum value is reached, at ∼40% conversion, which is then followed by a period of overall first-order kinetics. Figure 1b (red curve) gives the corresponding heat-flow conversion profile for this reaction. Similar rate behavior had previously been reported by Blackmond and co-workers in a Heck-type reaction.34 The data suggest that the active catalyst concentration increases until maximum turnover is reached as a result of an irreversible activation process. To probe this activation process, we then charged the reaction vial with additional starting material (azide 1 + terminal alkyne 3) and continued to monitor the heat flow. From Figure 1b (blue curve, left), it is clear that the initiation of the second protiotriazole reaction is much more straightforward, exhibiting no induction behavior and obeying overall first-order kinetics. Strikingly, despite the decrease in reaction concentration (nearly half that of the first reaction) following the second addition of substrate, we see that the rate of protiotriazole formation is much larger, with full conversion achieved in almost half of the time of the unactivated system. “Excess” experiments performed following activation (Figure 1c) revealed that the individual protiotriazole reaction has a firstorder dependence on terminal alkyne 3 and a zero-order dependence on azide 1, represented by the rate law in eq 1. (Full experimental details can be found in the Supporting Information.)

disfavored due to the lack of 5-protiotriazole formation from protonolysis of copper-bound intermediates, even in protic solvents.1,20 Heaney and co-workers offered an alternative mechanistic interpretation based on their studies of copper acetylide ladderane complexes, though no kinetic data were provided in ́ their report.21 Later, Diez-Gonzá lez and co-workers reported the first computational investigation employing copper bearing N-heterocyclic carbene (NHC) ligands as representative catalysts.22 The most recent reports by Zhu and co-workers have focused on the formation of iodotriazoles from terminal alkynes. In their work, an iodoalkyne is generated in situ via the stoichiometric reaction of Cu(ClO4)2·6H2O, KI, and Et3N.23,24 However, a systematic analysis of the factors influencing coppermediated iodotriazole formation under catalytic conditions has yet to be reported. During our mechanistic investigation of the CuI-catalyzed azide−iodoalkyne cycloaddition reaction, we observed several confounding kinetic phenomena that eluded our understanding until very recent. In particular, we were intrigued by the results of competition experiments where both 1-iodoalkyne 2 and terminal alkyne 3 were simultaneously subjected to triazoleforming conditions (Scheme 2). Reaction progress monitoring revealed an unusual profile bearing three distinct regimes: (i) rapid cycloaddition between the azide 1 and iodoalkyne 2 affording exclusive and quantitative generation of the corresponding iodotriazole 4, (ii) a well-defined period with no product generation and an apparent absence of catalytic activity, and (iii) cycloaddition to generate protiotriazole 5, exhibiting a sigmoidal profile. Given these observations in the face of the well-known (and well-assumed) reliability of copper-catalyzed “click” reactions, we sought to elucidate the chemical underpinnings of the three regimes. Through delineation of the complex catalytic network that exists within this deceptively simple system, this report provides detailed kinetic data that supports the following conclusions: (i) the copper-catalyzed cycloadditions to form 5protiotriazoles and 5-iodotriazoles are mechanistically distinct, (ii) the catalyst counterion has a linchpin role in facilitating the chemoselective generation of 5-iodotriazoles from 1-iodoalkynes in the presence of terminal alkynes, (iii) “activation” of the requisite catalyst for protiotriazole synthesis is highly influenced by the nature of the catalyst counterion, and last (iv) a more nuanced interpretation of the role of copper acetylides in triazole synthesis is required. Ultimately, new knowledge is provided that can be harnessed in the development of new chemoselective methods where 1-iodoalkynes and terminal alkynes are simultaneously present.

rate = kH[cat]0 [terminal alkyne]

(1)

In contrast, an RPKA treatment of the individual iodotriazole reaction revealed that this cycloaddition displays saturation kinetics in iodoalkyne 2 and first-order kinetics in azide 1, affording rate eq 2, where [xs] = [azide]0 − [iodoalkyne]0. (Full experimental details and a derivation of this rate equation can be found in the Supporting Information.) rate = kI[cat]0 [azide] = kI[cat]0 ([xs] + [iodoalkyne]) (2)

Unexpected Results from Competition Reactions. The need for further mechanistic study of copper-mediated azide− alkyne cycloaddition was spurred by intriguing kinetic data obtained from competition reactions involving benzyl azide (1, 0.10 M), (iodoethynyl)benzene (2, 0.05 M), and phenylacetylene (3, 0.05 M; Scheme 2). The competition was monitored by high-performance liquid chromatography-mass spectrometry (HPLC-MS) by removing timed aliquots of the reaction via an automated sampling apparatus developed by our group.25−28

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RESULTS AND DISCUSSION Initial Kinetic Analysis. To elucidate the differences between the cycloaddition mechanism of iodoalkynes and that of terminal alkynes, we began our work with a standard reaction 7890

DOI: 10.1021/acscatal.8b01342 ACS Catal. 2018, 8, 7889−7897

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Figure 2. Reaction progress graph of the competition in Scheme 2 depicting three distinct regimes. (Reaction conditions: CuI, 5 mol %; TCPTA, 5 mol %, MeCN, 25 °C.)

questions required answering: (i) Why does iodotriazole formation precede protiotriazole generation? (ii) What occurs during the “interim” period, regime II? and (iii) Why is protiotriazole formation sigmoidal? Is the Competition Behavior Due to the Presence of the Iodoalkyne or Iodotriazole? To rule out the possibilty that competition behaviors in Figure 2 were due to the presence of iodoalkyne 2 or iodotriazole 4, we collected reaction progress data on the individual cycloaddition reactions where iodoalkyne 2 or terminal alkyne 3 was separately subjected to the conditions in Scheme 2.29 As seen in Figure 3, graphical overlay of the

Figure 1. (a) Rate profile for the individual reaction of benzyl azide (1, 0.10 M) and phenylacetylene (3, 0.10 M) under standard conditions (Scheme 2), (b) conversion profiles for the individual protiotriazole reaction for the first addition of substrate (red curve, right) and the second addition of substrate (blue curve left), and (c) rate profiles for “excess” experiments for the second addition of starting materials as measured by heat-flow calorimetry.

Figure 3. Overlay of reaction progress graphs for individual triazole reactions of azide 1 (0.10 M) with iodoalkyne 2 (0.05 M) or terminal alkyne 3 (0.05 M; open markers) and the competition reaction (Scheme 2; closed markers). (The azide concentration is not plotted for clarity. Reaction conditions: CuI, 5 mol %; TCPTA, 5 mol %, MeCN, 25 °C.)

Upon examination of the reaction progress (Figure 2), three distinct regimes were observed: The reaction first proceeds with exclusive and quantitative formation of iodotriazole 4 (0−50 min; regime I), followed by a period with no apparent change in chemical speciation (50−175 min; regime II). Afterward, the reaction proceeds to completion with the formation of protiotriazole 5 (>175 min; regime III). Notably, the sigmoidal profile of 5 indicates that some type of in situ activation process is present during the last regime, suggesting that the initial complex formed by simply dissolving the CuI and TCPTA ligand is competent in facilitating cycloaddition with iodoalkyne 2 but not terminal alkyne 3. With these observations, three

reaction progress data from individual (open markers) and competition reactions (closed markers) strongly indicates that the respective catalytic reactions to form iodotriazole 4 during regime I and protiotriazole 5 during regime III (Figure 3) are identical to those in the individual reactions where iodotriazole 4 or protiotriazole 5 are the sole products. Otherwise stated, the mechanisms of iodotriazole formation appear to be invariant regardless of whether or not a terminal alkyne is present and, likewise, the presence of iodoalkyne 2 or iodotriazole 4 does not change the overall mechanisms of protiotriazole formation. 7891

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ACS Catalysis Influence of Iodide. We then returned to the competition reaction to determine if the kinetic phenomena of Figure 2 were still present following a second charge of starting material. Similar to the heat-flow calorimetry experiments, we allowed a competition reaction identical to that in Scheme 2 to go to completion, added a second charge of substrate (azide 1 + iodoalkyne 2 + terminal alkyne 3), and monitored the reaction by HPLC.35 Strikingly, as shown in Figure 4, we now see

Figure 5. Reaction progress graph of competition from Scheme 2 where AgNO3 (0.025 mmol, 5 mol %) was added after 90 min, leading to the immediate formation of protiotriazole. (The azide concentration is not plotted for clarity.)

induction behavior. In contrast, Cu(I) salts bearing hard anions (OAc−, BF4−) allow both triazoles to form simultaneously (Figure 6b,c). As a corollary to our previous experiment with AgNO3, we then monitored a reaction where iodide was deliberately added to the reaction. Figure 6d depicts the reaction progress for the competition catalyzed by (MeCN)4CuBF4, which normally affords iodotriazole 4 and protiotriazole 5 concomitantly. However, NaI was introduced into the operational reaction, selectively arresting formation of protiotriazole 5 but not iodotriazole 4. These data indicate that iodide, or similarly soft anions, is uniquely responsible for inhibiting the cycloaddition of the terminal alkyne, while no such inhibitory role is experienced by the iodoalkyne cycloaddition. Ruling out Electrophilic Capture of Iodine Prior to Protiotriazole Generation. To explain the apparent inhibitory nature of iodide, we examined the currently accepted mechanisms for CuAAC. Recent work from Bertrand and coworkers has shown two pathways for the generation of protiotriazoles, with each differing in the nuclearity of copper (Scheme 3).36 As a result, we envisioned three locations where iodide could interfere with protiotriazole formation: (i) iodide or polyiodides, such as I3−, may intercept copper triazolide 8, allowing only for the selective formation of iodotriazole 4, (ii) tight binding to Cu(I) or insufficient Brønsted basicity of iodide could prevent the formation of acetylide 7, or (iii) iodide may inhibit the formation of dicopper complex 9, which was identified by Bertrand and co-workers as the key intermediate in the kinetically favored pathway.36 The presence of triazolide 8 (Scheme 3) in protiotriazole synthesis was originally indirectly validated by Finn, Fokin, and co-workers.37 For analogous treatment, we reacted diazide 11 and alkynes 2 and 3 as a triazolide probe for the CuI system (Scheme 4). As seen in Figure 7, the first regime (0−70 min) shows exclusive formation of mono(iodotriazole) 12 and bis(iodotriazole) 13. The system then enters a stasis period lasting ∼125 min, followed by concurrent formation of iodo/ protiotriazole 14 and bis(protiotriazole) 15 during the final regime. Via the same logic of Finn et al., the sequential appearance of mono(iodotriazole) 12 followed by bis(iodotriazole) 13 in Figure 7 suggests that a copper triazolide is not involved in the CuI-catalyzed cycloaddition of 1-iodoalkynes. However, the direct formation of bis(protiotriazole) 15 avoiding mono-

Figure 4. HPLC conversion profiles for the second addition of starting material (azide 1, iodoalkyne 2, and terminal alkyne 3) following the competition reaction in Scheme 2. (The azide conversion is not plotted for clarity.)

concomitant consumption of both alkynes and the simultaneous appearance of triazoles 4 and 5. That is, the observed chemoselectivity in Figure 2 is no longer present, implying that the component controlling chemoselectivity during the first competition reaction (after the first charge of substrate) was removed as a direct result of triazole formation. In order to understand this drastic change in chemoselectivity, we re-examined the concentration data in Figure 2. Upon close examination, we see that the concentration of iodotriazole 4 shows an increase of exactly 5 mol % by the end of regime III relative to the end of regimes I and II. This rise, equal to the amount of iodide from CuI, occurs throughout the protiotriazole generation, indicating that the consumption of the catalyst counterion and its corresponding generation of iodotriazole are related to catalyst activation for protiotriazole formation. Following this, we then wanted to see if the deliberate removal of the catalyst counterion would also change the kinetic behavior of the competition. Figure 5 gives the reaction progress of an experiment identical to that in Scheme 2; however, after 90 min and during regime II, AgNO3 was added to deliberately remove iodide by precipitation of AgI. As seen in Figure 5, protiotriazole generation begins immediately in the now activated system. Counterion Effects. The competition was then carried out using a variety of copper salts, revealing that the nature of the counterion has a significant impact on both the chemoselectivity and rate of cycloaddition (Figure 6a−c). For these experiments, all reaction parameters in Scheme 2 were held constant except for the copper source. From Figure 6a−c, it seems that Cu(I) salts bearing soft anions (I−, PhS−) are efficient catalysts of the 1iodoalkyne cycloaddition but appear to require in situ activation to efficiently catalyze the reaction with terminal alkynes, which is reflected by the sigmoidal curve of 5 (Figure 6a; cf. Figure 2). This results in the selective generation of iodotriazole 4 at the onset of catalysis, followed by formation of protiotriazole 5 with 7892

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Figure 6. Reaction progress graphs of triazole products for Scheme 2 with different copper sources. Reaction conditions: [Cu], 5 mol %; TCPTA, 5 mol %; MeCN, 25 °C where (a) [Cu] = CuSPh, (b) [Cu] = CuOAc, (c) [Cu] = (MeCN)4CuBF4, and (d) [Cu] = (MeCN)4CuBF4 (10 mol %) with NaI (0.1 mmol, 20 mol %) added after 90 min. Starting material concentrations are not shown for clarity.

Scheme 3. Currently Accepted Pathways for Protiotriazole Formation, Adapted from Bertrand and Co-workers36

Scheme 4. Competition Reaction Involving 1,3-Diazide 11 (0.05 M), (Iodoethynyl)benzene (2, 0.05 M), and Phenylacetylene (3, 0.05 M)

(protiotriazole) indicates that cycloaddition involving the terminal alkyne does indeed proceed via this intermediate. Thus, the two cycloadditions do not involve common reactive intermediates and are better described as orthogonal pathways. Furthermore, this experiment rules out the possibility that the chemoselectivity during regime I of the original competition reaction (Scheme 2) is due to capture of the copper triazolide 8. Our conclusions are in agreement with observations by Zhu and co-workers who noted that exogenous electrophiles were not incorporated under their experimental conditions.23 Ruling out Inhibition of Copper Acetylide Formation. Lastly, we studied competition reactions employing differently substituted iodoalkynes and terminal alkynes (2 and 16a,b, respectively; Scheme 5). These reactions catalyzed by CuI still display three discrete reactivity regimes; however, the product distribution is significantly more complicated. Although iodotriazole 5 is the major product in the first regime, a separate

iodotriazole (17a,b) is also observed (Figure 8a,b). The generation of the minor iodotriazole occurs with concurrent consumption of corresponding terminal alkyne 16a,b and production of phenylacetylene (3). After the iodoalkynes are consumed, the reaction pauses before cycloaddition continues with the remaining terminal alkynes, producing 18a,b and 5 as 7893

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Figure 7. Reaction progress graph for Scheme 4.

the major and minor protiotriazoles, respectively. Again, the profiles in this last regime are sigmoidal. Interestingly, the length of the intermediate period between iodotriazole formation and protiotriazole generation seems to track with the electronic characteristics of the starting terminal alkyne. Relative to unsubstituted phenylacetylene (3), the competition reaction involving electron-deficient p-CF3-substituted terminal alkyne 16a experiences a shorter interim period (∼75 min; Figure 8a cf. Figure 2). Conversely, the competition involving electron-rich p-CH3-substituted terminal alkyne 16b experiences a longer interim period relative to 3 (∼175 min; Figure 8b cf. Figure 2). The formation of the 17a,b and 5 can be explained by exchange occurring between the acetylenic hydrogen/iodine of 4 and 16a,b to give 3 and 16a′,b′ (Scheme 6). This process has recently been studied and has been shown to likely proceed via a copper-catalyzed σ-metathesis.38 The observation of exchange implies that a copper acetylide is present during the initial regime of the competition and is capable of undergoing exchange but not cycloaddition to give protiotriazole. We conclude that the generation of the copper acetylide is possible during iodotriazole synthesis; however, it alone is inadequate for CuAAC in the presence of iodide or iodoalkyne. Expanded Catalytic Network. The observations presented thus far combined with the large body of experimental20,21,24,36,37,39−46 and theoretical47−54 mechanistic investigation on CuAAC can be used to construct a more detailed reaction manifold (Scheme 7). When terminal and iodoalkynes

Figure 8. Reaction progress graph of the crossover experiments in Scheme 5.

Scheme 6. Copper-Catalyzed Acetylenic H/I Exchange in Terminal and 1-Iodoalkynes38

are simultaneously present, coordination of iodoalkyne 19 to the copper catalyst to give 20 is heavily favored (K1 ≫ 1), and from this intermediate, two pathways are possible: First, coordination of azide 21 to complex 20 can lead to iodotriazole formation. This equilibrium is thought to also be favored (K2 > 1) because

Scheme 5. Crossover Studies with Benzyl Azide (1, 0.10 M), (Iodoethynyl)benzene (2, 0.05 M), and para-Substituted Phenylacetylenes (16a,b, 0.05 M)

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Scheme 7. Expanded Catalytic Network Detailing Competitive Cycloaddition and H/I Exchange Involving 1-Iodo- and Terminal Alkynes

copper acetylide formation as the source for the observed chemoselectivity during the competition. Therefore, it follows that iodide must interfere with the formation of dicopper species 30 (K9), which serves as the linchpin to access the kinetically favored protiotriazole-forming pathway. For the third regime of the competition reaction to begin, we propose oxidation of the anion as a means for catalyst activation. While the exact mechanism remains unclear, the interim period can be explained by the need to oxidatively remove the inhibitory counterion, presumably through the diffusion of oxygen into the system. For CuI, oxidation of the counterion leads to the formation of I3−, which can be captured by acetylide, generating additional 1iodoalkyne. In this case, iodide will be converted into iodotriazole 24, explaining the slight increase in iodotriazole products during the last regime of the competition reaction. Analogously, when employing CuSPh as the catalyst, the thiophenolate anion can be sequestered by oxidative dimerization to make diphenyl disulfide. Once these detrimental anions are consumed, dinuclear complex 30 can be formed, leading to the protiotriazole-forming cycle.

the iodinated terminal alkyne resulting from exchange (16a,b′; Scheme 6) does not reach measurable concentrations in competition reactions, despite formation of minor triazoles 5 and 17a,b (Scheme 5). (This is not the case for Cu(I)-catalyzed terminal alkyne/1-iodoalkyne H/I exchange in the absence of azide.38) Alternatively, if terminal alkyne 25 binds to 20, dialkyne intermediate 26 would form, providing an avenue for H/I exchange. Consistent with our previous study, we expect deprotonation of the π-bound terminal alkyne in 26 to afford acetylide 27 to be turnover-limiting for exchange (k5). Subsequently, σ-bond metathesis would afford acetylide 28, and protonolysis would give the exchanged terminal alkyne 19′. The observed rate of exchange is greater for electron-deficient alkynes than that for electron-rich alkynes, accounting for the larger concentration of minor triazoles 17a and 18a compared to 17b and 18b (Figure 8a,b).38 Once the iodoalkyne is consumed, free catalyst 6 becomes the dominant copper species. The preceding discussions have already ruled out triazolide interception and interference with 7895

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CONCLUSIONS This report has provided a detailed kinetic interrogation of the role of the catalyst counterion in the copper-catalyzed azide− alkyne cycloaddition of organic azides with either terminal or 1iodoalkynes. On the basis of a systematic study of competition reactions involving 1-iodoalkynes, terminal alkynes, and organic azides with different copper catalysts, it was discovered that the chemoselective formation of iodotriazoles from 1-iodoalkynes in the presence of terminal alkynes is a function of the disposition and speciation of the copper catalyst within a more complicated reaction network. Critically, the observed chemoselectivity is not due to a relative rate difference between the two cycloaddition reactions. For the CuI-catalyzed system, the experimental data suggest that iodide inhibits the formation of a key dicopper intermediate in the kinetically favored protiotriazole-forming pathway, explaining the initial exclusive formation of iodotriazole in the first reactivity regime. The consumption of the counterion via the formation of extra iodotriazole then allows for protiotriazole formation in the final reactivity regime. Furthermore, a previously unrecognized acetylenic hydrogen/iodine exchange pathway was identified and placed into context within the larger reaction manifold. Ultimately, this study offers two important advances. First, the added mechanistic and kinetic understanding of this important copper-catalyzed reaction provides new opportunities to develop other chemoselective methods where terminal and 1iodoalkynes are simultaneously present in the reaction. With these two species, judicious choice of the catalyst counterion is evidently critical to achieve differential reactivity. Second, this study reinforces the importance of continued developments in modern reaction analytical methodologies; the automated reaction monitoring technology used here has enabled rapid deconvolution of a complex and challenging reaction in reasonable time frames. The rich, impactful, and highly nuanced information revealed by the experiments detailed in this paper would have been undoubtedly overlooked had highly resolved, time course measurements not been available.

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IR and EasyMax). Financial support for this work was provided by the University of British Columbia, the Canadian Foundation for Innovation (CFI-35883) and the Natural Sciences and Engineering Resource Council of Canada (Engage, 2016RGPIN-04613) to J.E.H. Pfizer Worldwide Research and Development is thanked for a student research fellowship (to R.C.). Francis Manalastas and Tony Mittertreiner (UBC Department of Chemistry) are thanked for their assistance with computer programming. Finally, we thank Prof. Laurel L. Schafer (UBC Department of Chemistry) for rewarding discussions and Prof. Donna G. Blackmond (The Scripps Research Institute, La Jolla, CA, U.S.A.) for feedback during the preparation of this manuscript.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b01342. Detailed experimental procedures, characterization data, and reaction progress graphs (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (V.V.F.). *E-mail: [email protected] (J.E.H.). ORCID

Ryan Chung: 0000-0001-7242-1195 Valery V. Fokin: 0000-0001-7323-2177 Jason E. Hein: 0000-0002-4345-3005 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge Mettler-Toledo Autochem for generous donation of process analytical equipment (React7896

DOI: 10.1021/acscatal.8b01342 ACS Catal. 2018, 8, 7889−7897

Research Article

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DOI: 10.1021/acscatal.8b01342 ACS Catal. 2018, 8, 7889−7897