Substitution Reactions on Iodine and Bromine: Mechanisms for Facile

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Substitution Reactions on Iodine and Bromine – Mechanisms for Facile Halogenations of Heterocycles. Leah L. Donham, and Scott Gronert J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Mar 2019 Downloaded from http://pubs.acs.org on March 25, 2019

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The Journal of Organic Chemistry

Substitution Reactions on Iodine and Bromine – Mechanisms for Facile Halogenations of Heterocycles. Leah L. Donham1 and Scott Gronert1,2* 1

Department of Chemistry, Virginia Commonwealth University, 1001 W Main Street, Richmond, VA 23284 USA Department of Chemistry and Biochemistry, University of Wisconsin – Milwaukee, 3210 N. Cramer St., Milwaukee, WI 53211 USA 2

[email protected]

ABSTRACT: Gas-phase techniques were used to examine the halogenation of deprotonated heterocycles by perfluoro-

aryl and perfluoroalkyl halides. The results indicate that SN2@Br and SN2@I reactions can be very facile and are effective means of halogenating heterocycles. 2-iodoheptafluoropropane is exceptionally selective for SN2@I reactions with yields upwards of 90%. The results also provide evidence counter to the recent suggestion that t-butoxide-induced halogenations of heterocycles proceed via a radical mechanism.

Introduction Functionalized thiazoles and other heterocycles are important in a variety of industries including pharmaceutics,1–3 pesticides and fungicides,1 and polymers.4 One of the most common ways to functionalize heterocycles such as thiazole, is via halogenated thiazoles. Halogenated thiazoles are also highly useful in a variety of industries.5–9 Traditional methods to halogenate them often use harsh reaction conditions.9 Recently, it was demonstrated that thiazoles can be iodinated with high yields under relatively mild conditions by treating them with tbutoxide and pentafluoroiodobenzene.10,11 Shi et al.10 proposed a radical-based mechanism for these reactions that involves a one-electron reduction of the pentafluoroiodobenzene by t-butoxide to produce the radical

anion of the haloarene, which then transfers an iodine atom to the heterocycle. The process can be catalytic and is completed by transfer of an electron to another pentafluoroiodobenzene molecule followed by deprotonation of the heterocycle (propagation shown in Scheme 1). Liu et al. have shown that sodium t-butoxide can be used to induce similar heterocycle halogenations and offered evidence that the process was not radical mediated and involved ionic intermediates and the in situ formation of a hypoiodite iodination agent.12 In recent gas-phase studies,13,14 we have discovered that the reactions of anionic nucleophiles with agents such as pentafluorobromobenzene often give very efficient SN2@X reactions (i.e., direct nucleophilic attack on the halogen) to yield halogenation products. The similarity of the reaction processes

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led us to hypothesize that halogenation of a deprotonated thiazole via an SN2@X process could offer a facile alternative mechanism to the proposed radical or hypoiodite pathways. Scheme 1. Path proposed by Shi et al.10

Results and Discussion To test the premise that the halogenation of thiazoles could proceed via an SN2@X pathway, we allowed a set of deprotonated thiazoles and derivatives to react in the gas phase with perfluoroaryl and perfluoroalkyl halogenation reagents. Our working hypothesis was that the deprotonated thiazole is sufficiently nucleophilic to attack the halogen via the SN2@X pathway and displace a highly-stabilized perfluoroanion. Previously we have used gas-phase reactions along with computational modeling to show that SN2@X reactions can be very competitive with the conventional SNAr reactions of highly halogenated arenes.14 This competition is outlined in Scheme 2. The SNAr process can displace fluoride or the other halide in this process (bromide or iodide). Preferences for displacing the weaker leaving group (i.e., fluoride) are well known.15–17 However, if this occurs in the gas phase, the high basicity of fluoride drives an exothermic proton transfer to give a deprotonated, arylated, heterocycle and HF (middle pathway, Scheme 2). Scheme 2. SNAr and SN2@X paths in arenes

Scheme 3. SN2@X and SN2 paths in aliphatic systems.

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We included perfluoroaliphatic iodides in our study because they lack the SNAr pathway and therefore could be more effective iodination agents. Here, the competition with the SN2@X reaction is from a conventional SN2 reaction on the iodinated carbon (Scheme 3). This would lead to perfluoroalkylation of the heterocycle. Advantageously, the competing SN2 reactivity can be modulated by the substitution pattern on the iodinated carbon. By probing these reactions in the gas-phase, solvent effects are ignored, but previous work highlights that there are strong parallels in reactivity between the gas and condensed phase for processes like these.18,19 As sample heterocycles, we have examined the reactivity of 2-thiazolide, 5-thiazolide, and 5-isothiazolide (Scheme 4). Each was formed by decarboxylation of the appropriate precursor by collision-induced dissociation (CID). Experimental or computational proton affinities for the nucleophiles and leaving groups are listed in Table 1. All of the thiazolides are less basic than the potential leaving groups in the SN2@X, SN2, and SNAr reactions, suggesting exothermic reactions – fluoride loss is an exception in the SNAr process, but the subsequent deprotonation makes it exothermic (Scheme 2). Pentafluorobromobenzene and pentafluoroiodobenzene, are capable of the three pathways shown in Scheme 2. Product distributions are shown in Figures 1a and 1b. The rate constants are near the expected collision-controlled limit and the favored path is an SN2@X halogenation of the heterocycle - yields of this pathway range from 68 to 96%. a

Computed at MP2/6-311+G**//MP2/6-31+G* level. bIn a previous report, the gas phase free energies of protonation for 5-thiazolide and 5-isothiazolide were both bracketed at 365.7±2.9 kcal/mol (this correlates with a PA 0f ~373 kcal/mol).20 In earlier work, ring-opening of 2-thiazolide Table 1. Gas-phase proton affinities of reactant and product anions Reactant/Product Anion

PAa,b

2-thiazolide 374 5-thiazolide 371 5-isothiazolide 369 pentafluorophenyl 350 1-heptafluoropropyl 360 2-heptafluoropropyl 347 bromide 323c iodide 314c fluoride 372c 21 was viewed as a concern. The MP2/6311+G(d,p)//MP2/6-31+G(d) computed enthalpic barrier to ring opening is 32.3 kcal/mol (Supporting Information), suggesting that 2-thiazolide would be stable under our reaction conditions. cExperimental values from NIST Chemistry Webbook (webbook.nist.gov/chemistry/, accessed May 2018).


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Scheme 4. Selective formation of thiazolide anions

sample structure for the reaction of 5-thiazolide with bromopentafluorobenzene is shown in Figure 2. The intermediate is late on the reaction coordinate and there is a large asymmetry between the breaking and forming C-Br bonds (2.57 Å vs. 1.96 Å). This situation leads to a barrierless process and the halogenation can easily proceed via an energetically favorable SN2@X mechanism (Figure 3). Barrierless potential energy surfaces for SN2 reactions are generally seen in sufficiently exothermic processes with potential post-transition state complexes significantly below the energy of the starting reagents,23,24 similar to the SN2@X reactions in this study. A radical, single-electron transfer (SET) pathway was also considered for our gasphase halogenations, but the computed electron binding energies of the deprotonated heterocycles are sufficiently high to make electron transfer to the poly-halogenated substrates unfavorable (see Table S3, Supporting Information).

Figure 1. Partial rates for the reactions of nucleophiles with (a) pentafluoroiodobenzene, (b) bromopentafluorobenzene, (c) 1-iodoheptafluoropropane, and (d) 2iodoheptafluoropropane. Rate and product distribution data are listed in Table S1 (Supporting Information).

With the heptafluoropropyl iodides, the major competing pathway is an SN2 reaction on carbon with loss of iodide. However, in all cases, the SN2@I reaction dominates (>75% yield). The rate constants for these reactions are also high and reach about 50% of the expected collisioncontrolled limit. The reactions of 2- and 5-thiazolide with 2-iodoheptafluoropropane yielded 99% iodination, surpassing the iodination yields seen with pentafluoroiodobenzene. With 1-iodoheptafluoropropane, there is more competition with SN2 attack on carbon. In addition, there were some products that resulted from the nascent heptafluoropropyl anion product from the SN2@I reaction releasing a fluoride anion that either deprotonates or adds to the iodinated heterocycle, producing hexafluoropropene (Scheme 3). Yields of these minor pathways are shown in Figures S3, S4, S7, S8, S11 and S12 of the Supporting Information. The halogenation reactions of the thiazolide derivatives with bromopentafluorobenzene and 2-bromoheptafluoropropane were modelled at the MP2/6-311+G**//MP2/631G* level. Bromine was used instead of iodine because of the known challenges in modeling iodine with computational methods.22 Transition states cannot be located for the SN2@Br reactions and the systems appear to pass through hypervalent bromine intermediates that are more than 30 kcal/mol below the energy of the reactants. A

Figure 2. Intermediate for the SN2@Br reaction (top) and the transition state complex for the competing SNAr reaction (bottom) of 5-thiazolide with bromopentafluorobenzene. Computed at the MP2/6-31+G* level (bromine: red, fluorine: light blue, nitrogen: blue, sulfur: yellow, carbon: gray, and hydrogen: white).



Figure 3. Energy profiles (reactants, intermediates, and products) for SN2@Br reactions of thiazolide derivatives with bromopentafluorobenzene (MP2/6-311+G**//MP2/631+G* level).

We have also modeled the SNAr reactions in these systems, as shown in Figure 4. They have transition states that are well below the entrance channel and are expected to have high rates. For example, the transition state for the reaction of 5-thiazolide with bromopentafluorobenzene is about 15 kcal/mol below the energy of the starting reactants, with the overall exothermicity for the reaction being around -70 kcal/mol. Its structure is shown in Figure 2 and is very early on the reaction coordinate (breaking C-Br distance 1.90 Å). Because both pathways (SN2@X and SNAr) are very favorable, it is not surprising that some competition is observed; however, the intermediates in the SN2@X process are much more stable than the SNAr transition states and this can tilt the preference to the halogenation pathway. Moreover, in previous studies we have observed that the gas-phase SNAr process can face dynamics barriers14 and this may contribute to the strong preference for the SN2@X process in these systems.

Figure 4. Energy profiles (reactants, itransition states, and products) for SNAr reactions of thiazolide derivatives with bromopentafluorobenzene (MP2/6-311+G**//MP2/631+G* level).

The gas-phase experimental and computational data indicate that deprotonated thiazolide derivatives can readily be halogenated via a direct SN2@X reaction on the halogen atom if the corresponding leaving group is a reasonably stable anion. With the aromatic systems, SNAr reactions compete and reduce the halogenation yields, but with the aliphatic systems, competition with an SN2 on carbon reaction is very limited and near quantitative yields of the desired halogenation product are possible. This competition can be seen in Figure 1. Examining this SNAr(Br) reaction computationally, it is apparent that, although the overall reaction is exothermic, there are reaction dynamics that impede the reaction to proceed. As seen in previous work, localized nucleophiles prefer an attack on the periphery,14 in this case the halogen. There is a much larger area in which the nucleophile is able to attack in the SN2@X reaction, as opposed to the SNAr mechanism, which requires an attack directly at the plane of the ring in order to proceed. As seen with the computational data, there is no doubt that the SN2@X reaction can be a facile path to the halogenation of deprotonated heterocycles. Turning to Shi et al.’s report10 of the t-butoxide-induced iodinations of benzothiazole and other heterocycles, the need to invoke a radical mechanism is questionable given the current results. First, in the aprotic media used in the synthetic procedure (toluene), the benzothiazole will have an acidity that is in the range of that of t-butanol. Although data are not available in toluene, DMSO pKa’s indicate that benzothiazole is 5-orders of magnitude more acidic than t-butanol.25 In toluene, the potassium t-butoxide is likely aggregated so the DMSO data only give a rough picture; however, they do suggest that deprotonation of the heterocycle is likely viable under the reaction conditions. As shown in this study, once formed, the deprotonated heterocycle is a potent nucleophile for SN2@I processes. With pentafluoroiodobenzene, the leaving group is a pentafluorophenyl anion that could complete the catalytic cycle by deprotonating another heterocycle substrate. Streitwieser determined a pKa of approximately 26 for pentafluorobenzene,26 which aligns well with the heterocycles25 that were subjected to the tbutoxide-induced iodination. It should be noted that in several examples with t-butoxide, the Shi et al. systems were not catalytic and required stoichiometric or excess t-butoxide to go to completion. These may be cases where the pentafluorophenyl anion is not basic enough to deprotonate the heterocycle and continue the catalytic cycle. Additional insight into the nature of the mechanism can be derived from the selectivity that Shi et al. reported in the iodination of 3-cyanopyridine.10 Here iodination occurs exclusively at the 4-position. Fundamentally, one expects that the proposed radical pathway and the SN2@I pathway would have different selectivities because the electron demands of the processes are opposite - the


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halogen atom addition creates an electron deficiency whereas deprotonation creates an electron excess at the eventual site of substitution. To explore this issue, the relative energies of 3-cyanopyridine deprotonated at the 2, 4, 5, and 6 positions were computed as well as the relative energies of halogen addition (bromine) at the same four positions. The data (Table 2) indicate about a 2 kcal/mol preference for deprotonation at the 4-position, but halogen addition prefers the 5-position. In fact, the 4-position is the least favorable site for halogen addition. It is difficult to envision a scenario where a radical-based process would lead to the observed selectivity. Conversely, an SN2@I path perfectly aligns with Shi et al.’s experimental observations. The Liu et al.12 mechanism requires the formation of tBuO-I as the iodination agent from the reaction of tbutoxide with 1-iodononafluorobutane. It is unclear why this intermediate is necessary given that we have demonstrated that species like 1-iodononafluorobutane are potent iodination agents themselves. In addition, computational modeling suggests that the formation of t-BuO-I in this way would be endothermic (see Table S4, Supporting Information). Table 2. Energies of deprotonated 3-cyanopyridine relative to the 4-position anion and energies of the halogen addition intermediate relative to the 4-position intermediate.

Location

Energy (kcal/mol)a

4-anion 2-anion 5-anion 6-anion 4-intermediate 2-intermediate 5-intermediate 6-intermediate

0.0 10.4 1.9 12.8 0.0 -3.0 -3.5 -3.2

a

reported. The gas-phase data also indicate that 2-iodoheptafluoropropane is an excellent reagent for SN2@I reactions and in our studies, was a more effective iodination agent than iodopentafluorobenzene. Experimental Methods All experiments were performed in a modified LCQ DECA mass spectrometer, which is equipped with a quadrupole ion trap and electrospray ionization (ESI). The modification to introduce a neutral molecule into the system has been described before.14,18,27,28 All of the thiazolide anions were formed by starting with the respective thiazole carboxylic acids. The carboxylic acids were dissolved in methanol (10-5 M) and were then injected into the ESI interface at a rate of 5-10 μL/min. The precursor carboxylic acids led to carboxylates, which were decarboxylated either in the source via a high potential on the ring electrode or in the ion trap via conventional collisioninduced dissociation (CID). Neutral reagents were introduced via a custom gas-mixing manifold at flows that led to partial pressures in the 10-6-10-8 torr in the ion trap. The reported rates are measured at 3 different flow rates and based on ten kinetic runs at each flow rate, collected over two or more days. Kinetic plots all showed good linearity with correlation coefficients (r2) greater than 0.95. Previously, we have shown that the ion trap gives reactivity at near ambient temperature.29 The GAUSSIAN03, GAUSSIAN09, and GAUSSIAN16 quantum mechanical packages were used to complete all calculations.30, 31, 32 The energies were computed at the MP2/6-311+G(d,p)//MP2/6-31+G(d) level and then corrected with MP2/6-31+G(d) zero-point vibrational energies (ZPE, scaled by 0.966).33 An ab initio rather than DFT method was chosen because it is better suited for examining systems with small transition state barriers.34 Thermal corrections to 298 K were used to calculate the proton affinities, however, species on the reaction surfaces are reported at 0 K.

Computed at MP2/6-311+G**//MP2/6-31G* level.

Another important finding from these gas-phase data is the ability of 1- and 2-iodoheptafluoropropanes to act as iodination agents via the SN2@I mechanism, with the latter being extremely selective. These results suggest that 2-iodoheptafluoropropane would be an excellent reagent for iodinating any heterocycle that can be selectively deprotonated. Conclusions In conclusion, our gas phase and computational data indicate that an SN2@I path is a facile route to halogenation of deprotonated heterocycles. Unlike the previously proposed radical mechanism, an SN2@X mechanism is fully consistent with the results from Shi et al., including the observed regioselectivity. In contrast, a radical based mechanism does not align with the selectivity pattern they ACS Paragon Plus Environment


ASSOCIATED CONTENT Supporting Information. Spectra, tables of kinetic data and product distributions, and computational data including Cartesian coordinates for all species are available in PDF format. The Supporting Information is available free of charge on the ACS Publications website.

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AUTHOR INFORMATION Corresponding Author

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[email protected] (17)

Notes The authors declare no competing financial interest.

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Acknowledgements

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We thank the National Science Foundation (CHE- 1565852)

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Substitution Reactions on Iodine and Bromine: Mechanisms for Facile

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