Three Switchable Orthogonal Dynamic Covalent Reactions and

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Cite This: J. Org. Chem. 2018, 83, 9858−9869

Three Switchable Orthogonal Dynamic Covalent Reactions and Complex Networks Based on the Control of Dual Reactivity Yu Hai,†,§,|| Hanxun Zou,†,‡,|| Hebo Ye,†,‡ and Lei You*,†,‡ †

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State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China § College of Material Science and Engineering, Fujian Normal University, Fuzhou 350007, China S Supporting Information *

ABSTRACT: Achieving complexity is central to the creation of chemical systems, inspired by natural systems. Herein we introduce a strategy of switchable orthogonal dynamic covalent chemistry (DCC) toward the regulation of complex dynamic networks. The control of dual reactivity of tautomers and resulting pathways allowed reversible covalent bonding of a large scope of primary amines, secondary amines, alcohols, and thiols with high efficiency. The selection of reaction pathways next enabled the realization of orthogonal but switchable dynamic covalent reactions (DCRs) with nucleophile pairs of amine/alcohol, alcohol/thiol, and amine/thiol by varying protonation and oxidation states. Control experiments confirmed the crucial role of dual reactivity on the stability and switchability of DCRs. The specificity toward amines, alcohols, and thiols, as well as interconversion between their corresponding assemblies, was further accomplished in one vessel, thus creating tunable communicating networks with three types of DCRs. Moreover, the switchable orthogonality combined with differential reactivity of multiple sulfonamides and nucleophiles enhanced the complexity within dynamic libraries. The generality and versatility of our approaches should facilitate their incorporation into many aspects of chemistry endeavors.

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INTRODUCTION Studies on systems chemistry have been blossoming, which focus on complex mixtures to mimic biosystems, including signaling networks.1 Molecular systems with high and tunable complexity are of importance to access novel functions. Although many elegant examples have been reported, ranging from classical self-assembly2 and self-sorting systems3 to emerging self-replicating4 and dissipative systems,5 the control of complex reaction networks, especially those with multiple levels of communication, remains challenging.6 By rendering covalent bonds reversible, dynamic covalent reactions7 (DCRs, Figure 1) can generate complexity through component exchange and stimuli responsiveness. Dynamic covalent chemistry (DCC)8 is thus a powerful tool for the research of systems chemistry. DCC has also found application in the creation of frameworks,9 modification of nanomaterials,10 and regulation of biomolecules.11 The interplay between different types of DCRs is generating intensive interest, as a mixture containing multiple DCRs can significantly build up complexity.7,8,12 However, it is difficult to effectively handle them within one system considering specific conditions used for various DCRs. The selective turn on of individual DCRs enabled the orthogonality (Figure 1a).12 These DCRs themselves typically did not communicate with each other but instead were responsive independently to triggers (Figure 1a). Through such a strategy, Matile13 and Leigh14 constructed complicated surface architectures and © 2018 American Chemical Society

directional molecular machines, respectively. Moreover, Bonifazi15 and Anslyn16 realized three or four simultaneous and orthogonal DCRs without cross-reactivity. Recently, Otto proposed the concept of antiparallel DCC with thiols as a shared unit, and the switch between disulfides and thiaMicheal adducts was achieved by changing oxidation level (Figure 1b).17 The development of new platforms and mechanisms for addressable DCC composed of multiple DCRs should be highly desired. Aldehydes have become one of the central points for DCC studies (Figure 1c). For example, imine is among the most explored DCRs.18 Recently, Furlan added dithioacetal into the toolbox of DCRs and reported photoactivated simultaneous exchange of disulfides and dithioacetals.19 In contrast to imine and dithioacetal, for weakly nucleophilic monoalcohols their acetals are not quite stable thermodynamically, and therefore, driving forces are needed to shift the equilibrium, such as cyclization based on diols and metal coordination.20 The DCRs involving aminals have a similar stability issue, which is exacerbated with sterically congested secondary amines.21 An approach of diverse DCRs with desired stability and reversibility, especially those from common building blocks of amines, alcohols, and thiols, would have broad utility, and Received: May 24, 2018 Published: August 9, 2018 9858

DOI: 10.1021/acs.joc.8b01332 J. Org. Chem. 2018, 83, 9858−9869

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The Journal of Organic Chemistry

Figure 1. DCC strategies for creating diversity and complexity: (a) independent turn on of individual DCRs with different stimuli, (b) switch between two DCRs with a shared building block and varying conditions, (c) aldehyde based DCRs, and (d) three switchable orthogonal DCRs through the control of different pathways of equilibrating isomers.

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RESULTS AND DISCUSSION Design. In order to develop dual reactivity based orthogonal DCRs, attention was turned to tautomeric 2formylbenzenesulfonamides23 (1, Figure 2A), which have not been exploited for DCC purposes, to the best our knowledge. We postulated that for the open tautomer 1 the aldehyde DCC would dominate, such as imine formation and exchange with primary amines (pathway a in Figure 2A). In addition, intramolecular ring closure would also lead to ring−chain tautomers.24 In contrast, for the ring structure 2 nucleophilic attack on the tertiary carbon would be unlikely due to steric concerns. Instead, a cyclic sulfonyliminium ion25 could form under acidic conditions, which could be trapped by nucleophiles, such as monoalcohols, to create a hemiaminal ether (pathway b in Figure 2A). Furthermore, the adjacent sulfonyl group could have a stabilizing role on the assembly by delocalizing the sulfonamide nitrogen. Because tautomers 1 and 2 would exhibit different reactivity under neutral/basic and acidic conditions, respectively, such a special feature could enable us to achieve orthogonal DCRs. Moreover, the tautomerization equilibrium would be modulated by substituent R, which could in turn affect DCRs and hence provide another layer of complexity. In essence, we sought a tautomerism-regulated DCC platform with a diverse set of mononucleophiles, which could further allow the realization of orthogonality through controlling reaction

the interconversion between their assemblies could lead to communicating networks. Herein, we introduce a strategy of switchable orthogonal DCC toward the control of complex reaction networks (Figure 1d). The manipulation of dual reactivity22 and the ensuing competing pathways of tautomers could provide rich opportunities for harnessing DCRs and creating complexity. Tautomers could exhibit distinct reactivity and behave “independently”, thereby resembling orthogonal DCC in Figure 1a. Meanwhile, two interconverting isomers as a whole can be viewed as a shared component, and the reaction of one occurs at the expense of other’s. In this regard, our approach is analogous to antiparallel DCC (Figure 1b). First, dynamic covalent bonding of primary amines, secondary amines, alcohols, and thiols with high efficiency was realized based on tautomers of 2-formylbenzenesulfonamides. The preference for and stimuli-responsive switch between DCRs of amines, alcohols, and thiols were accomplished through the selection or suppression of reaction pathways, thereby combining orthogonal and antiparallel chemistries with three types of DCRs (Figure 1d). Dynamic networks and their tunable transformations were also realized through the interaction of multiple components, further enhancing the complexity. 9859


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amount of 1 as the arene became more electron-deficient, likely due to the enhancement of NH acidity. For 1(H) and 2(H), 2(H) accounted for 93% of the population in acetonitrile (a of Figure 2B). When DBU was titrated into a solution of 2(H), only the aldehyde resonances existed with the disappearance of peaks from 2(H) (b of Figure 2B). The downfield shift of the formyl proton is likely due to the formation of an intramolecular hydrogen bond between this proton and negatively charged sulfonamide nitrogen upon based induced deprotonation. The ring tautomer was recovered upon the addition of methanesulfonic acid (MA) (c of Figure 2B). The facile conversion between ring−chain isomers lays the groundwork for the manipulation of their corresponding reactivity toward orthogonal DCC. Scope of DCRs. With equilibrating tautomers in hand, their DCRs with a broad range of mononucleophiles were studied (Scheme 1). Reactions with primary amines tested were quantitative, and the distribution of aminal 3 and imine 4 was amine dependent (Figures S7−S15). Taking 1-butylamine as an example, the equilibrium was quickly reached after 5 min in the presence of molecular sieves (MS), and the formation of cyclic aminal 3 was detected (Figures S7 and S8). The rapid kinetics is likely due to intramolecular acid catalysis from ortho sulfonamide.26 With benzylamine or 1-phenylethylamine, both aminal 3 and imine 4 were observed (Figures S9 and S10). When bulkier amines, such as 3,3-dimethyl-2-butylamine and tbutylamine, were employed, imine was created (Figures S11 and S12). Compared to imine formation,18 DCRs of secondary amines are rare due to increased steric hindrance.21 We postulated that the combination of the aldehyde form of 2(H) (i.e., 1(H)) and a secondary amine followed by the elimination of hydroxide could give an iminium ion (5) intermediate, which could be trapped by nearby sulfonamide to afford aminal 6 (Scheme 1). Gratifyingly, DCRs of 2(H) with amines tested, including piperidine (PipNH), diethylamine, N-methyl-1-propylamine (MePrNH), N-methyl-2-propylamine, and 2-methylpiperidine, were nearly quantitative, and 6 was formed in all cases (Figures S19−S28). Having achieved DCRs of 2 with both primary and secondary amines, we set out to probe the reactivity of 2

Figure 2. (A) Proposed strategy for orthogonal DCC with diverse mononucleophiles through regulating dual reactivity and resulting pathways of tautomers (using amines and alcohols as examples). (B) The equilibrium between 1(H) and 2(H) (a) as well as the modulation by base (1.0 equiv, b) and acid (1.0 equiv, c). The formyl proton of 1(H) and the methine proton of 2(H) were tracked in 1H NMR spectra.

pathways and hence pave the way for the creation of complex chemical networks. To achieve our design, a series of 2-formylbenzenesulfonamides were synthesized (Figure 2A). Both aldehyde (1) and cyclic hemiaminal (2) forms were apparent, with the ring tautomer dominant (Figure S5). There was an increase in the

Scheme 1. DCRs of 2(H) with Primary Amines, Secondary Amines, Alcohols, and Thiols, Associated Intermediates, and Substrate Scope

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Figure 3. Component exchange as well as competition within the dynamic covalent system. (A) (a) The DCR of 2(H) with piperidine, (b) dynamic amine exchange of piperidine derived assembly with N-methyl-1-propylamine, (c) dynamic aldehyde exchange of 2(H) derived assembly with 2(OMe). (B) The competition (d) between benzylalcohol (a), cyclohexanol (b), and 2-propanol (c) for DCRs with 2(H). (C) The competition (d) between 2(OMe) (a), 2(H) (b), and 2(Br) (c) for DCRs with 2-propanethiol. (D) The competition (d) between 2(OMe) (a), 2(H) (b), and 2(Br) (c) for DCRs with piperidine. The most populated product is highlighted in red. The methine 1H NMR peaks of reactants/ products were followed. See the Supporting Information for details and full 1H NMR spectra.

under acidic conditions. Monoalcohols are considered as one class of weak nucleophiles, and therefore, their DCRs with high efficiency are challenging.20 As illustrated in Scheme 1, the highly electrophilic sulfonyliminium ion (7) could be promising for the development of alcohol DCRs. For example, when a mixture of 2(H) and 2-propanol was stirred in the presence of MA and MS, hemiaminal ether 8 was obtained in 86% yield (Figure S31). DCRs of 2 with other monoalcohols, such as ethanol, cyclohexanol, 3-methyl-2-butanol, benzylalcohol, and 1-phenylethanol, also proceeded smoothly (Figures S33−S41). The viability of intermediate 7 was validated by ESI mass spectral analysis (Figure S44).

Moreover, quantitative formation of hemiaminal thioether 9 was detected for the reaction of 2(H) with monothiols (1propanethiol, 2-propanethiol, and t-butanethiol in Scheme 1), further demonstrating the broad scope (Figures S45−S52). An analogous mechanism as alcohols is expected for thiols. Tying it together, DCRs with multiple classes of mononucleophiles (alcohols, thiols, primary amines, and secondary amines) were accomplished, thus providing a versatile platform for complexity and orthogonality studies. Dynamic Mixtures. In order to prove reversibility and hence interconversion between assemblies, component exchange was performed. For example, the reaction product of 2(H) with piperidine was formed initially (a of Figure 3A) 9861


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Figure 4. Communicating orthogonal DCC through the control of protonation level, oxidation level, or both. (A) Reversible switch between the assemblies incorporating an amine and an alcohol in the dynamic mixture, initially created by the reaction of 2(H), piperidine, and 2-propanol (a), by adding MA (b) and Et3N (c). The change upon the titration of Et3N into the mixture created after step b is shown in panel d. (B) Reversible switch between the assemblies incorporating an alcohol and a thiol in the dynamic mixture, initially created by the reaction of 2(H), 2-propanol, and 2-propanethiol (a), by adding I2 (b) and PPh3 (c). The change upon the titration of PPh3 into the mixture created after step b is shown in panel d. (C) Reversible switch between the assemblies incorporating an amine and a thiol in the dynamic mixture, initially created by the reaction of 2(H), piperidine, and 2-propanethiol (a) followed by the introduction of MA (b), by the addition of Et3N/I2 (e) and MA/PPh3 (f). The effect of sequential addition of Et3N (c) or I2 (d) on the conversion from 9 to 6 is also shown. The corresponding 1H NMR spectra of each step are shown. See the Supporting Information for details and full 1H NMR spectra.

followed by the addition of N-methyl-1-propylamine (b of Figure 3A). 1H NMR revealed a decrease in the amount of 6 incorporating piperidine with the appearance of N-methyl-1propylamine derived product, showcasing the exchange of secondary amine despite that the creation of original assembly was nearly quantitative. In addition, when a second sulfonamide (i.e., 2(OMe)) was added to the DCR of 2(H) with piperidine, aldehyde exchange was observed (c of Figure 3A), further corroborating the dynamic nature of the system. The reversibility was also supported by component exchange of the assemblies from primary amines, alcohols, and thiols, respectively (Figures S57−S62). Competition experiments in multicomponent mixtures were then conducted. First, a library of one sulfonamide and multiple nucleophiles was examined. For example, when a mixture of 2(H), 2-propanol, benzylalcohol, and cyclohexanol

was under equilibrium, the sequence of the product distribution (benzylalcohol > cyclohexanol > 2-propanol) was in agreement with the size of the alcohols (d of Figure 3B). The trend remained the same for thiols, primary amines, and secondary amines, favoring the assembly with less steric interaction (Figures S64−S66). More importantly, a suit of sulfonamides and one nucleophile were allowed to equilibrate. For the reaction of 2(H), 2(OMe), 2(Br), and 2-propanethiol, 2(OMe) afforded the most hemiaminal thioether (9(OMe, 2-PrSH), d of Figure 3C). An analogous trend was revealed for 2-propanol, though the differentiation between three sulfonamides was less pronounced (Figure S68). In contrast, with a mixture of the same set of sulfonamides and piperidine, 2(Br) derived aminal 6(Br, PipNH) accounted for the highest population (d of Figure 3D). Similar results were apparent for 1-butylamine 9862


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oxidation/reduction level (i.e., the titration of PPh3 in d of Figure 4B and Figure S78). The reversal of DCRs of alcohols and thiols by switching between different oxidation states was further validated with several more cycles (Figure S77). c. Regulation with Two Types of Stimuli. Having accomplished communicating orthogonal DCC with different types of external stimuli (acid/base and oxidant/reductant), we studied their combination. For DCR of 2(H), piperidine, and 2-propanethiol, only aminal 6 was created (a of Figure 4C). As the case with 2-propanol, the use of MA reversed the selectivity and facilitated the formation of hemiaminal thioether 9, albeit with quantitative yield (b of Figure 4C). After Et3N was introduced, only a tiny amount of 6 was observed, while 9 largely remained intact (c of Figure 4C). This is in sharp contrast with 2-propanol, and the incapability of base to reverse DCRs is likely due to high stability of 9. Oxidant I2 was thus employed to restore the switch of DCRs, and indeed, 6 emerged (100%) with the disappearance of 9 (e of Figure 4C). Moreover, the sequence of the addition of Et3N and I2 was changed. When I2 was used first, complete decomposition of 9 was detected, and 2(H) was recovered as thiols were oxidized to form disulfides (d of Figure 4C). It is notable that aminal 6 was not found at this stage. This is reasonable because the DCR of 2(H) with amine is suppressed under acidic media. It is worthwhile to mention that the reaction of thiols and I2 gives disulfides and hydroiodic acids. Nevertheless, 6 was afforded (100%) with Et3N present (Figure S79). The simultaneous addition of Et3N and I2 also gave same results (100% 6) (Figure S79). These findings demonstrate the efficiency of switch by combining two stimuli (Et3N and I2) and also confirm the dynamic nature of the system. Moreover, the combination of MA and PPh3 enabled the recreation of 9 (f of Figure 4C). The cycle of switch of DCRs was repeated with nearly quantitative conversion (Figure S81). The switch between thiol and primary amine derived assemblies also proceeded successfully (Figures S82 and S83). d. Orthogonality with Three Classes of Nucleophiles. With switchable DCRs in place by using the combination of amine/ alcohol, thiol/alcohol, as well as amine/thiol, these three classes of nucleophiles were mixed altogether in one vessel to prove the orthogonality (Figure 5). A mixture of 2(H), piperidine, 2-propanol, and 2-propanethiol in acetonitrile gave aminal 6 only, in accordance with the results described above (Figure 5a). The acid MA then turned on the reaction of 2(H) with 2-propanethiol, creating hemiaminal thioether 9 in quantitative yield (Figure 5b). Upon the oxidation of thiols by I2, the DCR with alcohols to afford hemiaminal ether 8 (82%) was finally observed (Figure 5c). Hence, the selectivity for amines, thiols, or alcohols was achieved within one flask. To further probe the transformation of the dynamic mixture, Et3N was added (Figure 5d). The reoccurrence of aminal 6 was revealed. With the addition of MA, the DCR of 2(H) with 2-propanol was again recovered to afford 8 with the disappearance of 6 (Figure 5e). When reductant PPh3 was employed, quantitative formation of hemiaminal thioether 9 was apparent (Figure 5f). Moreover, we expect no hurdle for the conversion between 9 and 6, as illustrated in Figure 4C. In short, switchable orthogonal DCRs with 2 and three classes of nucleophiles as inputs, as well as protonation and oxidation levels as triggers, can be dictated when desired, affording communicating reaction networks. Control Experiments. Although switchable DCC was achieved by using equilibrating aldehyde tautomers as well as

(Figure S70). The reversal of the trend of component distribution for alcohol/thiol and amine echoes the extent of ring−chain tautomerization equilibrium of 2, which shifts toward the aldehyde form with the aniline unit bearing an electron-withdrawing group. Furthermore, these findings are consistent with the pathways for alcohols/thiols and amines: the reaction of 2 with alcohols/thiols proceeds through the cyclic hemiaminal, while the open aldehyde contributes for the reactivity of 2 toward amines (Scheme 1). Switchable Orthogonality. Having attained DCRs of different classes of mononucleophiles (Scheme 1), potential interconversion between their assemblies would create reaction networks. Owing to the different reaction routes for amines and alcohols/thiols under neutral/basic and acidic conditions, respectively, the selection of mechanistic pathways in conjunction with the differential reactivity as well as the responsive feature of nucleophiles, such as tunable protonation (amines) or oxidation states (thiols), could lead to orthogonal DCC. a. pH Regulated Orthogonality. First, pH responsive dynamic covalent assemblies were examined, and the pair of an amine and an alcohol was investigated (Figure 4A). A mixture of 2(H), piperidine, and 2-propanol gave aminal 6 exclusively due to high nucleophilicity of the amine (a of Figure 4A). Upon the addition of MA, hemiaminal ether 8 was observed in high yield (86%, together with 14% 2(H)) with concomitant disappearance of 6 (b of Figure 4A). These results indicate the complete reversal of the selectivity between DCRs of the amine and the alcohol. The presence of a Brønsted acid leads to the protonation of piperidine, rendering it a good leaving group and poor nucleophile, and meanwhile facilitates the reaction of 2 with the alcohol. To turn on the DCR with the amine, Et3N was added. Gratifyingly, aminal 6 was the major component (60%), though a significant amount of 8 still existed (40%) (c of Figure 4A). To further fine-tune the communication, Et3N was titrated into the mixture after step b (Figure S73). The percentage of 8 gradually decreased with the emergence of 6 (d of Figure 4A). There was an increase in the amount of 2 in the initial stage of titration, followed by its conversion to 6. With around 2.2 equiv of Et3N, a plateau was reached. Hence, through the delicate control of pH the extent of the switch process was manipulated, allowing the coexistence of both DCRs. The cycle of the addition of acid/base was repeated twice, and the switch of DCRs was successful with comparable efficiency as the initial cycle (Figure S72). To probe the generality of the interconversion between DCRs of an amine and an alcohol, two primary amines with varied steric hindrance (1-butylamine and 3,3-dimethyl-2-butylamine) were studied, respectively, and similar results were afforded (Figures S74 and S75). b. Oxidation/Reduction Regulated Orthogonality. The next goal was to control the pathways for the development of orthogonal DCRs between alcohols and thiols. For example, the reaction of 2(H), 2-propanol, and 2-propanethiol with MA afforded hemiaminal thioether 9 quantitatively, while hemiaminal ether 8 was not detected (a of Figure 4B). When oxidant I2 was added, 9 vanished due to the formation of disulfides from thiols, while the DCR of 2(H) with 2-propanol was turned on (82% 8) (b of Figure 4B). Upon the introduction of reductant PPh3, the reaction of 2(H) and 2propanethiol was again recovered at the expense of 8 (i.e., 100% 9) (c of Figure 4B). Similar to Figure 4A, the degree of switch was modulated through the gradual change of the 9863


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Figure 6. Competition between 2(H) and benzaldehyde for DCRs with 1-butylamine (a), piperidine (b), 2-propanethiol (c), and 2propanol (d).

with a percentage of 62% after 28 days (d of Figure 7B). The slow transformation is in sharp contrast to 2(H) mediated switch of DCRs, in which the equilibrium was reached after 20 h. These findings are likely due to lower reactivity of protonated imine (10) than sulfonyliminium ion 7 (Scheme 2, 7 and 10 highlighted in red). After the departure of ammonium salt, 7 can be readily trapped by alcohols/thiols to complete the switch (Scheme 2a). However, the poor reactivity of iminium ion 10 results in the sluggishness of its conversion (Scheme 2b), as evidenced by its existence over a month. The intermediacy of 10 was supported by the downfield shift and doublet splitting (J = 17 Hz, coupling with NH) of methine proton (Figure 7A,B). Furthermore, the reaction of benzaldehyde, 2-propanol, and 2-propanethiol gave dithioacetal exclusively (a of Figure 7C). With I2 present, dithioacetal did disappear (b and c of Figure 7C). The recovery of benzaldehyde was observed, but not the formation of acetal (d of Figure 7C). These results are consistent with the poor reaction of benzaldehyde with 2propanol (Figure S85). Again the high reactivity of intermediate 7 makes the difference between 2(H) and benzaldehyde, demonstrating the crucial role of the pathway of ring isomers in conjunction with that of open aldehyde (i.e., due reactivity) on the efficiency and interconversion of DCRs. In all, although benzaldehyde exhibited preference toward stronger nucleophiles, the switch of DCRs was either unsuccessful or slow. Complex Systems. In order to enhance systematic complexity, the interplay of multiple equilibria between 2formylbenzenesulfonamides and nucleophiles within dynamic combinatorial libraries (DCLs) was explored. As a proof-ofconcept study, a mixture of 2(OMe), 2(Br), piperidine, and 2propanethiol was allowed to equilibrate, and the product distribution was followed (a of Figure 8A). The aminal 6 derived from 2(Br) dominated (see the red box). After MA was added, hemiaminal thioether 9 incorporating 2(OMe) was the major product (b of Figure 8A, see the red box). These results indicate that not only was the selectivity between amines and thiols reversed, the preference toward 2(OMe) and 2(Br) was also switched. Again the original product distribution favoring 2(Br) and piperidine was restored by using a combination of Et3N and I2 (c of Figure 8A). With the

Figure 5. Switch between the assemblies incorporating three classes of nucleophiles. (a) The mixture of 2(H), piperidine, 2-propanol, and 2-propanethiol; (b) the addition of MA into (a); (c) the addition of I2 into (b); (d) the addition of Et3N into (c); (e) the addition of MA into (d); (f) the addition of PPh3 into (e). The corresponding 1H NMR spectra of each step are shown.

amines, alcohols, and thiols, control experiments were conducted to validate the necessity of dual reactivity for such communications. Different from 2(H), no reaction was found between benzaldehyde and 2-propanol under similar conditions (Figure S85). Nevertheless, DCRs of 1-butylamine, piperidine, or 2-propanethiol were quantitative for both aldehydes (Figures S86−S88), in agreement with high nucleophilicity of primary amines and thiols. To further discriminate 2-formylbenzenesulfonamide and benzaldehyde, their competition for nucleophiles was performed. For 1butylamine, the assembly incorporating 2(H) was preferred (84%), with a small amount of imine (16%, Figure 6a). With piperidine, 2-propanethiol, or 2-propanol, only 2(H) derived adduct was found (Figure 6b−d). The domination of DCRs of 2(H) was also apparent as compared with 4-methoxy- or 4nitrobenzaldehyde (Figures S90 and S91). These results clearly suggest the effect of thermodynamic stabilization of neighboring sulfonamide unit on DCRs. Orthogonal DCC was next studied with benzaldehyde as the common component. A mixture of benzaldehyde, 1-butylamine, and 2-propanol afforded only imine (a of Figure 7A). Upon the addition of MA no acetal was detected even after 28 days, and instead, slow decomposition of imine to recover its aldehyde was observed (d of Figure 7A). For the pair of 1butylamine and 2-propanethiol, quantitative formation of imine was revealed (a of Figure 7B). The acid facilitated the reversal of DCRs, though dithioacetal emerged pretty slowly, 9864


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Scheme 2. Proposed Mechanism of the Transformation of Adduct Incorporating 2(H) and 1-Butylamine (a), or Benzaldehyde and 1-Butylamine (b) in the Presence of MA

In an alternative manner of constructing complex systems, the switch between DCRs of different classes of multiple nucleophiles was examined. For example, a library of 2(H), piperidine, diethylamine, and N-methyl-1-propylamine was initially formed, and the sequence of product distribution (piperidine > N-methyl-1-propylamine > diethylamine) was consistent with sterics (a of Figure 8B, see the blue box). When 2-propanol, cyclohexanol, benzylalcohol, as well as MA were added, all three aminals disappeared, and meanwhile, three hemiaminal ethers (8) incorporating corresponding alcohols were detected. The assembly from benzylalcohol was the most populated (b of Figure 8B, see the blue box), in agreement with Figure 3B. The reactions with amines were again observed with Et3N present, affording the same trend of percentages for aminals as the original mixture (Figures S101 and S102). Furthermore, the orthogonal assembly of 2(H) with multiple thiols and alcohols was also successful by changing the oxidation level (Figures S103 and S104). The assemblies with less steric interaction were favored irrespective of the classes of nucleophiles. Hence, the varying reactivity within each class of nucleophiles is compatible with the orthogonality of their respective DCRs. In an effort to further merge the complexity with orthogonality, a solution composed of two sulfonamides (2(OMe) and 2(Br), 1.0 equiv each), two amines (piperidine and N-methyl-1-propylamine, 0.75 equiv each), two alcohols (2-propanol and benzylalcohol, 0.75 equiv each), as well as two thiols (1-propanethiol and 2-propanethiol, 0.75 equiv each) was equilibrated (a of Figure 8C). The four aminals (6) were observed, favoring the assemblies from 2(Br) (see the red box) and piperidine (see the blue box). Upon the addition of MA, DCRs with alcohols and thiols were turned on, accompanied with complete decomposition of aminals (b of Figure 8C). For 2(OMe), the products derived from thiols (9) were dominant in relative to those of 2(Br) (see the red box). Accordingly, there was a higher population for hemiaminal ethers (8) incorporating 2(Br) than 2(OMe), since 2(OMe) was largely consumed by thiols. Again the products with less steric interaction were preferred (see the blue box). As thiols were oxidized by I2, hemiaminal ethers remained (c of Figure 8C). Now the sequence of products distribution largely fell in line with that of assemblies incorporating thiols in the previous step (see the red and blue boxes). The trend of affinity between sulfonamides and nucleophiles echoed those illustrated in Figure 8A,B (see the placement of red and blue boxes) as well as Figures S105 and S107, in which two classes of nucleophiles

Figure 7. Orthogonal DCC with benzaldehyde. (A) The reaction of aldehyde, 1-butylamine, and 2-propanol (a), and the change upon adding MA after 1, 11, 28 days (b−d). (B) Reaction of aldehyde, 1butylamine, and 2-propanethiol (a), and the change upon adding MA after 1, 11, 28 days (b−d). (C) Reaction of aldehyde, 2-propanol, and 2-propanethiol (a), and the change upon adding I2 after 1, 11, 28 days (b−d).

same set of sulfonamides, an amine and an alcohol also afforded opposite affinity toward 2 (Figures S97 and S98). However, when a thiol and an alcohol were combined, the favor of 2(OMe) was revealed for each nucleophile (Figures S99 and S100). These findings are in line with competition experiments in Figures 3. As a result, the dynamic library was regulated by taking advantage of the differential reactivity of sulfonamides as well as the orthogonality of their associated DCRs. 9865


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Figure 8. Complex systems through the combination of orthogonality and substrate reactivity. (A) Library created from 2(Br), 2(OMe), piperidine, and 2-propanethiol (a), as well as its transformation by adding MA (b) and I2/Et3N (c). (B) Library created from 2(H), piperidine, diethylamine, and N-methyl-1-propylamine (a), followed by the addition of benzylalcohol, cyclohexanol, 2-propanol, and MA (b). (C) Library created from 2(OCH3), 2(Br), piperidine, N-methyl-1-propylamine, benzylalcohol, 2-propanol, 1-propanethiol, and 2-propanethiol (a) as well as its transformation by adding MA (b) and I2 (c). The integrals of products are listed, with the favored aldehyde and nucleophile derived assemblies highlighted in red and blue, respectively. See the Supporting Information for details and full 1H NMR spectra.

orthogonality and the differential reactivity of sulfonamides as well as nucleophiles, complex systems and their transformation were accomplished, thereby constructing communicating complex reaction networks. Due to the prevalence of tautomerism, the strategies and results reported herein should open up opportunities for future DCC and systems chemistry endeavors.

were employed (thiols/amines and thiols/alcohols). Therefore, we showed that our system is capable of building up complexity while maintaining both switchable orthogonality and differential reactivity.

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CONCLUSIONS In summary, switchable orthogonal dynamic covalent chemistry (DCC) as well as complex systems was developed with three types of reversible covalent bonds. A series of 2formylbenzenesulfonamides with varied extent of ring−chain tautomerization equilibrium were prepared. The regulation of unique dual reactivity of those ring and open species allowed the realization of general dynamic covalent reactions (DCRs) of amines, alcohols, and thiols. By controlling reaction pathways with external acid/base and oxidant/reductant, the selectivity toward amines, alcohols, and thiols was achieved within one flask, and moreover, their dynamic covalent assemblies were switched facilely. Control studies revealed the importance of dual reactivity to the stability and switchability of DCRs. Through the combination of the

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EXPERIMENTAL SECTION

General. 1H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker Biospin Avance III spectrometer. The chemical shifts (δ) for 1H NMR spectra, given in ppm, are referenced to the residual proton signal of the deuterated solvent. Mass spectra were recorded on a Bruker IMPACT-II UHR-TOF spectrometer. IR was recorded on a Bruker VERTEX70 FT-IR spectrometer. Solid samples were measured using the pressed pellet method with anhydrous KBr. All other reagents were obtained from commercial sources and were used without further purification, unless indicated otherwise. Synthesis and Characterization. 2(H) were prepared according to the literature procedure.23a 9866



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Synthesis of 2(OCH3). 2-Formylbenzenesulfonyl chloride (302 mg, 1.48 mmol) was dissolved in DCM (3 mL), and Et3N (135 mg, 1.34 mmol) was added. To this solution, was added p-methoxyaniline (165 mg, 1.34 mmol) in DCM (2 mL) dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with DCM (100 mL) and washed with hydrochloric acid solution (2 M) and brine (100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography (silica gel, petroleum ether/ethyl acetate 10:1 to 1:1) to afford the product (312 mg, 80%) as a white solid. mp = 139−140 °C. 1H NMR (CDCl3): δ 10.19 (s, 0.05H, open form 1(OCH3)), 7.97−7.95 (dd, J = 7.6, 1.2 Hz, 0.10H, open form 1(OCH3)), 7.85 (d, J = 7.6 Hz, 1H, ring form 2(OCH3)), 7.75−7.65 (m, 3.15H, open form 1(OCH3), 0.15H; ring form 2(OCH3), 3H), 7.48−7.44 (m, 2H, ring form 2(OCH3)), 7.01−6.96 (m, 2H, ring form 2(OCH3)), 6.97− 6.92 (m, 0.10H, open form 1(OCH3)), 6.74−6.70 (m, 0.10H, open form 1(OCH3)), 6.09 (d, J = 10.8 Hz, 1H, ring form 2(OCH3)), 3.84 (s, 3H, ring form 2(OCH3)), 3.73 (s, 0.15H, open form 1(OCH3)), 3.09 (d, J = 10.8 Hz, 1H, ring form 2(OCH3)), 2.00 (s, 0.05H, open form 1(OCH3)). 13C NMR (CDCl3): δ 191.2, 159.7, 158.3, 139.0, 136.0, 134.9, 133.8, 133.6, 133.5, 133.2, 133.0, 131.0, 130.7, 129.8, 128.2, 125.7, 125.4, 125.3, 121.2, 115.0, 114.5, 83.2, 55.6, 55.4. ESIHRMS: m/z calculated for for C14H13NO4SNa [M + Na]+, 314.0457; found, 314.0457. IR (cm−1, thin film KBr): 3432, 1603, 1513, 1283, 1241, 1175, 1048, 837, 800, 745, 698, 601, 547. Synthesis of 2(Br). 2-Formylbenzenesulfonyl chloride (306 mg, 1.50 mmol) was dissolved in DCM (3 mL), and Et3N (135 mg, 1.36 mmol) was added. To this solution, was added p-bromoaniline (234 mg, 1.36 mmol) in DCM (2 mL) dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (100 mL) and washed with hydrochloric acid solution (2 M) and brine (100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography (silica gel, petroleum ether/ethyl acetate 10:1 to 2:1) to afford the product (252 mg, 54%) as a white solid. mp = 140−141 °C. 1H NMR (CDCl3): δ 10.22 (s, 0.35H, open form 1(Br)), 8.06 (d, J = 8.4, 0.70H, open form 1(Br)), 7.99 (dd, J = 7.6, 1.2 Hz, 0.35H, open form 1(Br)), 7.88 (d, J = 7.6 Hz, 1H, ring form 2(Br)), 7.82− 7.69 (m, 3.70H; open form 1(Br), 0.70H, ring form 2(Br), 3H), 7.63−7.59 (m, 2H, ring form 2(Br)), 7.49−7.45 (m, 2H, ring form 2(Br)), 7.36−7.34 (m, 0.70H, open form 1(Br)), 7.00−6.97 (m, 0.70H, open form 1(Br)), 6.27 (d, J = 11.6 Hz, 1H, ring form 2(Br)), 3.15 (d, J = 11.6 Hz, 1H, ring form 2(Br)). 13C NMR (CDCl3): δ 191.7, 138.2, 135.4, 135.2, 135.0, 134.5, 134.1, 134.0, 133.4, 133.3, 133.2, 132.8, 132.4, 131.3, 131.2, 125.9, 125.5, 123.8, 121.2, 120.5, 119.2, 82.0. ESI-HRMS: m/z calculated for C13H10NO3SBrNa [M + Na]+, 361.9455; found, 361.9457. IR (cm−1, thin film KBr): 3450, 1585, 1489, 1440, 1265, 1168, 1048, 969, 818, 752, 589, 528, 498. Dynamic Covalent Reactions. Dynamic covalent reactions (DCRs) were performed in situ in CD3CN without isolation and purification. To a stirred solution of sulfonamide 2 (∼26 mM, 1.0 equiv) in CD3CN (0.60 mL), were added one mononucleophile (RNH2 (1.2 equiv), R1R2NH (3.0 equiv), ROH (3.0 equiv), or RSH (3.0 equiv)), and activated 3 Å molecular sieves (MS, 4−8 mesh). For the reaction of ROH and RSH, methanesulfonic acid (MA, 0.4 equiv and 0.6 equiv, respectively) was also added. The mixture was stirred at room temperature for 20 h and characterized by 1H NMR and ESI mass spectral analysis. See specific conditions in figure captions of the main text or the Supporting Information if necessary.

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Lei You: 0000-0002-1649-803X Author Contributions ||

Y.H. and H.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank National Natural Science Foundation of China (Grants 21672214, 21403239, and 21504094), the Recruitment Program of Global Youth Experts, and the Strategic Priority Research Program (Grant XDB20000000), and the Key Research Program of Frontier Sciences (Grant QYZDBSSW-SLH030) of the Chinese Academy of Sciences for financial support. We also thank The CAS/SAFEA International Partnership Program for Creative Research Teams.

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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/acs.joc.8b01332. Selected NMR and mass spectra of compounds, dynamic covalent reactions, as well as complex mixtures (PDF) 9867


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Three Switchable Orthogonal Dynamic Covalent Reactions and

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