Dual Sequence Control of Uniform Macromolecules through

Letter Cite This: ACS Macro Lett. 2017, 6, 1398−1403

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Dual Sequence Control of Uniform Macromolecules through Consecutive Single Addition by Selective Passerini Reaction Yu-Huan Wu, Jian Zhang, Fu-Sheng Du, and Zi-Chen Li* Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, Department of Polymer Science and Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China S Supporting Information *

ABSTRACT: The selective Passerini reactions of 4-formylbenzoic acid and 4isocyanobenzoic acid with aliphatic isocyanides and aldehydes were utilized to synthesize sequence-defined uniform macromolecules. Our strategy does not involve any protecting groups or reactive group transformation steps and allows direct and consecutive propagation of sequence in each step. Introduction of diverse side groups by using different aliphatic components provided a range of sequence-defined uniform macromolecules in high yield and gram scale. The strategy also allows further Passerini self-coupling or cross-coupling of the formed sequences with other small molecules, affording polymers with up to 5098.3 Da and 20 side groups. Thus, this strategy will show promise for more efficient synthesis of new sequence-defined macromolecules.

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tions.28−33 Further developed template approaches differentiate the reactivity of monomers by spatial control to realize a single addition.34−38 Nevertheless, currently only a few reactions have satisfactory selectivity for efficient single monomer addition, and complicated templates are still required. Therefore, it is essential to devise a facile method to increase the chemoselectivity and thus improve the efficiency of the multistepgrowth strategy toward sequence-defined uniform macromolecules. Multicomponent reactions such as Passerini, Ugi, KabachnikFields, Biginelli, and alkyne-based reactions have been introduced into polymer science either as a new polymerization method or as a postpolymerization modification method for the synthesis of polymers with a range of diversity in both structure and function.39−48 Among them, the Passerini three-component reaction (P-3CR) of an oxo compound with an isocyanide and a carboxylic acid is a good candidate to regulate the sequence of macromolecules.49−51 Sequence-defined uniform macromolecules have been successfully synthesized via the elegant two-step iterative strategies of different multicomponent reactions.52−54 However, these strategies still require an additional group transformation step, thus reducing the overall efficiency of the processes. Our design was based on the chemoselectivity of aliphatic aldehyde and isocyanide groups over aromatic ones in the P3CR (Scheme 1A), similar to the priority of aliphatic isocyanide observed in the synthesis of macrocycles by Ugi reaction.55 4Formylbenzoic acid (AB) and 4-isocyanobenzoic acid (AC)

recision polymers with defined sequence and uniform chain length are the foundation to understand the structure−property relationship of macromolecules, to improve their properties, and finally to expand their applications.1 However, primary sequence control of synthetic polymers is still one of the most challenging tasks even in modern polymer chemistry.2,3 Among the many known approaches toward uniform polymers with defined sequence, the solid-phase peptide synthesis,4,5 one of the most classical multistep-growth strategies, inspires us that monomers can be iteratively added to the propagating chain ends with the highest level of fidelity. However, how to improve the efficiency of the whole processes remains a crucial problem. The multistep-growth strategy generally includes three elements in one synthetic cycle: controlling a single monomer addition, introducing a sequence structure, and reforming or recovering a reactive group for the next monomer addition.6 The single monomer addition step is the most important and challenging one, as the effectiveness and efficiency depend greatly upon the chemoselectivity as well as the rate and yield of the utilized reactions. Traditionally, the single monomer addition is accomplished by using a monomer with suitable protecting groups, but deprotection steps are needed to recover the reactive groups.7−14 Thus, many known protecting-groupfree methodologies have recently been developed,15,16 including orthogonal coupling of building blocks17−23 and excess use of bifunctional monomers.24−27 These methods, though successful, still contain at least two steps in each synthetic cycle including tailor-made transformation for reactive groups, which functions similarly to the traditional protecting groups. Besides the use of protecting groups and the like, a more direct strategy is to link only one polymerizable monomer to the polymer chain end under optimized selective condi© XXXX American Chemical Society

Received: November 2, 2017 Accepted: November 28, 2017

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DOI: 10.1021/acsmacrolett.7b00863 ACS Macro Lett. 2017, 6, 1398−1403

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ACS Macro Letters Scheme 1. Two Types of Selective P-3CR (A) and Synthetic Strategy toward Sequence-Defined Uniform Macromolecules (B)

Figure 1. (A) CHO-NC transformation conditions: 1 (0.30 mmol), AC (0.45 mmol), 2 (0.92 mmol), DCM (0.6 mL), 30 °C, 24 h. NC− CHO transformation conditions: 4 (0.30 mmol), AB (0.45 mmol), 5 (0.91 mmol), DCM (0.6 mL), 30 °C, 24 h. (B) Time-dependent conversion of aldehyde 1 and isocyanide 4.

traces of the above two transformations after 24 h (Figures S4 and S5). The CHO-NC transformation product contains a little dimer, while the NC−CHO transformation is totally absent of any oligomers. Therefore, the aromatic aldehyde and the aromatic isocyanide could switch to each other in high conversion with neglitable oligomerization and other side reactions. The high efficiency and selectivity of these transformations would thus ensure a high overall yield when applied to multistep synthesis of sequence-defined uniform macromolecules. With the powerful tool in hand, we then synthesized sequence-defined uniform macromolecules in a minimal number of steps (Figure 2A). An aromatic aldehyde (S1) was first obtained from the P-3CR of cyclohexyl isocyanide, 10undecenal, and monomer AB. For this reaction, about 4% of diaddition product was observed because both the isocyanide and the aldehyde were aliphatic and had relatively higher reactivity than the aromatic ones in later steps. After 16 h of reaction, compound S1 was purified by column chromatography in 92% isolated yield. In the second step, the aromatic isocyanide S2 was obtained in 87% yield by the CHO-NC transformation of S1 with 1.5 equiv of monomer AC and 2.5 equiv of t-butyl isocyanide after 24 h. This first cycle involves two transformations, during which the end group was converted back into the starting isocyanide group, the backbone was the amide−ester−ester sequence, and simulatenously, two side groups were introduced by using an alphatic aldehyde and an alphatic isocynide, respectively. Then the cycle of NC−CHO and CHO-NC transformations were applied alternately to extend the sequences consecutively (S3−S8), a range of side groups were introduced by using different aliphatic components (Table 1, entries S1−S8). Among these products, compounds S1, S3, S5, and S7 have reactive aldehyde end groups while the other four coumpounds S2, S4, S6, and S8 have isocyanide end groups for further cycles. All the compounds were easily purified by column chromatography by virtue of the clean reaction, high conversion

were used as two bifunctional building blocks, and aliphatic aldehydes (B′) and isocyanides (C′) were used for simultaneous monomer addition and side group introduction. Specifically, the strategy involves two chemoselective transformations: (1) CHO-NC transformation: the P-3CR of an aromatic aldehyde (B), an aliphatic isocyanide (C′), and compound AC occurred selectively among B + C′ + A with the aromatic C group of compound AC unaffected, thus, this single step fulfilled three tasks: one monomer addition, one side group introduction, and the transformation of the end group into C; (2) NC−CHO transformation: similarly, the selective P-3CR of an aromatic isocyanide (C), an aliphatic aldehyde (B′), and compound AB resulted in the formation of a compound with the aromatic aldehyde (B) as the end group. On the basis of these two transformations, we propose an innovatory strategy toward sequence-defined uniform macromolecules in high yield and large scale (Scheme 1B). The CHO-NC and the NC−CHO transformations are used alternately, and the dual sequence control is fulfilled by using different aliphatic isocyanides and aldehydes in each cycle of the two transformations. Since the product of the CHO-NC transformation could serve as the reactant of the next NC− CHO transformation, and vice versa, no extra steps for reactive group reformation or recovery are needed. First, model reactions were performed to testify the selectivity of aliphatic over aromatic components in the P3CR. We followed the reaction using time-dependent 1H NMR, and the conversion over time of the two transformations is shown in Figure 1. In the CHO-NC transformation, the aromatic aldehyde 1 reacted with the carboxylic acid of AC and excess t-butyl isocyanide 2 in DCM, and the conversion of aldehyde 1 was 96% after 24 h. In the NC−CHO transformation, the aromatic isocyanide 4, after reacting with AB and aldehyde 5 under similar conditions, was converted quantitatively to the aromatic aldehyde 6 (Figures S2 and S3 in the Supporting Information). We also measured the GPC 1399

DOI: 10.1021/acsmacrolett.7b00863 ACS Macro Lett. 2017, 6, 1398−1403

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ACS Macro Letters

Figure 2. (A) Consecutive synthesis of S1−S8. (B) 1H NMR spectrum of S8 with assigned signals. (C) GPC traces of S1−S8.

compatible with P-3CR such as halide, hydroxyl, and alkynyl group can also be easily introduced as side groups. The structures of these compounds were characterized by 1H and 13C NMR spectroscopy, high resolution ESI-MS, and MALDI-TOF-MS (see the Supporting Information). For example, the proton signals in the 1H NMR spectrum of S8 (Figure 2B) can be assigned unambiguously, in which the characteristic signals 4, 12, 17, 24 and 9, 14, 20, 26 generated by P-3CR confirm the expected sequence structure. GPC traces (Figure 2C) displayed shorter retention time with increasing sequence, and all the dispersities remain narrow, manifesting the monodispersity and high purity of the obtained sequences. DSC results revealed that the glass transition temperatures of compounds S2−S8 have a positive correlation with the molecular weight, and are also influenced by the end groups (Figure S18). Taking advantage of the reactive end groups, we further extended the sequences by coupling the obtained chains using P-3CR. Self-coupling of the aldehyde-terminated S7 with adipic acid and t-butyl isocyanide formed macromolecule C1 with 18 side groups. Similarly, the P-3CR of the isocyanide-terminated S8 with adipic acid and undecanal generated macromolecule C2 (Figure 3A), which had a molecular weight of 5098.3 Da and 20 sequence-defined side groups (Table 1, entries C1 and C2). The yields of both reactions were satisfactory due to the relatively high reactivity of the aliphatic components.

Table 1. Sequences Synthesized by Consecutive Additions and Couplings entries

side groupsa

Mn (Da)

isolated yield (%)

overall yield (%)

S1 S2 S3 S4 S5 S6 S7 S8 C1 C2 C3 C4

2 3 4 5 6 7 8 9 18 20 18 14

427.6 657.8 880.1 1166.4 1436.7 1779.2 2041.5 2305.8 4395.4 5098.3 4407.3 3390.2

92 87 90 93 93 91 88 86 76 78 31 35

92 80 72 67 62 57 50 43 38 33 13 17

a

Total number of the side groups, including one end group of S1−S8 and two end groups of C1−C4.

and the large polarity difference between the products and the excess isocyanides or aldehydes. Because of the high efficiency of the reactions and workup, 1.99 g of the final product S8 was obtained in an overall yield of 43% by only four cycles of eight consecutive steps. Compound S8 contains nine side groups orginated from five isocyanides and four aldehydes respectively. Other functional groups 1400

DOI: 10.1021/acsmacrolett.7b00863 ACS Macro Lett. 2017, 6, 1398−1403

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Figure 3. (A) Synthesis of C2. (B) Structure of C4 constructed from S7, S4, and 10-undecynoic acid. (C) GPC traces of C1−C4 compared with S7 and S8. (D) MALDI-TOF mass spectra of S7, S8 and C1−C4 with calculated molecular weight in parentheses.

groups. Combining this efficient and scalable strategy with Passerini coupling, we can access polymers with up to 5098.3 Da and 20 side groups in high overall yields. Further research will focus on applying highly efficient process of separation and developing more multifunctional monomers suitable for the selective Passerini reactions. This synthetic strategy will innovate the toolbox toward sequence-defined uniform macromolecules and afford polymers with more intriguing properties.

Furthermore, we expanded the versatility of this strategy by coupling the sequences with two different end groups with an acid. Thus, P-3CR of the aldehyde-terminated S7 and the isocyanide-terminated S8 with acetic acid yielded compound C3, while S7+S8+10-undecynoic acid formed compound C4 (Figure 3B and Table 1, entries C3 and C4). Although the yields of C3 and C4 are relatively low due to the limited reactivity of the aromatic aldehyde and isocyanide, these crosscouplings demonstrate the feasibility of constructing complex sequence-defined uniform macromolecules by directly using the sequences synthesized via consecutive single addition as building blocks. Besides, a desired functional group could be simultaneously installed at a specific position by varying the acid component for the Passerini coupling. The GPC traces (Figure 3C) again confirmed the monodispersity of the coupled products, and the MALDI-TOF mass spectra (Figure 3D) identfied the presence of single molecular ions equal to the theoretical calculations. In conclusion, we have developed two selective Passerini CHO-NC and NC−CHO transformations based on two aromatic bifunctional monomers, and applied them to the synthesis of sequence-defiend uniform macromolecules with two different end groups. In this approach, three elements in each cycle of the conventional multistep-growth strategies have been integrated in just one step, completely avoiding the use of protecting groups or the additional transformation for reactive

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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/acsmacrolett.7b00863.

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Details of synthesis and characterization, NMR spectra, and DSC thermograms (PDF).

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Fu-Sheng Du: 0000-0003-3174-6107 Zi-Chen Li: 0000-0002-0746-9050 1401

DOI: 10.1021/acsmacrolett.7b00863 ACS Macro Lett. 2017, 6, 1398−1403

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ACS Macro Letters Author Contributions

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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by the National Natural Science Foundation of China (Nos. 21534001 and 21225416). We also thank Miss Lianjun Zheng for helpful advices on the manuscript.

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