Arylhydrazine Trapping of Benzynes: Mechanistic Insights and a Route to Azoarenes

Abstract

Arylhydrazines (ArN_αHN_βH₂) are ambident nucleophiles. We describe here their reactivity with benzynes generated in situ by thermal cyclization of several multi-ynes. Products arising from attack of both the alpha- and the beta-nitrogen atoms are observed. These competitive modes of reaction were explored by DFT calculations. Substituent effects on the site-selectivity for several substituted phenylhydrazines were explored. Interestingly, the hydrazo products from beta-attack (ArNHNHAr’) can be oxidized, sometimes in situ by oxygen alone, to give structurally complex, unsymmetrical azoarenes (ArN=NAr’). Toluenesulfonohydrazide and benzohydrazide analogs were each demonstrated to undergo similar transformations, including oxidation to the corresponding benzyne-trapped azo-compounds.

Graphical Abstract

Azoarenes (ArN=NAr’) are notable for their light-driven cis/trans isomerization and, thereby, their potential to act as photoswitches. In this capacity, they have been employed in biological probes, molecular machines, drug delivery systems, optical devices, and data storage.¹ Currently (and classically), most azoarenes are constructed by way of the addition reaction of phenoxides to aryl diazonium ions (Figure 1a).² This reaction, however, has limitations in terms of its substrate scope and efficiency. Alternatively, the Mills reaction involves condensation of anilines with aryl nitroso compounds and allows for the synthesis of structurally more complex azoarenes (Figure 1b).^3,4,5 A limitation in that method is that the attacking aniline typically needs to be electron rich, and efficiencies can suffer due to side reactions including over-oxidation of the requisite nitroso compound.

Figure 1.

Complementarity of this de novo construction of one arene of an azoarene (panel c) with the most common, classical methods for their conjunctive synthesis (panels a and b).

To our knowledge, nucleophilic addition of an aryl hydrazine to a benzyne species has never been reported. Herein, we demonstrate one-pot formation of azoarenes 4 via reaction of benzynes generated by the hexadehydro-Diels-Alder (HDDA) reaction (1 to 1*) with aryl hydrazines 2 to produce intermediate hydrazoarenes 3 (Figure 1c). These are readily and conveniently oxidized with MnO₂ (or, even, via autooxidation). Via this strategy, both electron-donating and, especially, electron-withdrawing substituents on the hydrazine are tolerated and significant structural complexity is introduced into the products in a single step via the trapping of 1*. The results described here constitute a complementary strategy for the construction of complex azoarenes.

Our initial experiment involved heating of the triyne HDDA substrate 5 in chloroform at 90 °C in the presence of one equivalent of phenylhydrazine (2a, Figure 2). The characterized products were the 1,2-diarylhydrazine (hydrazo compound) 6a, the azoarene 7a, the 1,1-diarylhydrazine 8a, and, to a small extent, the aniline derivative 9a.⁶ The relative amounts of these products depended upon the amount of oxygen present in the reaction vessel. That is, under aerobic conditions, none of the hydrazo product 6a was observed. Under an atmosphere of nitrogen, this compound was clearly evident in the NMR spectrum of the crude product mixture and, although it could be isolated, its further conversion to the oxidized azoarene 7a occurred both upon routine handling as well as while kept in solution in an NMR sample tube over time. Notice that the ratio of the total amount of 6a and 7a to that of 8a was ca. 1.5 in both experiments. This, in turn, implies that the nucleophilic addition of 2a to the benzyne is competitive at the α- vs. β-nitrogen atoms.

Figure 2.

Product distribution from reaction of the benzyne derived from heating triyne 5 in the presence of phenylhydrazine (2a). ^a Isolated yield

The competition between the two nitrogen atoms is surprising given that the reaction of 2a with dimethyl acetylenedicarboxylate (DMAD) is reported to occur exclusively at the β-nitrogen atom (NH₂).^7,8,9 This is in line with the notion that the phenyl substituent would reduce the nucleophilicity of the α-nitrogen atom for both steric and electronic reasons. Therefore, we decided to explore whether DFT calculations would shed any light on this curious outcome of a preference for attack by N_α. In particular we computed the energetics for reaction of o-benzyne (I) with 2a (Figure 3). The overall free energy of reaction leading to IVβ vs. IVα (the analogs of 6a and 8a, respectively) is, as expected, largely exergonic, the former more so because of the greater resonance delocalization into each of the two phenyl rings.

Figure 3.

DFT calculations for reaction of o-benzyne (I) with phenylhydrazine (2a). [SMD(CHCl₃)/M11/6-31+G(d,p)]

The transition structures associated with attack by N_β (TS-I→IIβ) vs. N_α (TS-I→IIα), leading to the zwitterions IIβ or IIα, respectively, are quite similar in energy, consistent with the experimental observation of comparable amounts of products arising from these two processes. The nearly barrierless exergonic events that convert IIβ/α to IIIβ/α (simple proton transfers) indicate that the initial α- vs. β-attacks by 2a onto I are both the rate- and product-determining steps for the two overall reactions. The final conversions of IIIβ/α to products IVβ/α would most likely be mediated by an external proton shuttle such as PhNHNH₂.

We also briefly explored by DFT the two modes of competitive reaction between PhNHNH₂ (2a) and DMAD (see SI for details). While a full exploration of the potential surface for this process is complex, one potentially significant difference between the transition structures for the DMAD vs. benzyne reactions is the distance between the attacking nitrogen atom and the electrophilic sp-hybridized carbon atom. In TS-I→IIβ and TS-I→IIα that distance is 3.0 and 3.7 Å, respectively. In contrast, for the analogous TSs for the addition to DMAD, the TSs have much smaller separation of the reacting centers (2.0 Å for both N_β–C and N_α–C). This reflects a reaction surface with a much later transition state, consistent with the considerably higher exergonicity for addition of 2a to benzyne (I) vs. DMAD (ΔΔG° ~ 25 kcal mol⁻¹) for the first elementary step of formation of the zwitterions IIβ/α vs. that of the DMAD analogs. The much longer N–C distances in the reactions with benzyne via TS-I→IIβ/α significantly minimize the role of steric interaction in approach of the nucleophile to benzyne.

We next examined the effect of substituents on the arylhydrazine. (Table 1) The presence of electron withdrawing groups on the phenyl ring significantly enhanced the preference for attack by N_β; none of the products from reaction at N_α were seen (entries b-e). In the case of the p-nitrophenyl analog, the diarylhydrazine precursor of 7b was isolable, although it too was seen to air oxidize slowly, for example, in an NMR sample solution. MnO₂ was used to fully convert the crude product to the azo adduct. Likewise, the crude material from trapping with 2-hydrazinopyridine (2e) was also proactively oxidized with MnO₂ to ensure full conversion to 7e. Entries f and g show results using phenylhydrazine derivatives similar in electronic character to that of 2a itself. And similarly, comparable amounts of products from both N_β and N_α attack were isolated. Results using p-methoxyphenylhydrazine are conspicuously absent from Table 1. This substance is known to be very challenging to prepare and handle because of its sensitivity to autoxidation.¹⁰ The o-methoxy analog (2h) was free-based immediately prior to use; the azo derivative 7h was isolated in low yield. Analysis of the NMR spectrum of the crude reaction mixture suggested the presence of a significant amount of 8h, but that material also degraded upon attempted purification.¹¹

Table 1.

Azoarenes 7 (and 1,1,-diarylhydrazines 8, where observed) formed from reactions of the HDDA-benzyne from triyne 5 in the presence of arylhydrazines 2, followed by oxidation (in air or with MnO₂).

entry	Ar	MnO2	azoarene (yield)	1,1-diaryl-hydrazine (yield)
a		No	7a (30%)	8a (43%)
b a		Yes	7b (65%)	not obs.
c		No	7c (62%)	not obs.
d		No	7d (61%)	not obs.
e		Yes	7e (50%)	not obs.
f		Yes	7f (49%)	8f (49%)
g		Yes	7g (33%)	8g (30%)
h		No	7h (10%)	(8h)b

^aThis example was also performed on a 1 mmol scale and 7b was isolated in 74% yield.

^bEvidence for this compound was seen in the NMR spectrum of the crude product mixture, but it proved to be too labile for isolation.

Several experiments were then performed to address several complementary aspects of this chemistry (Figure 4). Unsurprisingly, the iodophenyl derivative 7f smoothly underwent cross-coupling to the biaryl derivative 10. We then showed that the linker unique to triyne 5 was not a requirement for the reaction. That is, the tetraynes 11a and 11b were each trapped by the nitrophenylhydrazine 2b to give, following oxidation, the azo compounds 12a and 12b (Figure 4b).⁶ We also showed that hydrazides 13a and 13b, each perforce having a quite different level of nucleophilicity of its two nitrogen atoms, react smoothly with the benzyne produced by heating triyne 5. Direct oxidation by addition of MnO₂ produced the azo derivatives 14a and 14b, respectively. It is notable that while the former appeared to be quite stable, the arylazosulfone analog was observed to photobleach rather easily upon handling in the ambient laboratory conditions. This presumably reflects the reported photoinitiated homolytic fragmentation of compounds containing an ArN=NSO₂R moiety.¹²

Figure 4.

a) The azo functionality is compatible with a Pd°-catalyzed (Suzuki) cross-coupling reaction. b) The nature of the HDDA-benzyne is not limited to that derived from 5. c) Benzo- and sulfonohydrazides undergo analogous transformations.

Finally, because we were unable to identify reports of any reactions of hydrazines with arynes generated by conventional methods (i.e., non-HDDA), we briefly explored the reaction of the Kobayashi-benzyne from precursor 15^13,14 with three phenylhydrazine derivatives (Figure 5). In each instance, by far the major product, following isolation, was the 1,1-diarylhydrazine product 16. Trace amounts of a compound deemed to be the corresponding azoarene were detected by GC-MS analysis of the crude product mixture. This high selectivity for attack by N_α in 2 suggests that hydrogen bonding by fluoride ion to the more acidic PhNH preferentially activates N_α for addition compared to the additive-free reaction conditions of the thermal HDDA variant.

Figure 5.

Reactions of o-benzyne with arylhydrazines 2a,b,g gave 1-phenyl-1-arylhydrazines 16a,b,g.

We have described here the first examples of nucleophilic trapping of benzynes by arylhydrazines. Either of the nitrogen atoms is capable of adding to produce either 1,2- or 1,1-diarylhydrazine compounds via attack by either the β- vs. α-nitrogen atoms, respectively. The ratio of these competitive processes is influenced by the electronic character of the aryl substituent in the hydrazine. DFT calculations suggest that the greater proportion of addition through the α-nitrogen compared to reactions with simple electron-deficient alkynes supports the idea that the addition to (the highly electrophilic) benzyne proceeds via a transition state lying much earlier on the reaction coordinate. In many instances, the 1,2-diarylhydrazines were observed to undergo air oxidation to the corresponding azo-analogs. This process could be readily forced to completion by exposing the crude reaction products to MnO₂ prior to purification; the 1,1-isomer was not oxidized. The benzo- and sulfonohydrazide analogs 13a and 13b were shown to add to an HDDA-benzyne exclusively through the unsubstituted, more nucleophilic nitrogen atom. The initial adducts could again be oxidized to the corresponding azo compounds, now bearing an electron withdrawing group. Several arylhydrazines were used to trap o-benzyne itself to produce the 1-phenyl-1-arylhydrazine isomer highly selectively. This method of construction of azoarenes complements known, classical approaches and is capable of providing structurally complex azo compounds.