Halide-Rebound Polymerization of Twisted Amides | Journal of the

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Halide-Rebound Polymerization of Twisted Amides Liangbing Fu, Mizhi Xu, Jiyao Yu, and Will R. Gutekunst J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 Feb 2019 Downloaded from http://pubs.acs.org on February 6, 2019

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Journal of the American Chemical Society

Halide-Rebound Polymerization of Twisted Amides Liangbing Fu,‡ Mizhi Xu,‡ Jiyao Yu, and Will R. Gutekunst* School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive NW, Atlanta, Georgia 30332, United States. Supporting Information Placeholder ABSTRACT: The first living polymerization of twisted

amides is reported using simple primary alkyl iodides as initiators. Polymerization occurs through a haliderebound mechanism in which the nucleophilic twisted amide is quaternized and subsequently ring-opened by the iodide counterion. The covalent electrophilic polymerization generates polymers with living chain ends that are both isolable and stable to ambient conditions, enabling the synthesis of block polymers. This presents a new class of polymers for study that possess high glass transition temperatures and robust thermal stability.

A. Twisted Amides

O

increased nucleophilicity

N

O

N

0º

O N

N

O

N

90 º

pyramidalization O (χN)

0º

N 60 º

B. Aubé (2005): Halide-Rebound Ring-Opening of a Twisted Amide H

H

H

10 equiv Me I N

H

Amides have a longstanding presence in polymer science. DuPonts’ early discovery of nylon paved the way for the rational use of synthetic polymers as engineering materials, and polypeptide biomacromolecules continue to play an active role in medicine.1-3 Amides are generally regarded as robust, hydrolytically resistant chemical functionalities due to a significant resonance contributor arising from nN to π*C=O donation of the nitrogen lone pair.4-5 Twisted amides represent a unique subsection of amide chemistry due to the bicyclic framework (e.g. 1 and 2 in Figure 1) or bulky substituents that geometrically resists population of this resonance structure. This leads to a more electrophilic carbonyl group and a nitrogen atom with enhanced nucleophilicity, the degree of which correlates to the geometric parameters defined by Winkler and Dunitz: the twist angle, t, and the degree of pyramidalization, cN (Figure 1A).6 As a result, twisted amides feature a wealth of distinct reactivity compared to their planar cousins, as documented in numerous experimental and computational investigations over the past decades.7-19 In this communication, the unique reactivity of twisted amides is leveraged to produce a living, covalent electrophilic polymerization initiated by alkyl iodides, termed Halide-Rebound Polymerization (HaRP).20

O

twist angle (τ)

O

N

N Me

DCM 40 ºC

H

H

I

O

I

Me

O

100%

1

C. This Work: Halide-Rebound Polymerization of Twisted Amides n equiv R

N

I

I

SN2

O

O

2

R

SN2

N

N

N

I

R

R

N

I

O O

O n

Figure 1. (A) Twisted amide and the parameters t and cN describing the amide bond distortion; (B) Halide-rebound ring-opening of twisted amide 1 by Aubé; (C) Proposed mechanism for halide-rebound polymerization of 2.

In a landmark study by Stoltz, the prototypical twisted amide 2-quinuclidone was synthesized through an AubéSchmidt strategy.21-22 This long-sought molecule was only isolable as the tetrafluoroboric acid salt, which rapidly underwent hydrolysis in water. Interestingly, it was reported that attempts to neutralize this compound resulted in largely polymeric material. This undesired result prompted interest in the potential to use these high energy molecules as potential monomers for

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macromolecular synthesis. Further evaluation of the literature demonstrated early efforts by Hall and evidence of oligomeric material formed in studies by Szostak and Aubé during the synthesis of novel twisted amide structures. However, none of these products were further characterized for composition or molecular weight.15, 2326 Recently, acyclic bis(Boc) twisted amides have found application in the synthesis of poly(allyl alcohol) by Hillmyer due to their facile reduction with sodium borohydride.27 The reactivity of twisted amides is directly correlated to the cN and t parameters, with examples ranging from barely isolable to others that are chromatographically and hydrolytically stable.28 A distinct mode of reactivity was identified for exploration in polymerization studies based on a 2005 report by Aubé where twisted amide 1 reacted with methyl iodide and also later observed by Szostak in another twisted amide system (Figure 1B).7-8, 29 Due to the increased nucleophilicity of the amide nitrogen, alkylation occurred to form a transient amidinium ion. The halide counterion rebounded to quantitatively ringopen this intermediate in a mechanistic sequence reminiscent of the Arbuzov and von Braun reactions.30-31 A key driving force in this process is the rehybridization of the nitrogen atom to sp2 that regains resonance stabilization. Inspired by this reactivity, it was hypothesized that simply employing the iodide as the limiting reagent would lead to polymerization, as the product also contains a reactive primary alkyl iodide. This was of particular interest as it would generate a covalent electrophilic polymerization that possesses a living, yet isolable chain-end. (Figure 1C) The mechanism is reminiscent of oxazoline polymerization, though propagation in these systems generally proceeds through cationic intermediates.32-35 The twisted amide 1 was a byproduct produced en route to a total synthesis of stenine, which required 12 steps to prepare.36 Therefore, a more readily synthesized twisted amide structure was needed to test the Halide-Rebound

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Scheme 1. Scalable Synthesis of Twisted Amide 2. O OMe

B(OH)2 +

2.5% Pd(PPh3)2Cl2 N Na2CO3 THF/H2O, 80 ºC 90%

N

I

MeO O

Na2CO3 workup N

75%

O

3

5 wt% PtO2 H2 (1 atm) HCl

H 2N MeO O 4

2

MeOH, rt 10 gram scale

Polymerization (HaRP) concept. The twisted amide 2 was prepared by Szostak in a three step sequence based on Grigg’s earlier reports and was calculated to be significantly twisted (cN = 50.9º and t = 36.6º).37 Further, it was observed to react with simple alkyl halides in high yields, making this an ideal candidate for investigation.29, 38-40 While this preparation was expedient, the key Heck cyclization required dilute reaction conditions and purification that limited throughput to generate substantial quantities for polymerization studies, prompting the invention of a second-generation synthesis. The new synthesis was enabled by observations made after ring-opening of 2 in an acidic methanol solution to give ester 4. While the intermediate hydrochloride salt was stable, it spontaneously cyclized back to the parent monomer 2 upon neutralization.14, 41 This facile cyclization suggests that the twisted amide is geometrically destabilized, but does not possess significant ring strain. With this intermediate as a new synthetic target, a Suzuki coupling of pyridine-3-boronic acid and methyl 2-iodobenzoate was performed to give 3 in high yield. Hydrogenation under acidic conditions with Adam’s catalyst selectively reduced the pyridine ring to the piperidinium salt 4, which cyclized to 2 upon workup in 75% yield (Scheme 1).42 In addition to granting practical, multi-gram access to the monomer, this two-

Table 1. Halide-rebound polymerization of twisted amide 2 targeting different degrees of polymerization (DP) 1 equiv C12H25I

n equiv

N O

N

C11H23

I

O

CH3CH2CH2CN (2.5 M) 140-150 ºC

n

P2

2

Entry a

Target DP (n)

Temperature (°C)

Time (h)

Conversion b

Mn,theo (kg/mol) c

Mn,SEC (kg/mol) d

Ðd

1 2 3 4 5 6

10 25 50 75 100 200

140 140 140 140 150 150

12 24 30 48 52 64

98% 96% 94% 94% >95% 91%

2.1 4.8 9.4 13.5 18.1 34.4

2.1 5.1 9.4 12.1 17.3 24.5

1.21 1.20 1.20 1.26 1.26 1.46

Polymerization of 2 was carried out with 0.75 mmol scale in sealed tube; b Conversions were determined by 1H NMR of crude reaction mixture; c Mn,theo = n ´ conv. ´ M(2) + M(C12H25I); d Number average molecular weights and dispersities were determined by size-exclusion chromatography using polystyrene standards.

a


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Figure 2. (A) Size exclusion chromatograms for different DPs; (B) Mn-conversion correlation and Ð-conversion correlation; (C) First-order kinetic plot for the polymerization of 2 targeting DP 25.

step sequence also avoided the need for expensive tetrahydropyridine. With scalable access to the key monomer 2 in place, polymerization studies were undertaken with dodecyl iodide as the initiator to facilitate chain-end analysis using the isolated methyl protons. Initial studies with acetonitrile demonstrated HaRP was successful, but solubility issues prevented formation of high molecular weights and resulted in unpredictable kinetic behavior. Switching the solvent to butyronitrile gave increased solubility of the resulting polymer, P2, and permitted the reactions to be performed at a higher temperature due to the increased boiling point. In a general HaRP experiment, the monomer and initiator are simply mixed under a nitrogen atmosphere and heated for 12-64 hours at 140-150 ºC to achieve high conversion. The results of the optimized conditions are shown in Table 1. When a 50:1 ratio of monomer to initiator was employed, a unimodal polymer was observed by SEC analysis (Figure 2A) that had a number-average molecular weight (Mn) of 9.4 kg/mol and a dispersity (Ð) of 1.20 (Table 1, Entry 3). Targetable molecular weights were obtained by varying the monomer-to-initiator ratios to give series of low dispersity polymers from DP 10 to DP 100 that gave a linear increase in molecular weight while maintaining low dispersity (Figure 2B). Some broadening of the molecular weight distribution was observed at higher degrees of polymerization (Table 1, Entry 6), possibly due to chain-end decomposition or solubility issues. Proton NMR analysis of the isolated polymer displayed the expected broadening of the proton signals due to the presumably atactic backbone resulting from the use of racemic 2, and chain-end analysis was in good agreement with observed molecular weight (See Figures S1-3). Direct evidence was provided by MALDI-TOF-MS to confirm the proposed structure and the presence of the alkyl iodide chain-end after polymerization (See Figure S4). To further demonstrate the living nature of the polymerization, kinetic studies and chain-extension experiments were performed. By sampling the reaction at different time intervals, the growth of the polymers was

found to display linear first-order kinetic behavior, consistent with a living process (Figure 2C). To test the chain-end fidelity of the iodide at the end of the polymerization, chain-extension experiments were performed. Methoxy-substituted twisted amide 5, prepared in a similar fashion to 2 (Scheme S2), was subjected to the polymerization conditions using P210 as an initiator. Analysis of the diblock polymer product by size-exclusion chromatography showed the formation of a higher molecular weight species, P210-b-P540, that retained low dispersity (Figure 3). The complete shift of the elution peak suggests that the polymer maintained high chain-end fidelity. Notably, the P210 initiator was isolated through precipitation and handled in an ambient atmosphere without chain-end decomposition, highlighting the stable and living nature of the HaRP

Figure 3. (A) Synthesis of copolymer P210-b-P540; (B) Size exclusion chromatograms of macroinitiator P210 and copolymer P210-b-P540.



A.

R

R

PBu3

N

N

I

O

P2-PBu3+

OBz

O

n

n

P2-OBz O

PBu3

Ph R

N

OK

I

O n

P2

NaN3

R

N

RfSH

R

N3

O

N

SRf

O n

n

P2-N3

P2-SRf

R = -C11H23

B. MALDI-TOF

Rf = -CH2CH2(CF2)7CF3

P2-OBz DP = 11; [M+H]+ Observed: 2350.3 Expected: 2350.3 n = 11 n = 10 n = 12

∆m/z = 187.1

n = 13 n = 14 n = 15

n=8

1500

2000

2500

3000

m/z m/z

Figure 4. (A) Post-polymerization modification of iodide terminated P2; (B) MALDI-TOF spectrum of P2-OBz. method. Further experiments with the monomers 2 and 5 also showed the successful generation of copolymers (See Figure S12-13). The polymers prepared using HaRP are structurally distinct from other polymers prepared to date. This is formally a ring-opening polymerization of the piperidine ring in which a C–N cleavage occurs, so the amides are displayed as annulated side-chains and not directly in the backbone.43 This led to interest in the thermal properties of the materials. Differential scanning calorimetry (DSC) showed polymer possesses a high glass transition temperature (123 ºC, Figure S29). Further, the polymers exhibit significant thermal stability with a 10% mass loss seen at 424 ºC in a nitrogen atmosphere (Figure S28), implying future potential in high-temperature applications. The inherent versatility of the iodide chain-end was further demonstrated through a series of postpolymerization modification experiments.44 As the HaRP mechanism is simply a series of nucleophilic substitution

reactions, the halide was found to be readily displaced by a range of partners including phosphines, azides, thiols and carboxylates (Figure 4A). The substitution with potassium benzoate reinforced both the initial chain-end fidelity and the quantitative nature of the functionalization. MALDI-TOF-MS analysis of the P2OBz product displayed a single distribution of [M+H]+ molecular ions directly corresponding to the esterterminated oligomer without any of the initial iodide present (Figure 4B). Reaction with tributylphosphine cleanly delivered the ionic phosphonium chain-end in P2PBu3+. Further changes to the chain-end chemistry were easily introduced via displacement with fluorinated decanethiol to give P2-SRf. Notably, formation of P2-N3 through substitution with sodium azide provides a great handle for further integration of these materials with classical polymers through click chemistry. In conclusion, a controlled, living polymerization of twisted amide monomers is demonstrated using a haliderebound mechanism, HaRP. To reach this end, a new and scalable two-step synthesis of the twisted amide monomers was developed using cross-coupling and chemoselective arene hydrogenation. The polymers feature living alkyl iodide chain-ends that are stable to ambient conditions, in contrast to other electrophilic polymerizations known. The produced polymers are structurally distinct from other polymers prepared to-date and feature high glass transition temperatures and robust thermal stability. Future studies aim to explore new twisted amides capable of halide rebound polymerization and the post-polymerization modification of the poly(twisted amide)s towards targeted materials applications. ASSOCIATED CONTENT

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: XX. Synthetic details and spectral data (PDF) AUTHOR INFORMATION Corresponding Author

*[email protected] Author Contributions

‡These authors contributed equally. Funding Sources

No competing financial interests have been declared. ACKNOWLEDGMENT

This work was supported by start-up funds generously provided by the Georgia Institute of Technology. We acknowledge support from Science and Technology of Material Interfaces (STAMI) at GT for use of the shared characterization facility. William F. Penniman is thanked for early methanolysis studies. We thank David Bostwick for assistance in MALDI analysis. REFERENCES


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HaRP: Halide-Rebound Polymerization I R

I

N O

O twisted amide

• stable, isolable living polymer • facile postfunctionalization • thermally robust and high Tg

R

N

R

N

I

O R

N

I

N O

O n


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Halide-Rebound Polymerization of Twisted Amides | Journal of the

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