SINGLE-CHAIN PHOTOCATALYTIC NANOPARTICLES: TOWARD A …

The Pennsylvania State University

The Graduate School

SINGLE-CHAIN PHOTOCATALYTIC NANOPARTICLES: TOWARD A NEW CLASS

OF POLYMERIC NANOREACTORS

A Thesis in

Chemistry

by

Jacob Joseph Piane

© 2020 Jacob Joseph Piane

Submitted in Partial Fulfilment

of the Requirements

for the Degree of

Master of Science

December 2020

ii

The thesis of Jacob Joseph Piane was reviewed and approved by the following:

Elizabeth Elacqua Assistant Professor of Chemistry Thesis Advisor Raymond Schaak Professor of Chemistry Christian Pester Professor of Chemical Engineering Robert Rioux Professor of Chemical Engineering Phil Bevilacqua Professor of Chemistry Head of the Department of Chemistry

iii

Abstract

Approach A: Internal Crosslinker Approach B: External Crosslinker

Figure 1. General Approaches to Single-Chain Polymer Nanoparticles

Catalytic transformations are ubiquitous in the development of pharmaceuticals, complex

natural products, and materials. Despite the wide breadth of transformations currently

available to synthetic chemists, eliminating toxic waste and recovering expensive catalytic

material remains a significant bottleneck. Single-chain polymer nanoparticles (SCNPs)

have emerged as a class of confined nanomaterials consisting of intramolecularly cross-

linked polymers (Figure 1).1 Chain collapse is either achieved by direct cross-linking of

side chains through the introduction of an external stimuli such as heat or light, or it is

induced upon introduction of a cross-linking agent. The confined nature of these materials

enables the incorporation of discrete catalytic domains that are often analogized to the

active sites of enzymes.2 The polymeric structure provides a platform that is easily

solubilized and also removed and recycled from the final reaction mixture.3 This work

focuses on broadening the types of transformations that are available using SCNP

catalysts. This is achieved by developing new SCNP catalysts that contain common

iv

small-molecule catalysts as pendant groups and act as the polymer “active site.” One

class of the target nanoparticles consists of a poly(methylmethacrylate) backbone with

dipyrrin ligands as pendant groups. These polymers were prepared with the goal of

developing a user-friendly platform for ligand diversification. This would facilitate the

optimization of transition metal catalyzed reactions using recyclable, homogeneous

polymer-supported catalysts.

The other targeted nanoparticles consisted of a methyl methacrylate backbone

randomly copolymerized with a 2,4,6-triphenylpyrylium tetrafluoroborate derived

comonomer, which formed the catalytically active domain, and a styrylpyrene derived

comonomer, which acted as a cross-linking agent upon visible light irradiation.4 These

polymers were prepared with the goal of developing the first photocatalytic SCNPs using

a common, easily prepared photocatalyst. The catalytic activity of these SCNPs was

demonstrated in the photocatalyzed amidation of benzaldehyde derivatives. Further, the

SCNPs were interrogated for cooperative catalysis in the metal-free dimerization of

electron-rich styrenes. In these studies, the SCNP demonstrated accelerated rates

compared to both monocatalytic polymers and small molecules, while maintaining product

selectivity in the dimerization of trans-anethole. The enhanced rates were ascribed to the

ability of the SCNP to induce colocalization of cooperative catalysts under confinement,

which in turn, allowed for enhanced single-electron transfer between the TPT

photocatalyst and pyrene-based electron-relay catalyst.

v

Table of Contents

List of Figures vii

List of Schemes viii

List of Tables x

Chapter 1: Introduction 1

1.1 Homogeneous and Heterogeneous Catalysis 1

1.2 Supramolecular Catalysis: Homogeneous Catalysis with Product Selectivity and

Rate Enhancements 3

1.3 Polymer-Based Catalysts 6

1.4 Single-Chain Polymer Nanoparticles as Catalysts 7

1.5 Thesis Overview 9

Chapter 2: Dipyrrin SCNPs – A Versatile Platform for Rational Ligand Design 10

2.1 Background and Introduction 10

2.2 General Design of Dipyrrin Pendant Groups 11

2.3 Design of Dipyrrin Polymers 13

2.4 Ongoing and Future Work 17

Chapter 3: Photocatalytic SCNPs 19


3.2 Photocatalytic Polymer Design 20

3.3 Photocatalytic SCNP Design 22

vi

3.4 Photocatalyzed Amidation of Benzaldehyde Derivatives 23

3.5 Future Directions 31

Chapter 4: Accelerated Dual Photoredox Catalysis Under Confinement 32


4.2 Cocatalytic Polymer Design 35

4.3 [2+2] Cyclodimerization of Electron-Rich Styrenics 41

4.4 Future Directions 46

Chapter 5: Ongoing and Future Work 47

5.1 Water-Soluble SCNPs as Sustainable Nanoreactors 47

5.2 Enabling Tandem Reactions with Multi-Domain SCNPs 48

5.3 Transient Radical Capture with Covalently Linked Catalysts 49

5.4 Facilitating Dual Nickel-Photoredox Catalysis with SCNPs 51

Appendix: Experimental 54

References 68

vii

List of Figures

Figure 1. General Approaches to Single-Chain Polymer Nanoparticles iii

Figure 2. Asymmetric Aza-Cope rearrangement catalyzed by supramolecular tetrahedral cage 5

Figure 3. Enantioselective intramolecular cyclization in aqueous media 6

Figure 4. Differences between molecular catalysts and catalytically-active SCNP

nanoreactors 8

Figure 5. Proposed Mechanism of Photocatalyzed Oxidation of Benzyl Alcohols 28

Figure 6. Confined environments from (top) M4L6 MOC that facilitates an Aza-Prins cyclization,

and (bottom) Ni/Ir-MOF for dual photoredox catalysis 33

Figure 7. Design of Cooperative Photoredox-Enabled SCNPs for [2+2] Cycloadditions 45

Figure 8. Design of Water Soluble SCNPs 48

Figure 9. Dual Nickel-Photoredox Catalysis in Confinement 50

Figure 10. Cocatalysis in Single-Chain Polymer Confinement 52

viii

List of Schemes

Scheme 1. Radical Precursors in Photoredox Catalysis 2

Scheme 2. Single-Chain Polymer Nanoparticles as Homogeneous Catalysts 10

Scheme 3. Synthesis of Aryl Dipyrromethanes 12

Scheme 4. Oxidation and Chlorination of Dipyrromethanes 12

Scheme 5. Synthesis of Dipyrrin Monomers by Nucleophilic Aromatic Substitution and

Nucleophilic Acyl Substitution 13

Scheme 6. Synthesis of Two Carbon Linker by Nucleophilic Acyl Substitution 14

Scheme 7. Synthesis of Dipyrrin Monomers by Deboronation of BODIPY 15

Scheme 8. Cross-Linking Strategy for Dipyrrin Polymers 18

Scheme 9. Synthesis of Triarylpyrylium Acrylate and Methacrylate Monomers 21

Scheme 10. Synthesis of Styrylpyrene Methacrylate Monomer 22

Scheme 11. Cross-Linking of TPT-co-SP Polymers by Photochemical [2+2] Cyclodimerization 23

Scheme 12. Random Copolymerization of Styrylpyrene Methacrylate with Triarylpyrylium and

Methyl Methacrylate 25

Scheme 13. Scope of oxidation reactions. (A) Scope of oxidation of benzyl alcohols. (B)

Amidation of 4-bromobenzaldehyde. a Yields determined by proton NMR spectroscopy

Using 1,3,5-trimethoxybenzene as an internal standard. b Reaction conducted in a

1 dram vial 27

Scheme 14. Copolymerization of Styrylpyrene Methacrylate with Triarylpyrylium and Methyl

ix

Methacrylate and Characterization 37

Scheme 15. [2+2] Cycloadditions of styrenyl derivatives through TPT-SCNP-catalyzed

photoinduced-electron transfer 38

Scheme 16. Cross-Dimerization of Styrene with Trans Anethole 43

Scheme 17. Synthesis of Tethered Catalyst by EDC Coupling 51

Scheme 18. Synthesis of bifunctionalized monomer toward dual nickel-photoredox catalysis 53

Scheme S-1. Synthetic route for the photocatalyst TPT-based monomer 58

x

List of Tables

Table 1. Molecular Weight and Dispersity of Activated Ester Polymers 16

Table 2. Optimization of Small Molecule and Polymer-Based Amidation of

4-Bromobenzaldehyde 30

Table 3. Comparison of Monocatalytic Polymer Systems with Small-Molecule ER or TPT in the

[2+2] Dimerization of Anethole 40

Table 4. Comparison of Monocatalytic Polymer Systems with Small-Molecule ER or TPT in

[2+2] Cross-Dimerizations with Anethole 44

Table S-1. Optimization of Cyclodimerization 65

1

Chapter 1

Introduction

Novel synthetic methods enable the preparation of structurally diverse molecules

with a variety of applications including pharmaceuticals, materials, plastics, flavors, and

fragrances. Catalytic transformations facilitate challenging transformations proceeding

through lower energy transition states and intermediates than their analogous

uncatalyzed processes, providing access to structural motifs that would require harsh

conditions or multiple steps to install, or that are otherwise impossible to form. Rational

design of catalysts lies at the heart of organic methodology development. Structural

nuances in catalysts enable unique reactivity, and affect properties such as solubility

profile, accessible redox states, and substrate selectivity.

1.1 – Homogeneous and Heterogeneous Catalysis

Two common modes of catalysis are homogeneous and heterogeneous, and each

possesses a unique set of benefits and drawbacks. Homogeneous systems typically

enjoy a higher degree of selectivity, but are often based on toxic transition metal species

that can be difficult to remove after reaction completion. In contrast, heterogeneous

catalysts can often be easily removed from final reaction mixtures, potentially eliminating

toxic waste and saving costs, but lack the synthetic versatility of homogeneous catalysts.5

2

Important advances in each of these categories have yielded powerful strategies

to construct carbon−carbon and carbon−heteroatom bonds. In 2010, the Nobel Prize in

chemistry was awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki for the

development of palladium-catalyzed cross-couplings. The Heck reaction enables

vinylation of aryl halides with terminal olefins.6 The Suzuki and Negishi reactions form

biaryls by coupling aryl halides with aryl boronic acids7 and aryl zinc halides,8 respectively.

More recent advances have broadened the utility of these classic transformations to

encompass a variety of functional groups and electrophilic coupling partners. Additionally,

carbon−heteroatom bonds can be forged using Ullman9 or Buchwald-Hartwig10 coupling.

More recently, photoredox catalysis has emerged as a powerful method for

generation of radicals under mild reaction conditions.11, 12, 13 Traditional methods for

generating radicals rely on toxic and hazardous reagents such as organotin species and

peroxides, or harsh conditions including high temperature and high energy UV irradiation.

In contrast, photoredox catalysis enables the generation of reactive radical species at

ambient temperature without the use of harmful radical initiators upon visible light

irradiation.

Scheme 1. Radical Precursors in Photoredox Catalysis

3

Since 2008, a bevy of functional groups have been exploited as radical precursors

based on single-electron redox chemistry (Scheme 1). Pioneering work from the groups

of MacMillan and Yoon revealed the ability of Ru(bpy)3 to catalyze the alkylation of

aldehydes14 and [2+2] enone cycloadditions,15 respectively. In addition to these seminal

contributions, MacMillan has developed a variety of methods using carboxylic acids as

radical precursors.16 Molander and coworkers have demonstrated the utility of organo

trifluoroborates as activating groups.17 Aliphatic halides and alcohols are among other

functional groups utilized in photoredox catalysis.18, 19

1.2 − Supramolecular Catalysis: Homogeneous Catalysis with Product Selectivity

and Rate Enhancements

High substrate selectivity and molecular recognition makes supramolecular

chemistry attractive for applications in catalysis. Byproducts in catalytic reactions are

often produced as a result of competing reactions occurring within a mixture. One

common example in synthetic chemistry is the palladium catalyzed Suzuki-Miyaura cross-

coupling reaction, in which a new C—C bond is formed from a carbon-halide and boronic

acid. In this reaction, significant amounts of homo-coupled boronic acid is often

observed.20

Supramolecular catalysis seeks to minimize the impact of competing reactions by

selectively binding substrates in a manner that promotes the desired reactivity. Ideally,

binding of the guest molecule will orient the substrate in a manner that facilitates the

formation of the transition states required for productive reactivity, thus minimizing the

2

energy required to form target products. In nature, enzymes serve as highly selective

supramolecular host molecules. Each enzyme contains a binding pocket capable of

recognizing a specific molecule in biosynthetic and metabolic pathways. Biocatalytic

systems rely on well-defined architectures to carry out a very specific function with a high

degree of efficiency, yet they are often limited by their native functions. The substrate

specificity of enzymes makes them ideal catalysts and serves as a naturally occurring

prototype for synthetic supramolecular catalysis.21

Asymmetric transformations are ubiquitous in biological systems and are highly

sought after in synthetic chemistry. According to Njardarson and coworkers, eleven of the

top 200 pharmaceutical products prescribed in 2016 possess one or more

stereocenters.22

Enantiomerically impure forms of pharmaceutical agents may lead to undesired

and often devastating side effects, as was the case with the morning sickness drug

Thalidomide during the 1950s.23 Enzymes produce enantiomerically pure products due

to well-defined three-dimensional architectures consisting of chiral supramolecular

binding pockets. Synthetic chemists have used enzymes as model systems in the

development of asymmetric catalysts. Despite the vast wealth of research associated

with asymmetric synthesis of small molecules, the preparation of materials with well-

defined architecture is not yet fully understood. The best examples of large molecules

with highly specific three-dimensional structures are naturally-occurring biological

macromolecules including proteins, DNA, and RNA. The ability to incorporate higher

order structures into synthetic products is an important step towards mimicking the

5

important functions of biomolecules, and unlocks new avenues in the context of

nanomedicine and small molecule synthesis.

In 2012, the Meijer group described a new method for preparing helical self-

assembled stacks. Chirality was induced within the helical stacks by introduction of a

supramolecular auxiliary. Auxiliary molecules were recovered upon removal with no

change to the helical structure of the stacked assembly. D- and L- helices were selectively

prepared depending on the orientation of the chiral auxiliary.24

The interplay between transition metal complexes and supramolecular cages has

been studied in the

context of

enantioselective

catalysis. Tetrahedral

cage complexes have

been particularly useful

in asymmetric

catalysis. Raymond

and coworkers

reported the

preparation of

diastereotopic metal-ligand complexes in which cationic ruthenium species were

encapsulated in tetrahedral [Ga4L6] cage complexes with diastereomeric excess up to

70%.25 This was achieved using chiral host and guest molecules. These tetrahedral

Figure 2. Asymmetric Aza-Cope rearrangement catalyzed by supramolecular

tetrahedral cage

6

complexes were later shown to catalyze the Aza-Cope rearrangement with up to 64% ee

(Figure 2).26

Seeking to extend the reactivity of chiral tetrahedral cages, the Raymond group

developed a new method for preparing cage complexes with improved stability in acidic

environments, low susceptibility to oxidation, and better reactivity towards neutral

substrates. Additionally, this new generation of chiral tetrahedral cage complexes are

prepared as single diastereomers. This is achieved by incorporation of an amide-

containing chiral directing group (Figure 3). The ability to encapsulate neutral substrates

is a vast improvement from the previous generation of host molecules, which required a

cationic guest to

displace the

cationic species

responsible for holding the assembly together. To further demonstrate the utility of these

supramolecular hosts as catalytic species, Raymond and coworkers demonstrated the

enantioselective cyclization of neutral substrates in aqueous media. Hydrophobic

interactions within the core of the cage allows substrate encapsulation, creating a high

local concentration of reactive species and greatly accelerating reaction rates. This

reaction proceeded in yields up to 94% and ee as high as 69%.27

1.3 − Polymer-Based Catalysts

Continuing advances in catalyst design enable challenging transformations under

mild conditions. Current efforts to minimize toxic waste generated from catalysts involves

Figure 3. Enantioselective intramolecular cyclization in aqueous media

7

the use of heterogeneous catalysts, including metal-organic frameworks, catalyst

functionalized surfaces, and polymer-supported catalysts. However, heterogeneous

catalysts often suffer in terms of efficiency when compared to their homogeneous

counterparts and require harsher conditions to observe similar reactivity.28

Polymer-supported catalysts are a particularly intriguing class of catalysts in terms

of their versatility. For instance, polymeric materials are not inherently insoluble. In fact,

their solubility can be conveniently tuned by simply changing the backbone or

incorporating solubilizing comonomers. In contrast, the solubility of small-molecule

catalysts cannot be easily changed without altering the catalytic activity of the molecule.

Polymer-supported catalysts provide a method of solubilizing catalysts that is

unparalleled in small-molecule systems.

1.4 − Single-Chain Polymer Nanoparticles as Catalysts

Single-chain polymer nanoparticles (SCNPs) represent a class of nanomaterials

consisting of intramolecularly cross-linked polymers.1 Cross-linking under high dilution

diminishes the probability of intermolecular cross-linking to the point where only intrachain

cross-links are present. Pendant groups can either cross-link directly upon introduction of

external stimuli (heat, light, etc.), or by binding to an external molecule.29 The

compartmentalized structure of SCNPs have inspired the development of drug delivery

vehicles, molecular sensing, and biomimetic catalysis.30 The ability to tune the solubility

of SCNPs makes them particularly intriguing for applications in catalysis (Figure 4).

8

Figure 4. Differences between molecular catalysts and catalytically-active SCNP nanoreactors. In (A), product ratios are affected in a cross-coupling reaction utilizing a SCNP-based catalyst. In (B), substrate selectivity is observed in oxidative coupling. (Adapted with permission from ref 3. Copyright 2018, American Chemical Society).

Lemcof demonstrated bimetallic cross-couplings using poly(cyclooctadiene)

complexed with iridium and rhodium.31 CuII-based SCNPs were employed for the

selective oxidative coupling of terminal alkynes32 and separately for carbamate cleavage

reactions of mono-protected rhodamines33 by the groups of Pomposo and Meijer,

respectively. Barner-Kowollik and coworkers have demonstrated how tunable solubility

facilitates catalyst recyclability under homogeneous conditions using Pt(PPh3)2 SCNPs to

catalyze the amination of allyl alcohol.34 This strategy combines the benefits of high

efficiency and mild reaction conditions observed in solution with the ease of purification

and reusability of heterogeneous catalysts. In 2019, Zimmerman and coworkers

developed CuI SCNPs capable of accelerating click reactions for modification of

proteins.35

9

1.5 − Thesis Overview

This thesis describes the preparation and use of functionalized single-chain

polymer nanoparticles as compartmentalized catalysts. In Chapter 2, the synthesis of

dipyrrin-functionalized SCNPs is described. These polymer nanoparticles are intended to

serve as a diverse set of ligands to aid the optimization of SCNP-catalyzed cross-coupling

reactions. In Chapter 3, the synthesis of photocatalytic SCNPs bearing pyrylium pendant

groups is described. Their use as catalysts for the oxidation of benzyl alcohols and

amidation of benzaldehydes are described. In Chapter 4, these bifunctionalized

photoredox catalytic SCNPs were used for the dual catalyzed [2+2] dimerization of

electron rich styrene derivatives, wherein it was found that cocatalysis was accelerated

under confinement in comparison to combinations of small molecules and monocatalytic

polymers. Future directions of these projects are described in Chapter 5, including

cooperative catalysis using tethered small-molecule catalysts, tandem catalysis in

SCNPs bearing multiple catalytic domains, and extending these catalytic paradigms to

aqueous media by exploiting the unique control of solubility demonstrated within polymer

systems.

10

Chapter 2

Dipyrrin SCNPs – A Versatile Platform for Rational Ligand Design

2.1 – Background and Introduction

While ligand selection plays a key role in optimization of catalytic transformations,

most SCNP catalysts contain ligands that are not easily derivatized. SCNPs have been

used for Ir/Rh cross-couplings (Scheme 2A)36 and for the amination of allyl alcohol

(Scheme 2B).34 We are developing a user-friendly platform by which a broad range of

ligands with varying steric and electronic properties can be incorporated in an SCNP

framework (Scheme 2C).

Scheme 2. Single-Chain Polymer Nanoparticles as Homogeneous Catalysts

11

Building on the work of Barner-Kowollik and coworkers, we have begun preparing

a new class of ligands to incorporate into single-chain polymer nanoparticles. Dipyrrins

were selected as ligands, which consist of two pyrrole subunits and an aryl ring at the 5-

position. These were selected due to ease of preparation, providing a modular approach

to rational ligand design while aiding in the optimization of catalytic transformations using

SCNPs. We have prepared a variety of 5-aryl dipyrrins. Ongoing efforts seek to optimize

the attachment of these dipyrrins to polymers and cross-link them using a variety of

transition metals. Once the cross-linked SCNPs have been formed, their utility will be

demonstrated in the optimization of a biaryl Suzuki-Miyaura cross-coupling reaction.

2.2 – General Design of Dipyrrin Pendant Groups

Dipyrromethanes are prepared by the acid-catalyzed condensation of aryl

substituted benzaldehydes in a large excess of pyrrole (Scheme 3).37 The broad

commercial availability of benzaldehyde derivatives provides excellent control over steric

and electronic effects at the aryl position. Preparation of chlorinated 5-aryl dipyrrins from

dipyrromethanes is well reported in good yields.38 We have synthesized dipyrrins with a

variety of electronic and steric effects by in situ chlorination using N-chlorosuccinimide

and oxidation with DDQ (Scheme 4). Mono substitution of chlorinated dipyrrins by

nucleophilic aromatic substitution with secondary amines proceeds in excellent yields,

which is attributed to a drastic increase in electronegativity at the other chlorinated

position in the molecule upon nucleophilic addition of the amine (Scheme 5). We elected

to use methylethanolamine as a means to attach the dipyrrin ligands to the polymer

scaffold.

12

Scheme 3. Synthesis of Aryl Dipyrromethanes

Scheme 4. Oxidation and Chlorination of Dipyrromethanes

13

From here, two approaches were taken to incorporate dipyrrins within polymeric

systems. The first approach was an attempt to directly, randomly copolymerize dipyrrin-

derived acrylate ligands. The second approach was to attach dipyrrins to activated ester

polymers post-polymerization.

2.3 – Design of Dipyrrin Polymers

Scheme 5. Synthesis of Dipyrrin Monomers by Nucleophilic Aromatic Substitution and Nucleophilic Acyl Substitution

For the direct, random copolymerization of dipyrrins with methyl acrylate, it was

necessary to design dipyrrin monomers bearing an acrylate functionality. A few

approaches were taken to functionalize dipyrrins with acrylates. The first approach was

to allow alcohol- functionalized dipyrrins to react with acroloyl chloride in a nucleophilic

acyl substitution (Scheme 5). This resulted in substitution at both the alcohol and the

nitrogen of one of the pyrrole rings. Given the necessity of the unsubstituted nitrogen for

metal coordination, this approach was unfit for preparing dipyrrin monomers.

14

Scheme 6. Synthesis of Two Carbon Linker by Nucleophilic Acyl Substitution

Another strategy involved the convergent synthesis of chloro-substituted dipyrrins

and acrylate linkers (Scheme 6). Linkers were prepared from aminomethyl ethanol in

three steps. The amino position of the linker was first protected with either tert-

butylcarbonyl (boc) or fluorenylmethyloxycarbonyl (fmoc) protecting groups. Nucleophilic

acyl substitution with acroloyl chloride yielded the N-protected acrylate linker. In the case

of both protected linkers, deprotection of the nitrogen resulted in oxidation of the acrylate

functional group.

The third strategy involved the preparation of boron-dipyrromethanes (BODIPY) to

mask the nucleophilic nitrogen atoms of the dipyrrin while adding acroloyl chloride

(Scheme 7). BODIPY complexes were prepared from linker-substituted dipyrrins, which

were then allowed to react with acroloyl chloride in a similar fashion to the original

strategy. Next, the boron difluoride coordinating group was removed in the presence of

the Lewis acid zirconium(IV) chloride. With the desired dipyrrin monomer in hand, random

co-polymerization with methyl acrylate by reversable addition fragmentation chain-

transfer polymerization (RAFT) was carried out. Unfortunately, this resulted in the

oxidation of dipyrrin, likely at the chlorinated 2-position, rather than polymerization.

15

Scheme 7. Synthesis of Dipyrrin Monomers by Deboronation of BODIPY

Given the difficulties with carrying out direct polymerization of dipyrrin-containing

monomers, we attempted to attach dipyrrins by post-polymerization functionalization.

Activated ester functionalized polymers were prepared in varying molecular weights

bearing succinimide and pentafluoroaryl ester pendant groups as 10% of the polymer

(Table 1).

16

Table 1. Synthesis and Characterization of Activated Ester Polymers

Nucleophilic acyl substitution of hydroxy dipyrrins with activated ester

functionalized polymers proved difficult and led to low incorporation of dipyrrins. In order

to increase the electrophilicity of activated ester pendant groups, several Lewis acids and

bases were evaluated in the post-polymerization modification by nucleophilic acyl

substitution at varying temperatures. Polymers were isolated by precipitation in methanol

and subsequent centrifugation.

After running duplicate experiments, zirconium (IV) chloride was found to yield the

highest yield of substitution. Yields also increased at 60 °C compared to room

temperature, but were not significantly affected when switching between triethylamine

17

and diisopropyl ethylamine as bases. When zirconium (IV) chloride was used as a Lewis

acid at 60 °C, a 30% yield was observed, which translates to 3% incorporation of dipyrrin

into the polymer.

After scaling up the post-polymerization functionalization, it was observed that

upon filtering the dipyrrin functionalized polymer, a red filtrate was obtained. It was

hypothesized that precipitation in methanol had led to removal of dipyrrin pendant groups

and incorporation of methanol in the polymer side chain. Indeed, when switching from

methanol to diethyl ether as the precipitating solvent, incorporation of dipyrrin increased

from 3% to 8%.

2.4 – Ongoing and Future Work

With the desired dipyrrin polymers in hand, cross-linking studies will be conducted

using a variety of metal precursors (Scheme 8). Metal-dipyrrin SCNPs will be prepared

by slow addition of dilute metal solutions (e.g., Pd- or Ni-based species) to dilute solutions

of dipyrrin polymers. Preliminary attempts to crosslink the polymer using Pd appeared to

cleave the perfluoroaryl dipyrrin from the chain, suggesting other metals or methods of

crosslinking will have to be optimized. Slower additions can be achieved under inert

atmosphere using a syringe pump, and solvent screening along with different

concentrations of both metal and linear polymer will be interrogated for optimal SCNP

formation. Successful SCNP formation can be observed using 1H NMR spectroscopy, in

combination with GPC and DOSY measurements (which can give more information on

molecular weights before and after crosslinking, as well as confirm controllable

18

crosslinking). Once optimal conditions for cross-linking are found, we will begin studying

the catalytic properties of the resulting nanoparticles. A variety of dipyrrin SCNPs will be

prepared and used in the optimization of a biaryl Suzuki-Miyaura cross-coupling reaction,

wherein it is anticipated that metal-coordination with slightly different ligands that can tune

catalytic activity. Specifically, the small structural changes will affect the rate of the

elementary steps in cross-coupling reactions.

Scheme 8. Cross-Linking Strategy for Dipyrrin Polymers

O

O

O

O

eN

N e

19

Chapter 3

Photocatalytic SCNPs

A portion of this chapter has been submitted for publication, and is in review at the

time of submitting this thesis [J. J. Piane, L. T. Alameda, L. E. Chamberlain, A. C. Hoover,

E. Elacqua, 2020, submitted].


Homogeneous catalysis enables important transformations in organic synthesis

that facilitate drug discovery, natural products synthesis, and materials design. While

solution-based catalysts have been shown as efficient methods for producing target

molecules, they often lack selectivity and require the use of expensive, harmful transition

metals which ultimately turn into waste. Small molecule catalysts are also often difficult

to separate from desired products, requiring extensive purification. Single chain polymer

nanoparticles (SCNPs) have recently been introduced as attractive alternatives to

traditional small-molecule catalysts. SCNPs enjoy the benefit of well-defined,

compartmentalized structures, which enable a high degree of selectivity similar to that

seen in enzymes. Due to their tendency to aggregate in poor solvents, SCNP catalysts

are easily removed from reaction mixtures and may be reused, providing a greener route

to synthetic targets.

Major developments in photoredox catalysis has enabled generation of radicals

under mild reaction conditions.11, 12, 13 Despite the overwhelming surge in interest in the

development of new synthetic methods using photoredox catalysis, a major bottleneck

20

remains in the purification of these processes. Often, removal of expensive and

sometimes toxic catalytic material is challenging, particularly when operating under

homogeneous reaction conditions.39 We envision a new approach towards tandem

catalysis using SCNPs that feature two distinct catalytic domains. Embedding a

photocatalytic and cross-coupling domain into the same SCNP will provide a novel

approach to achieve tandem reactions utilizing a single catalyst. We anticipate that the

reactivity of this catalyst will be controlled depending on the presence or absence of

visible light. Additionally, our SCNP catalysts may be easily removed from the reaction

mixture by precipitation in polar organic solvents, and can be recycled for further

reactions.

This work seeks to develop a fully recyclable, homogeneous organic photocatalyst

using the organic dye 2,4,6-triphenylpyrylium tetrafluoroborate (TPT) as a photocatalyst.

Towards this goal, single-chain polymer nanoparticles bearing pendant TPT functional

groups were prepared. The utility of these SCNP phootocatalysts was highlighted in the

photocatalyzed the amidation of benzaldehyde derivatives.

3.2 – Photocatalytic Polymer Design

Pyrylium salts are prepared by a Lewis acid catalyzed condensation of

benzaldehyde derivatives with acetophenone derivatives.40 TPT containing polymers

were prepared from by random copolymerization of TPT methacrylate with methyl

methacrylate (MMA) and a styrylpyrene derived methacrylate. The target monomer

incorporation ratios are 5% TPT, 5% styrylpyrene, and 90% MMA.

21

Scheme 9. Synthesis of Triarylpyrylium Acrylate and Methacrylate Monomers

TPT methacrylate monomers were prepared in two steps from 4-

hydroxybenzaldehyde and acetophenone (Scheme 9). First, 4-hydroxybenzaldehyde was

allowed to react with methacroloyl chloride, giving 4-formylphenyl methacrylate in 91%

yield. A subsequent Lewis-acid catalyzed condensation with two equivalents of

acetophenone gives TPT methacrylate as a yellow, bench stable powder in 29% yield.

Styrylpyrene was selected as a comonomer due to its ability to cyclodimerize upon

visible light irradiation, as well as its ability to act as an electron relay for the highly

oxidizing TPT photocatalyst.25 The styrylpyrene-derived comonomer was prepared in two

steps from 1-bromopyrene in a convergent route consisting of three total synthetic steps

(Scheme 10). 1-bromopyrene was allowed to react with 4-vinylphenylacetate in a

palladium catalyzed Heck cross-coupling to give 1-(4-hydroxyvinylphenyl)pyrene in 31%

yield as a chalky yellow powder. A short hydrocarbon linker was prepared in 78% yield

by nucleophilic acyl substitution of 2-hydroxyethylmethacrylate with 5-bromovaleryl

chloride. Nucleophilic substitution of 1-(4-hydroxyvinylphenyl)pyrene into the brominated

position of the newly formed linker provided the styrylpyrene-derived monomer in 74%

yield as a yellow powder.

22

Scheme 10. Synthesis of Styrylpyrene Methacrylate Monomer

3.3 – Photocatalytic SCNP Design

Random copolymers of TPT meth acrylate, styrylpyrene, and methyl methacrylate

were prepared by RAFT polymerization. Photocatalytic polymers with target molecular

weight of 25-35 kDa. Nanoparticle formation was achieved by irradiation with white light

(Scheme 11). The formation of nanoparticles was determined through a combination of

UV-Vis spectrometry and gel permeation chromatography.

23

Scheme 11. Cross-Linking of TPT co SP Polymers by Photochemical [2+2] Cyclodimerization

3.4 – Photocatalyzed Oxidation of Benzyl Alcohols

Single-chain polymer nanoparticles (SCNPs) are compartmentalized

nanostructures that result from intramolecular cross-linking under high dilution.1 The

confined nature of SCNPs has been exploited in biomimetic catalysts.30 The ability to tune

the solubility of SCNPs with careful selection of comonomers addresses major

bottlenecks in sustainable catalysis, including catalyst recovery and improved reactivity

in aqueous media. Moreover, the substrate specificity that arises from the intrinsic

properties of discretely-folded polymer nanoparticles such as hydrophobicity and

supramolecular binding cavities is reminiscent of enzyme catalysis.41 The three-

dimensional architecture of SCNPs allows catalysts to be placed in close proximity to one

another in a single macromolecule, facilitating dual catalysis that bypasses the diffusion

limitations inherent to small-molecule catalytic systems.

24

Photoredox catalysis has emerged as a powerful method for generation of radicals

under mild reaction conditions.42, 43 Traditional methods for generating radicals rely on

toxic and/or hazardous reagents (e.g., organotin species and peroxides), or harsh

conditions including high temperature and high energy UV irradiation, along with high

catalyst loadings. In contrast, photoredox catalysis enables the generation of a reactive

radical species at ambient temperature without the use of harmful radical initiators upon

visible light irradiation. Recently, Palmans and coworkers utilized phenothiazine-

functionalized amphiphilic SCNPs as reductive photoredox catalysts as a stimuli-

responsive catalytic platform that moves toward sustainable and biomimetic catalysis.

The catalytic activity was demonstrated through the oxidation of benzyl alcohols under

ambient conditions. The synthetic utility of this transformation, in concert with the

versatility of the SCNP photoredox catalyst, was further highlighted in a photocatalyzed-

amidation of benzaldehyde derivatives, which proceeds through a transient aminal

intermediate and subsequent photocatalyzed-oxidation to yield the desired benzamide.

Triarylpyrylium salts are potent photooxidants, with an excited state potential of

+1.9 V vs. SCE for the parent compound 2,4,6-triphenylpyrylium tetrafluoroborate

(TPT).43 Triarylpyrylium salts are synthesized in one step from benzaldehydes and

acetophenones, providing facile access to photocatalysts with varying electronic nature

and therefore tunable redox potentials. This, in conjunction with the absence of precious

metals such as ruthenium and iridium that are present in many common photoredox

catalyst systems, provides a highly tunable and sustainable platform for achieving

photocatalyzed oxidations.

25

Key to our design is the use of styrylpyrene (SP) as a tactical component; facile

visible-light-mediated intramolecular cross-linking of SP-containing polymers at high

concentrations relative to other crosslinking methods has been reported.4 Given reports

suggesting polycyclic compounds are broadly capable of acting as electron relay catalysts

in photoredox systems,44, 45 we sought to introduce SP has a dual-functional unit. In our

design, SP first partakes in covalent crosslinking to enable a confined SCNP structure,

while subsequently acting as an electron relay catalyst in the targeted photooxidative

reactions. Our strategy realizes a dual organocatalytic SCNP in which the two catalysts

are contained within the same polymer framework, which enables their proximal

confinement, while decreasing the diffusion requirements inherent to small-molecule

catalytic systems.

Scheme 12. Random Copolymerization of Styrylpyrene Methacrylate with Triarylpyrylium and Methyl Methacrylate

A backbone of methyl methacrylate (MMA) was selected for the photocatalytic

SCNPs to facilitate their solubility in organic solvents. Polymers targeting 90:5:5

[MMA]:[TPT]:[SP] were prepared by reversible addition-fragmentation chain-transfer

polymerization (RAFT) with target molecular weight of 25-35 kDa (Scheme 12). Briefly,

methyl methacrylate, SP, and TPT were combined in dimethylformamide with AIBN as a

radical source and 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid as

the RAFT chain transfer agent. The reaction was heated at 80 °C for 24 hours. The

26

polymerization was quenched, and the resulting polymers were purified through

reprecipitation in ether and methanol. Characterization using 1H-NMR spectroscopy

revealed with 6% of the polymer consisting of the TPT photocatalyst, 4% SP, and 90%

MMA. The incorporation ratio was determined by proton NMR spectroscopy, with

characteristic, broad ether methylene peaks from SP at 4.26 ppm and 4.14 ppm and the

methyl ester of MMA appearing at 3.55 ppm. The percent incorporation of TPT

photocatalyst was determined by the remaining aromatic protons not attributed to

styrylpyrene. Size-exclusion chromatographic analysis in THF revealed the polymer to be

well-defined (Đ = 1.10-1.12) with a molecular weight of 30.7 kDa.

Formation of the photoredox-active SCNPs was achieved by a [2+2]

cyclodimerization of styrylpyrene pendant groups. The linear polymer precursor was

covalently crosslinked through irradiation with a white household CFL for 1 hour at a

concentration of 10 mg/mL in acetonitrile. Successful cross-linking was confirmed by

UV/vis spectroscopy. Specifically, a decreased absorption was observed at 391 nm in

the UV-Vis spectrum, attributed to a loss in conjugation upon dimerization and

concomitant cyclobutane formation. No significant increase in molecular weight or

dispersity was observed by GPC, suggesting that cross-linking occurred intramolecularly.

The synthetic utility of these polymer nanoparticles was first demonstrated in the

oxidation of benzyl alcohols to the respective aldehyde (Scheme 13). The oxidation

occurs with 7.5 mol % of the photocatalyst with respect to equivalents of catalytic

subunits. After assessing solvents, dichloromethane was selected as the ideal solvent for

the oxidation, while cross-linking was achieved in acetonitrile. In a typical experiment, the

benzyl alcohol was added to a 0.2 M solution of the crosslinked TPT-SCNP in a 20 mL

27

vial. The vial was irradiated with a 427 nm Kessil lamp for 1 hour with stirring. The

reactions were complete after one hour of irradiation, and were terminated by rotary

evaporation of the solvent in the dark. The oxidation product was not observed when a

copolymer of TPT and MMA was used in the absence of any electron relay catalyst.

Scheme 13. Scope of oxidation reactions. (A) Scope of oxidation of benzyl alcohols. (B) Amidation of 4-bromobenzaldehyde. a Yields determined by proton NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. b Reaction conducted in a 1 dram vial

Visible light photoredox catalysis using photocatalytic SCNPs enabled the

oxidation of a variety of benzyl alcohols in good yields. Our catalyst system is capable of

oxidizing a variety of electron rich benzyl alcohols in good yields, while more challenging

28

electron deficient substrates proceeded with decreased efficiency. In the case of primary

benzyl alcohols, only the corresponding benzaldehydes were observed without any over-

oxidation to the benzoic acid. These polymeric catalysts also facilitate the oxidation of

secondary benzyl alcohols to their respective ketone.

Figure 5. Proposed Mechanism of Photocatalyzed Oxidation of Benzyl Alcohols

We hypothesized that the photocatalyzed oxidation of benzyl alcohols proceeds

first through excitation of the pyrylium photocatalyst upon visible light irradiation. Pyrylium

then activates the electron relay catalyst through a single electron oxidation, yielding

pyrene cation radical as the active oxidant. Pyrene may then oxidize the benzyl alcohol

to the corresponding arene cation radical, which is further oxidized to the desired

benzaldehyde by oxygen. The role of oxygen was apparent from improved yields upon

increasing the size of the reaction vessel. Upon oxidation with oxygen, hydrogen peroxide

29

is generated in situ, which may also serve as an oxidant in this system. The resulting

benzaldehyde cation radical is oxidizes reduced TPT to turn over the catalytic cycle and

give the product (Figure 5).

Intrigued by the oxidation results, we postulated that a photocatalyzed-amidation

proceeding through a transient aminal intermediate was possible. The reported

photocatalyzed oxidative amidation of benzaldehyde occurs using a phenazine-based

photocatalyst. Given the higher oxidation potential of pyrylium-based organic photoredox

catalysts, we examined the possibility that the small molecule could also catalyze the

amidation reaction. Using 4-bromobenzaldehyde and pyrrolidine with 5 mol % p-tol TPT

in MeCN, we irradiated the sample with 427 nm LEDs and obtained a conversion of 84%,

but only a 49% yield of the amidation product (Table 2). We hypothesized that the

addition of a polyaromatic hydrocarbon could work to increase the product yield by acting

as an electron relay. Addition of anthracene afforded up to 60% of the amidation product

when using 0.5 equivalents of the cocatalyst.

With successful formation of the amide product from small-molecule visible light

photoredox catalysis, we then turned our attention toward utilizing our TPT-SCNP to

facilitate the reaction. Given the co-localization of the PC and ER catalysts, we

envisioned the SCNP might be able to promote more efficient electron transfer for the

reaction. Indeed, the visible-light-catalyzed amidation of 4-bromobenzaldehyde with

pyrrolidine using the TPT-SCNP affords the benzamide in 75 % yield (Table 2) suggesting

that colocalization of the two catalysts aided product formation. To further examine the

effect of confinement, a non-folded polymer comprising both catalysts, TPT-co-Py-co-

MMA, was used to mediate the photoredox catalysis. While high conversion was

30

observed, only 32% of the amidation product was observed. Attempts to form the

benzamide from benzyl alcohols in a one-pot oxidation to the corresponding

benzaldehyde and subsequent amidation afforded no amidation

Table 2. Optimization of Small Molecule and Polymer-Based Amidation of 4-Bromobenzaldehyde.

In sum, we introduced triarylpyrylium tetrafluoroborate single chain polymer

nanoparticles as bifunctionalized homogeneous catalysts. Our catalysts add oxidative

photoredox catalysis to the growing repertoire of reactivity achievable with SCNPs. The

synthetic utility of these materials was demonstrated with the oxidation of benzyl alcohols

and amidation of 4-bromobenzaldehyde.

Anthracene (0.5 equiv.)

5 mol% p-tol TPT

MeCN (0.1 M)

427 nm, 25% light intensity, 24 h

O

Br

variation from standard conditions

none

no additive

naphthalene instead of anthracene

THF instead of MeCN

DCM instead of MeCN

1 mol % PC

10 mol % PC

TPT as PC and pyrene as ER

TPT-SCNP as PC and ER

TPT-co-Py-co-MMA as PC and ER

TPT-co-MMA as PC, no anthracene

entry

1

2

3

4

5

6

7

8

9

10

11

Yield (NMR)

60%

49%

40%

9%

25%

53%

46%

29%

75%

32%

43%

conversion (NMR)

96%

86%

83%

90%

92%

92%

87%

98%

quant.

95%

99%

O

Br

NHN

+

31

3.5 – Future Directions

In addition to the preparation of photocatalytic polymers, we are also preparing

monomers capable of acting as ligands in a metal-binding domain. In this respect, there

are two main goals. One goal is to achieve tandem reactions using a single catalyst with

multiple catalytic domains. In this case, two independent reactions will be catalyzed in

separate domains within the same nanoparticle depending on the presence or absence

of light. The second goal is to achieve dual catalysis within the same SCNP. In this case,

rather than acting as independent catalytic domains, the two domains must interact with

one another in order to promote the desired reactivity. Most typically, a photocatalyst in

an excited state participates in single electron redox chemistry with a transition metal

capable of catalyzing cross-coupling reactions, such as nickel or copper, yielding a more

reactive transition metal catalyst. This single electron oxidation or reduction occurs

through a ligand-to-metal charge transfer, and therefore requires ligands which can

transport charge easily. This class of ligands is referred to as redox-active ligands.

32

Chapter 4

Accelerated Dual Photoredox Catalysis Under Confinement

A portion of this chapter was published in ACS Catalysis, and is adapted with

permission from [J. J. Piane, L. E. Chamberlain, S. Huss, L. T. Alameda, A. C. Hoover,

E. Elacqua, ACS Catalysis, 2020 (DOI: 10.1021/acscatal.0c04499)]. Copyright 2020,

American Chemical Society.


Cooperative catalysis enables synthetic transformations that are not feasible using

monocatalytic systems. Such reactions are often diffusion controlled and require multiple

catalyst interactions at high dilution. We developed a confined dual-catalytic polymer

nanoreactor that enforces catalyst co-localization to enhance reactivity in a fully-

homogeneous system. The photocatalyzed-dimerization of substituted styrenes is

disclosed using confined-single-chain polymers bearing triarylpyrylium-based pendants,

with pyrene as an electron relay catalyst. Enhanced reactivity with low catalyst loadings

was observed compared to monocatalytic polymers with small-molecule additives. Our

approach realizes a dual-catalytic single-chain polymer that provides enhanced reactivity

under confinement, presenting a further approach for diffusion-limited-photoredox

catalysis.

ompartmentalization is one of Nature’s design principles: enzymes are shielded

from incompatible environments and partitioned such that cooperative functions like

catalysis are optimized. Confined-space effects in catalysis have also been reported with

33

organic molecules and porous materials (e.g., cucurbit[n]urils, metal-organic frameworks

(MOFs), and metal-organic cages (MOCs)). Systems like MOFs or MOCs provide distinct

benefits, including periodic arrangements

of transition metal catalysts that facilitate

increased local concentrations of reactive

species,46 thus, accelerating the rate of

organic reactions. Localized rate

enhancement is also observed in

molecular systems, such as the hydrogen-

binding Rebek’s softball, in which reactive

species diffused toward a catalytic center

allowing for a 200-fold rate enhancement.47

In close analogy to Nature, these

supramolecular frameworks also aid in

stabilization of different conformations.

Raymond’s 4L6 cluster,48 for example,

has a unique interior microenvironment

that lowers entropic barriers to reactivity,

while enthalpically favoring compact

transition states that are not observable in bulk solution (Figure 6).

Recently, sunlight-enabled-photoredox catalysis has emerged as a pillar for

synthesis, particularly for C—C and C—N bond construction while exploiting mild reaction

conditions.42,43 Commonly-employed photocatalysts (PCs) are based upon iridium or

Figure 6: Confined environments from (top) M4L6

MOC that facilitates an Aza-Prins cyclization, and

(bottom) Ni/Ir-MOF for dual photoredox catalysis.

Adapted with permission from ref 48 (Copyright

2015, American Chemical Society) and 62

(Copyright 2018, John Wiley and Sons).

34

ruthenium metal complexes and organic dyes that feature long excited-state lifetimes,

high redox potentials, and strong visible absorption. Dual photoredox catalysis enables

challenging transformations that cannot be achieved with either catalyst alone.30 The

merger of photoredox with transition metal catalysis has achieved multiple C—H

activation reactions with Pd,49 as well as trifluoromethylation,50 difunctionalization,51 and

other strategies with copper co-catalysts.52 Much interrogation into dual photoredox/Ni

catalysis has unleashed potent sp3—sp2 cross-coupling methods from the groups of

MacMillan,16, 53 Doyle,54 and Molander,55, 56 including decarboxylative and organoboron

couplings.55 Additional strategies by Yoon and coworkers have interrogated Bronsted and

Lewis acids as co-catalysts for metallaphotoredox-mediated [2+2] cycloaddition

reactions, leading to high control over product chirality.57, 58, 59 Further, Nicewicz has

pioneered a photoredox/electron relay co-catalysis system for [2+2] dimerizations to

realize natural lignan-based cyclobutanes.44

The efficiency of co-catalytically-powered reactions relies on proximal catalyst

locations, a bottleneck difficult to control with the degrees of freedom often afforded in

solution-phase chemistry. In addition, challenges remain in optimization, as expensive

PCs can be loaded at amounts exceeding maximum solubility.60 Strategies to circumvent

these limitations in heterogeneous photoredox catalysis have been realized using MOFs

and quantum dots (QDs) by the groups of Lin and Weix,61 respectively. While the MOF

confines Ir- and Ni-catalytic components within 0.6 nm of each other (Figure 6)62 and

facilitates electron and radical transfers between them that allows for efficient turnover,

the QDs were highly effective at extremely low loadings.

35

4.2 – Cocatalytic Polymer Design

Considering the successful heterogeneous dual catalysis in MOFs, we

hypothesized that single-chain polymer nanoparticles (SCNPs)3 could provide a versatile

platform to drive homogeneous dual catalysis within nanoreactors. The SCNP would

provide several advantages, including controlled catalyst loadings, solubility, and well-

defined crosslinking that enables co-localization of cooperative catalysts. Herein, we

disclose a triarylpyrylium (TPT)-based polymer that functions as an organic single-

electron oxidant/electron relay nanoreactor. Our design features a styrylpyrene (SP)

monomer that acts as both a covalent crosslink4 to generate the confined environment,

but also as a functioning electron relay (ER) for the photoredox-catalyzed [2+2]

cycloadditions. Our TPT-SP-based nanoreactor operates in low loadings of both the

photocatalyst and ER (1 mol % TPT, 0.67 mol % ER), and demonstrates enhanced

reactivity in comparison to monocatalytic polymer analogues. We attribute these results

to efficient colocalization of the PC and ER, owing to confinement.

Our motivation lies in developing versatile and efficient homogeneous catalysts.

In studies to realize co-catalytically-active polymers for sustainable chemistry, we noted

that SCNPs whose folding featured metal crosslinks had demonstrated reasonable

catalytic activity in reactions such as oxidations and cross-couplings.3 Further reports by

Zimmerman identified a single-chain polymeric ‘ lickase’ that accelerates copper-click

reactions.63 Given the success of these monocatalytic systems, combined with recent

reports of enhanced reactivity, we intuited that a crosslinked polymer comprising another

catalyst could feature accelerated reactions owing to confinement if the crosslink could

additionally act as an organocatalyst. Recognizing the potential of pyrene to act as an

36

ER catalyst, we designed SCNPs bearing strongly oxidizing TPT and pyrene to study the

effects of confining two cooperative catalysts in close proximity. Photocatalyzed [2+2]

cycloadditions are reported with electron rich styrene derivatives.44 When strongly

oxidizing photocatalysts are employed, cycloreversion of the resulting cyclobutane adduct

can predominate and shift the equilibrium of this reaction towards the starting alkene. The

addition of a polyaromatic electron relay catalyst circumvents oxidative cycloreversion by

acting as the active oxidant with a lower potential that is not sufficient to oxidize the

cyclized product. Specifically, the potent photooxidant first oxidizes the electron relay

catalyst, which subsequently oxidizes the substrate. Honing in on the interaction between

the two catalysts, we hypothesized that catalysts confined within the same polymer

backbone would enhance the kinetics of single electron transfer between the catalysts.

Triarylpyrylium salts are easily prepared with a variety of functionalities at the aryl

positions, providing access to photocatalysts with varying electronic properties. This

facilitates tuning of excited state redox potentials. Methacrylate-derived pyrylium

monomers were prepared according to previous reports.64 Methyl methacrylate (MMA)

was selected as the backbone in order to maintain solubility in common organic solvents.

With the desired monomers in hand, statistical copolymers comprising TPT-methacrylate,

SP-methacrylate, and MMA were prepared with targeted incorporation of 90:5:5

[MMA]:[TPT]:[SP]. Polymers were synthesized using reversible-addition fragmentation

chain-transfer (RAFT) polymerization (Scheme 14). The polymers were characterized

using 1H- NMR spectroscopy, wherein 6% incorporation of TPT and 4% incorporation of

SP was confirmed. The molecular weight of the polymer was determined to be 14 kDa

37

through size exclusion chromatography (SEC). SEC also confirmed that the polymers are

well-defined (Đ = 1.35).

Scheme 14. Copolymerization of Styrylarene Methacrylate with Triarylpyrylium and Methyl Methacrylate and Catalyst

Characterization

38

Cross-linking was achieved by irradiation of linear polymer solutions in MeCN (10

mg/mL) with a white compact fluorescent lamp. The cyclization of styrylpyrene and

nanoparticle formation was characterized by UV/Vis spectroscopy, wherein the

disappearance of the characteristic styrenyl absorbance (λ = 391 nm) and concomitant

appearance of cyclobutane features at λ = 333 nm and 352 nm. SEC confirmed

intramolecular cross-linking with a distinct shift to a lower molecular weight and a

dispersity of 1.35 (Scheme 14). Successful folding was also confirmed using diffusion-

ordered spectroscopy (DOSY). DOSY measurements of TPT-co-SP-co-MMA revealed a

diffusion coefficient of 1.5 x 10-10 m2 s-1. After crosslinking to form TPT-SCNP, a diffusion

coefficient of 2.7 x 10-10 m2 s-1 was observed, in line with compaction resulting from SP

dimerization that achieves a smaller hydrodynamic diameter.

Scheme 15. [2+2] Cycloadditions of styrenyl derivatives through TPT-SCNP-catalyzed photoinduced-electron transfer

39

Trans-anethole was selected as a model system to study the [2+2]

cyclodimerization using the SCNP (Scheme 15), given prior reports of TPT-catalyzed

single-electron oxidant-electron relay photocatalysis in the cyclodimerization of

anethole.44 In a typical experiment, the styrenic small molecule was added to a solution

of the SCNP (0.0004 mmol loading, which corresponds to 1.0 mol% TPT) in MeCN, and

was irradiated with 427 nm Kessil LEDs (approximate light-to-vial distances of ~7.5 cm),

with conversion monitored using 1H NMR spectroscopy. When using the confined TPT-

SCNP photocatalyst bearing the pyrene-based ER, a 66% yield of the dimerized product

was observed within 24 hours. Increasing the concentration to 0.4 M gave moderate

improvements (71%), while further changes (e.g., altering photocatalyst concentration

and light intensity) adversely affected cycloaddition. Pyrylium catalysts are prone to

photobleaching and dimerization of the pyranyl radical; accordingly, longer reaction times

did not yield more product, likely because the amount of active pyrylium in solution

decreases. Reactions conducted without the TPT-SCNP or in the absence of light yielded

no cycloadduct. For comparison, small molecule co-catalysts TPT and pyrene afforded

only 31% of the cycloadduct. Further, reactions conducted without crosslinking the

polymer (i.e., unfolded TPT-co-SP-co-MMA) furnished 39% of the cycloadduct,

suggesting the TPT-SCNP provided substantive benefits for cooperative photoredox

catalysis.

Typically, visible-light-organocatalyzed [2+2] cyclodimerizations proceed in a

sluggish manner, often in a period of 48+ hours, and reported TPT-catalyzed

cycloadditions similarly plateau in conversion over days, we sought to further investigate

the SCNP system and elucidate the effect of confinement. Given the optimized results

40

suggested that the photocatalyzed [2+2]cycloaddition proceeded with ease, control

experiments were conducted using monocatalytic polymers and compared with the dual

catalytic SCNPs (Table 3). We synthesized copolymers of MMA and TPT-methacrylate

and MMA and SP-methacrylate. Both polymers were prepared by RAFT polymerization

using the same procedure as for the target co-catalytic polymer. Proton NMR

spectroscopy indicated 1.83% incorporation of TPT and 0.68% incorporation of SP in

TPT-co-MMA and SP-co-MMA, respectively. The molecular weight of the TPT copolymer

was determined to be 18 kDa using SEC in THF, with a dispersity of 1.17. The molecular

weight of the SP copolymer was determined to be 21.5 kDa, with a dispersity of 1.02.

Similar to the co-catalytic SCNP, the SP-co-MMA monomer was crosslinked to mimic a

confined network, denoted SP-SCNP.

Table 3. Comparison of Monocatalytic Polymer Systems with Small-Molecule ER or TPT in the [2+2] Dimerization of

Anethole.

41

4.3 – [2+2] Cyclodimerization of Electron-Rich Styrenics

With the monocatalytic polymers in hand, we attempted to catalyze the [2+2]

cycloaddition of trans-anethole with TPT-co-MMA in the absence of the ER (Table 3).

Using our optimized conditions resulted in 2% of the cycloadduct, suggesting the

presence of the ER and confined interior is critical. Further, irradiation of trans-anethole

with TPT-co-MMA in the presence of pyrene as a small-molecule additive similarly

resulted in trace amounts of cycloadduct. These results suggested confinement was a

significant design element and led to accelerated rates and higher conversion with TPT-

SCNP. We, thus investigated the possibility that SP-SCNP could function similarly,

provided small-molecule TPT and the reactant could efficiently diffuse toward the ER for

co-catalysis. This afforded the desired product in 21% yield, while reaction in the absence

of TPT gave none of the desired product. Further, when TPT-co-MMA and SP-SCNP

polymers were used together as co-catalysts, trace amounts of product were observed.

We also interrogated an ‘unfoldable’ TPT/pyrene polymer (TPT-co-Py-co-MMA, Table 3).

Dimerization attempts resulted in trace amounts of cyclodimer with approximately 50% of

anethole being recovered (Table 3) and other oxidative products dominating. The

collective results confirm that both catalysts are necessitated within the same single-chain

polymer, consistent with a diffusion limited process. The improved yields and rate

accelerations when using the designed TPT-SCNP are, indeed, a result of polymer

confinement and subsequent co-localization of TPT and ER.

We then interrogated the role of confinement on cycloreversion by resubmitting the

cyclodimer to the standard conditions. For comparison, in the presence of small molecule

TPT, and the absence of an ER, the cyclodimer was recovered in 18% yield, with 8% of

42

alkene present. The unfolded polymer bearing both TPT and ER (TPT-co-Py-co-MMA)

recovered 50% of the cyclodimer, while furnishing 2% of the alkene. In contrast, the TPT-

SCNP recovered 65% of the cyclodimer, while affording 5% of the alkene. The combined

results suggest that the SCNP impedes cycloreversion processes during the dimerization.

Given multiple polyarenes can function as electron relays, we investigated other

arenes in our dual catalytic SCNP. Additional monomers featuring styryl naphthalene

(SNap) and styryl phenanthrene (SPhen) were synthesized and polymerized. The

resultant polymers, TPT-co-SNap-co-MMA and TPT-co-SPhen-co-MMA were

subsequently characterized and crosslinked in MeCN (Scheme 14). Similar to SP-

containing polymers, crosslinking reactions of naphthalene and phenanthrene polymers

(TPT-co-SNap-co-MMA and TPT-co-SPhen-co-MMA, respectively) were monitored using

UV-Vis spectroscopy wherein both systems exhibited a lessened intensity for the main

absorbance after 60 minutes. In contrast to the SP-continuing polymer, we observed that

crosslinking under the same concentration (10 mg/mL) led to a significant amount of

intermolecular crosslinking and increased molecular weights through SEC analysis.

Higher dilutions (down to 0.5-1.0 mg/mL) afforded unimodal SEC distributions for

both TPT-Nap-SCNP and TPT-Phen-SCNP, confirming intermolecular crosslinking. In

both cases, shifts to slightly higher molecular weight were observed (vide infra) which

may be attributed to a heightened degree of rigidity within these SCNPs compared to the

TPT-SCNP and/or differences in localized compaction or overall global compaction of the

SCNP in the crosslinking process. Given the crosslinking of these ERs de facto

necessitated a higher dilution, it is reasonable to intuit that the crosslinking process is

different. The combined observations suggest that these crosslinking reactions proceed

43

without the enhanced photoreactivity as observed with SP, which could result in a

different local compaction at the high dilutions required to attain SCNPs from SPhen and

SNap.

Using our optimized conditions, we attempted to catalyze the cycloaddition of

trans-anethole. With TPT-Nap-SCNP, 16% of the cycloadduct and 28% of starting

material was recovered. Similarly, the TPT-Phen-SCNP afforded 14% of the cyclodimer,

with 40% of the anethole being recovered. In both, the remaining mass balance is

attributed to other oxidative products. High consumption of the alkene and lower yield of

the cycloadduct suggest that Nap and Phen are less efficient ERs in our system, and are

unable to mediate cycloreversion processes.

Dimerization of 4-methoxystyrene was also possible in 26% yield, with poly(4-

methoxy)styrene unsurprisingly forming as the main byproduct, given methoxystyrene’s

reported cationic polymerization using TPT.40 Additionally, α-asarone was cyclized to give

the natural product (±) Magnosalin in 49% yield. More challenging electron deficient vinyl

arenes did not undergo the desired transformation.

Scheme 16. Cross-Dimerization of Styrene with Trans Anethole

We sought to further investigate the versatility and compatibility of our SCNP with

cross [2+2] cycloadditions. (Scheme 16). The cyclization of trans-anethole and styrene

was used as a model system. Optimal conditions for the cross [2+2] cycloaddition were

44

found using 1.5 equivalents of styrene. Using our co-catalytic SCNPs, the cross product

was obtained in 44% yield with 22% of the dimer with 1 mol% SCNP with respect to TPT.

Similar controls were conducted using the cross [2+2] system to probe the effects of

confinement (Table 4).

Table 4. Comparison of Monocatalytic Polymer Systems with Small-Molecule ER or TPT in [2+2] Cross-Dimerizations with Anethole.

Using TPT-co-MMA without any electron relay catalyst resulted in 5% of the

desired product, with 3% of the trans anethole dimer as the major byproduct. The addition

of pyrene to this system resulted in trace amounts of the cross product and of the dimer.

SP-co-MMA with TPT as a co-catalyst gave the cross product in 1% yield with 2% of the

dimer. The separate polymers SP-co-MMA and TPT-co-MMA as the co-catalyst system

gave 5% of the desired product and 3% of the byproduct. In both the dimerization and

cross [2+2] cycloaddition, reaction conducted without any photocatalyst or in the absence

of light gave none of the desired product.

45

Figure 7. Design of Cooperative Photoredox-Enabled SCNPs for [2+2] Cycloadditions

We present a confined dual-catalytic single-chain polymer system bearing both a

photocatalyst and an electron relay catalyst (Figure 7). The solubility of these

homogeneous polymer catalysts is controlled by including MMA as the polymer

backbone. Preliminary studies suggest that the proximity of the catalysts improves the

efficiency of the co-catalyzed [2+2] cycloaddition compared with the analogous reaction

using separate polymeric catalytic components. We believe this effect is due to improved

efficiency of SET between the photocatalyst and the electron relay catalyst.

46

4.4 – Future Directions

Future studies will look to interrogate different substituent patterns within the TPT

monomer to enable different annulation/cycloaddition reactions to be probed (e.g., the

[2+2+2] cycloaddition to install N-heterocycles, which requires a much more oxidizing

form of TPT for higher efficiency in small molecule methodology). In addition, plans to

install bulkier aromatic units (i.e., mesitylene) on top of the pyrylium ring will be pursued

as a means to reduce the ability of the TPT-SCNP to undergo photobleaching. With

proper tuning of oxidation potential of TPT, and the ability to tune the styrylarene so as

to incorporate other cocatalysts, the scope of styrenes accessed should be increased.

Further, the ability to interrogate other oxidative cycloadditions like the [4+2] Diels-Alder

reaction will be enabled through optimization of the SCNP. Lastly, directions to induce

further compaction by increasing crosslinker density within the polymer chain may

promote more localized regions of high cocatalyst loading, which is expected to impact

the cooperative photoredox reactions being studied.

47

Chapter 5

Ongoing and Future Work

5.1 – Water-Soluble SCNPs as Sustainable Nanoreactors

Organic solvents account for a large amount of toxic waste generated in synthetic

laboratories.39 For this reason, finding methods to reduce the amount of organic solvents

used is desirable, especially in large scale synthesis. In addition to reduction of toxic

chemical waste, performing organic reactions in aqueous media provides a unique

opportunity to utilize confinement effects to increase the local concentration of reactive

species, leading to rate enhancement in challenging transformations. This has been

elegantly demonstrated by the Raymond laboratory, who have used metal-centered

tetrahedral complexes in water to greatly accelerate reactions.48

SCNPs have been used to address solvent compatibility issues and create water

soluble catalysts.65 We will prepare water soluble, bi-functionalized catalytic

nanoreactors, providing a greener method for achieving difficult chemical

transformations. Water solubilizing comonomers will be prepared as reported in the

literature (Figure 8).66 We anticipate that organic compounds will be attracted to the

hydrophobic catalytic core of the SCNPs, creating a high local concentration of reactive

species and great rate enhancement.

Building on the results of our photocatalytic SCNPs, we will develop a polymeric

system that consists of photocatalytic pyrylium pendants and hydrophilic solubilizing

acrylate comonomers. Terminal dihydroxy functionality will allow polymer nanoparticles

48

to be solubilized in water, while the acrylate backbone will create a hydrophobic pocket

where the organic reactive species will congregate. This system will enable

photocatalyzed single-electron oxidation to occur in aqueous media. We anticipate that

confinement effects will lead to significant rate enhancement compared to reactions

taking place in organic media.

Figure 8. Design of Water Soluble SCNPs

5.2 – Enabling Tandem Reactions with Multi-Domain SCNPs

The ability to perform multiple synthetic steps within a single mixture reduces

waste by eliminating costly purification steps that potentially require large amounts of

volatile, harmful organic solvents. Multi-faceted catalysts would enable orthogonal

reactions to occur at different catalytic sites, greatly improving the efficiency of synthetic

routes. We aim to prepare multi-domain single-chain polymer nanoparticles capable of

=

= O

O

e

O

O

49

catalyzing multiple reactions in a single batch depending on the presence or absence of

a specific driving force, such as heat or light. Combining these catalysts into a single

polymer network would provide a recyclable platform to achieve several bond formations

by sequential introduction of external stimuli.

Building on the results obtained from our photocatalytic SCNPs, we will target the

preparation of SCNPs bearing multiple catalytic domains. We hypothesize that the

reactivity of these SCNPs will be controlled by the presence or absence of visible light.

This is enabled by incorporation of separate photocatalytic and a cross-coupling domains.

Initial studies will investigate sequential Suzuki-Miyaura cross-couplings of 4-

bromobenzaldehyde in the absence of light, and subsequent photocatalyzed amidation

as previously described. We anticipate this method spanning a vast breadth of

transformations, providing an efficient, recyclable catalytic platform.

5.3 – Transient Radical Capture with Covalently Linked Catalysts

The combination of photocatalyzed radical generation with cross-coupling

chemistry has provided access to many new transformations that would not be feasible

with either method alone.22 This methodology enables the formation of new carbon-

carbon bonds by coupling photocatalytic radical precursors with traditional carbon

electrophiles, such as carbon-halides.

Despite the vast library of radical precursors used in dual photoredox/cross-

coupling processes, transient radical capture remains a significant bottleneck. Aryl radical

capture is a particularly challenging task. Intriguingly, generation of aryl radicals is not the

50

issue, and is often not difficult. For instance, the single electron redox potential of an aryl

carboxylate is +1.4V, which is well within the range of several common photocatalysts.58

The inherent instability and high reactivity of these radicals leads to rapid quenching

through off-cycle events that prevent the crucial radical capture step by the transition

metal catalyst. Ongoing work in our group pushes towards the development of a dual

functionalized catalyst containing both a photocatalyst and a nickel catalyst. The proximity

of the transition metal relative to the site of radical generation will increase the likelihood

of transient radical capture, facilitating otherwise unattainable transformations (Figure 9).

Figure 9. Dual Nickel-Photoredox Catalysis in Confinement

To ensure close proximity of catalytic domains, both catalysts will be covalently

linked. This will promote the generation and subsequent capture of fleeting radical

species. For nickel to capture radical species, it must be coordinated to redox-active

ligands. We have designed routes to prepare several redox active ligands tethered to the

organic photocatalyst 2,4,6-triphenylpyrylium tetrafluoroborate. These ligands include

ν

51

dipyrrin, bipyridine, and 1-bpp derived species. Derivatives of these ligands will be

prepared with terminal alcohol groups bound by a short hydrocarbon linker. Alcohol-

functionalized ligands will then be linked to the TPT photocatalyst through and EDC

coupling (Scheme 17). These catalysts will be used to unlock new radical precursors for

dual nickel/photoredox catalyzed cross-coupling reactions.

Scheme 17. Synthesis of Tethered Catalyst by EDC Coupling

The optimal proximity of the catalytic domains will be determined by preparing

catalysts of varying linker length. Once high-yielding conditions have been achieved, we

will explore the scope of aryl halide and aryl carboxylate species capable of undergoing

the desired transformations.

5.4 – Facilitating Dual Nickel-Photoredox Catalysis with SCNPs

The compartmentalized, well-defined local structures of SCNPs are reminiscent of

biological molecules, and as such they are often thought of as being analogous to

enzymes, particularly for applications in catalysis.41 One common feature of enzymes is

52

the presence of multiple catalytic domains that work synergistically to perform one

function. In this sense, dual catalysis is inherently related to enzyme catalyzed

biofunctions. Building on our results using small-molecule bifunctionalized catalysts, we

aim to incorporate proximally located nickel and photocatalysts into SCNPs to prepare

biomimetic dual functioning polymeric nanoreactors (Figure 10). We anticipate this will

provide a versatile, recyclable platform to perform dual nickel/photoredox catalyzed

reactions with high control over solvent compatibility. Additionally, we anticipate

enhanced reaction rates due to the confined nature of the catalytic center.

Figure 10. Cocatalysis in Single-Chain Polymer Confinement

In order to ensure that the two catalytic regions can interact with one another, we

have designed a monomer that contains both catalysts as pendant groups. This provides

a way to ensure close-proximity of the photocatalyst and the transition metal catalyst. The

first step in the preparation of this monomer is a [4+2] cycloaddition of furan and maleic

anhydride. Subsequent nucleophilic substitution with an alcohol-functionalized dipyrrin

53

and EDC coupling with an alcohol-functionalized pyrylium salt would give a highly

strained, bifunctionalized catalytic monomer (Scheme 18). This strained cyclic system

can then undergo a ruthenium catalyzed ring opening metathesis polymerization to give

the polymeric nanoparticle precursors. Introduction of nickel to this polymer system under

high dilution will enable nanoparticle formation.

With the desired polymers in hand, we anticipate that similar reactivity to the small-

molecule dual catalytic system can be achieved. Optimization studies will be completed

to determine the best combination of ligands and photocatalyst, optimum distance

between catalytic regions, and polymer molecular weights. In addition to rate

enhancement by confinement effects, we will demonstrate that the polymeric catalysts

can be easily separated and recycled.

Scheme 18. Synthesis of bifunctionalized monomer toward dual nickel-photoredox catalysis

54

Appendix: Experimental

General Procedure A: Synthesis of meso-aryl dipyrromethanes

Benzaldehyde (1.00 equiv) was dissolved in freshly distilled pyrrole (50 equiv).

Catalytic TFA (0.1 equiv) was added to the solution in the dark. The mixture was allowed

to stir at room temperature in the dark for 5 minutes. The reaction was quenched with 1

M KOH (50 mL). The product was extracted into ethyl acetate (150 mL) and was washed

with water (3 x 100 mL) and saturated sodium chloride (100 mL). The organic phase was

dried over anhydrous sodium sulfate and filtered. Solvent was removed using rotary

evaporation. The resulting crude solid was purified by silica gel chromatography

(hexanes/ethyl acetate), yielding a grey or white powder.

General Procedure B: Synthesis of bis-chlorinated dipyrrins

Aryl dipyrromethane (1.00 equiv) was dissolved in dry THF (0.066 M) and cooled to -

78 °C. NCS (2.05 equiv) was added, and the mixture was stirred for 1.5 hours at -78 °C.

The mixture was then warmed to room temperature and stirred for an additional 3 hours.

55

The solvent was removed using rotary evaporation and the resulting solid was dissolved

in DCM (0.033 M). The mixture was washed with H2O (50 mL), then washed again with

saturated sodium chloride (50 mL). The organic phase was dried with sodium sulfate and

filtered. DDQ (1.15 equiv) was added, and the reaction was stirred for 1 hour at room

temperature. The mixture was filtered and solvent was removed using rotary evaporation.

The resulting solid was purified by silica gel chromatography (hexanes), yielding an

orange solid.

General Procedure C: Synthesis of N-methylethanolamine-functionalized dipyrrins

Chlorinated dipyrrin (1 equiv) was dissolved in acetonitrile (26 mL), followed by the

addition of N-methylethanolamine (4 equiv). NEt3 (6 equiv) was added, and the mixture

was allowed to reflux overnight. The resulting dark red mixture was condensed using

rotary evaporation, diluted with DCM (50 mL), and washed with H2O (50 mL). The

aqueous layer was extracted with DCM (3 x 10 mL), and the combined organic phase

was dried with Na2SO4 and filtered, and the resulting material was purified by silica gel

chromatography (hexanes/ethyl acetate), yielding a red solid.

56

General Procedure D: Synthesis of N-methylethanolamine-substituted BODIPY

complexes

N-methylethanolamine-substituted dipyrrin (1.00 equiv) was dissolved in DCM (0.5 M).

Diisopropylethylamine (26.3 equiv) was added. BF3·OEt2 was added. The mixture was

stirred at room temperature for 24 hours. Solvent was removed by rotary evaporation,

and the crude oil was purified by silica gel chromatography (acetone/dichloromethane),

yielding a dark red powder.

General Procedure E: Synthesis of acrylate-substituted BODIPY complexes

N-methylethanolamine-substituted dipyrrin complex (1.00 equiv) was cooled to 0°C,

then dissolved in acetonitrile (0.1 M). Diisopropylethylamine (3.60 equiv) was added.

57

Acroloyl chloride (1.80 equiv) was added dropwise. The mixture was allowed to warm to

room temperature. The mixture was stirred at room temperature for 24 hours. Solvent

was removed by rotary evaporation. The crude oil was purified by silica gel

chromatography (hexanes/ethyl acetate), yielding a dark red powder.

General Procedure F: Deborylation of BODIPY complexes

Acrylate-substituted BODIPY (1.00 equiv) was dissolved in acetonitrile (0.033 M). ZrCl4

(5.00 equiv) was dissolved in MeOH (0.1 M). The resulting solution of ZrCl4 was added to

the BODIPY solution and stirred at room temperature. After 2 hours, the reaction was

quenched with water (10 mL), and the product was extracted into dichloromethane (10

mL). The aqueous layer was washed with DCM (3 x 10 mL), and the combined organic

layers were washed with water (3 x 10 mL) and saturated sodium chloride (1 x 10 mL).

The combined organics were dried over anhydrous sodium sulfate and filtered. Solvent

was removed by rotary evaporation, yielding the product as a red solid.

58

Synthesis of TPT

Scheme S-1: Synthetic route for the photocatalyst TPT-based monomer

4-formylphenyl methacrylate (3) 1 (6.11 g, 50 mmol) was dissolved in 50 mL of DCM.

7.7 mL of triethylamine was added to the solution, and the resulting mixture was cooled

to 0 °C. 2 (5.4 mL, 55 mmol) was added dropwise to the mixture with stirring. The reaction

was stirred at room temperature for 24 hrs. The reaction mixture was extracted with water

(3 x 50 mL) and brine (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4

and concentrated. The resulting product was purified via flash chromatography (5-10%

EtOAc/Hex) to yield 8.65 g (91%) of as a clear gel. 1 N R (400 z, D l ) δ 10.00

(s, 1H), 7.93 (d, J = 8.59 Hz, 2H), 7.31 (d, J = 8.52 Hz, 2H), 6.38 (s, 1H), 5.81 (s, 1H),

2.07 (s, ). 1 N R (125 z, D l ) δ 191.14, 165.29, 155.85, 1 5.60, 1 4.12,

131.39, 128.31, 122.61, 18.50.

4-(4-(methacryloyloxy)phenyl)-2,6-diphenylpyrylium tetrafluoroborate (4) 3 (8.65 g,

45.5 mmol) and acetophenone (13.3 mL, 113.8 mmol) were dissolved in 45 mL of DCM.

Boron trifluoride diethyl etherate (14.6 mL, 118.3 mmol) was added dropwise to the

mixture with stirring. The reaction was heated to 50 °C under reflux and stirred for 24 hrs.

59

The resulting reaction mixture was cooled to room temperature and the product was

precipitated in diethyl ether (100 mL). The product was collected by filtration and washed

with diethyl ether (3 x 25 mL) to yield 6.07 g (29%) of 4 as a dark yellow solid. 1 H NMR

(400 z, D l ) δ 8.62 (s, 2 ), 8. 8 (m, 6 ), 7.74 (m, 6 ), 7. 8 (d, J = 8.81, 2 ), 6. 0

(s, 1 ), 5.80 (s, 1 ), 2.02 (s, ). 1 (125 z, D l ) δ 170.64, 135.70, 132.04,

130.50, 128.85, 128.72, 123.73, 114.47, 18.43.

Compounds 7, 10 and 11 were synthesized as previously described in the literature (ref:

Frisch, H.; Menzel, J. P.; Bloesser, F. R.; Marschner, D. E.; Mudsinger, K.; Barner-

Kowollik, C. J. Am. Chem. Soc. 2018, 140, 9551-9557.)

60

(E)-4-(2-(pyren-1-yl)vinyl)phenol (7) 5 (4.05 g, 14.4 mmol,) and Pd(OAc)2 (0.135 g, 0.60

mmol) were dissolved in triethanolamine (60 mL). 6 (1.82 mL, 12.0 mmol) was added and

the reaction mixture was stirred at 100 o C for 17 hours. The reaction mixture was then

cooled and diluted with 30 mL each of water and EtOAc. The mixture was filtered through

a plug of celite and then extracted with EtOAc (2 x 30 mL) and washed with water (2 x 30

mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and

concentrated. The resulting solid was recrystallized in DCM to yield 1.026 g (27%) of 7

as a powder. 1 N R (400 z, D l ) δ 8.49 (d, J = 9. 0, 1 ), 8. 0 (d, J = 8.09, 1 ),

8.19-8.16 (m, 3H), 8.13 (d, J = 9.28, 1H), 8.08-8.04 (m, 3H), 8.00 (t, J = 7.2, 1H), 7.59 (d,

J = 8.51, 2H), 7.30 (d, J = 16.02, 1H), 6.91 (d, J = 8.54, 2H), 4.80 (s, 1H).

2-(methacryloyloxy)ethyl 5-bromopentanoate (10) DMAP (0.305 g, 2.5 mmol), 9 (2.43

mL, 20 mmol) and triethylamine (5.3 mL)were dissolved in 30 mL of THF and cooled to

0°C. 8 (3.36 mL, 25 mmol) was dissolved in 10 mL of THF and added dropwise to the

reaction mixture. THF (10mL) was used to ensure complete transfer of 8. The reaction

was stirred at 0°C for 1hr and then warmed to room temperature and stirred for an

additional 30 min and then concentrated. The contents of the flask were diluted with

EtOAc (250 mL) and washed with water (2 x 50 mL), NaHCO3 (2 x 50 mL) and brine (1

x 50 mL). The organic layer was died over anhydrous Na2SO4 and concentrated. The

resulting product was purified via flash chromatography (0-5-20-100% EtOAc/Hex) to

yield 4.12g (78%) of 10 as a clear oil. 1 N R (400 z, D l ) δ 6.08 (s, 1 ), 5.55

(m, 1H), 4.29 (m, 4H), 3.36 (t, J = 6.56 2H), 2.33 (t, J = 7.23 2H), 1.90 (s, 3H), 1.88-1.82

(m, 2H), 1.78-1.71 (m, 2H).

61

2-(methacryloyloxy)ethyl (E)-5-(4-(2-(pyren-2-yl)vinyl)phenoxy)pentanoate (11) 7

(1.037 g, 3.24 mmol) and 10 (1.54 g, 5.83 mmol) were dissolved in MeCN (50 mL).

Cs2CO3 (1.90 g, 5.83 mmol) was added and the reaction mixture was sparged with N2 for

20 min. The reaction was stirred under N2 at 45 °C for 24 hrs. The reaction mixture was

cooled to room temperature and filtered. The filtrate was diluted with MeOH (150 mL) and

placed in the freezer. The product was filtered off to yield 1.131g (74%) of 11 as a bright

yellow powder. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 9.29, 1 ), 8. 0 (d, J = 8.08, 1 ),

8.18-8.15 (m, 3H), 8.12 (d, J = 9.28, 1H), 8.07-8.04 (m, 3H), 8.00 (t, J = 7.6, 1H), 7.61 (d,

J = 8.65, 2H), 7.30 (d, J = 16.02, 1H), 6.95 (d, J = 8.69, 2H), 6.15 (s, 1H), 5.61 (q, J =

1.56, 1H), 4.37 (m, 4H), 4.03 (m, 2H), 2.46 (m, 2H), 1.97 (s, 3H), 1.87 (m, 4H). 13C NMR

(125 MHz, CDCl3) δ 17 . 6, 167. 0, 159.02, 1 6.10, 1 2.48, 131.74, 131.58, 131.17,

130.75, 130.74, 128.37, 128.13, 127.66, 127.60, 127.24, 126.28, 126.13, 125.32, 125.09,

123.69, 123.67, 123.29, 114.93, 67.58, 62.60, 62.23, 33.92, 28.80, 21.79, 18.48.

62

Copolymer (13) TPT monomer (341 mg, 0.74 mmol), SP monomer (118 mg, 0.23 mmol),

CTA (49.2 mg, 0.122 mmol) and AIBN (4 mg, 0.024 mmol) were dissolved in MMA (3.5

mL, 36.54 mmol) in the dark. DMF (5.3 mL) was added to the reaction mixture and it was

sparged with N2 for 30 minutes. The polymerization was stirred at 80°C for 24 hours under

N2. The reaction was cooled to room temperature and then precipitated into MeOH (150

mL). The polymer was filtered off and washed with MeOH (2 x 30 mL) and Et2O (2 x 30

mL) to yield 2.43 g of 13 as a light green solid. The percent incorporation of the monomers

was found to be 6% TPT and 4% SP by 1H NMR. The ratios of the actual over the

theoretical integrations of TPT and MMA were calculated as shown below. The actual

integration of the TPT aromatic hydrogens was determined by subtracting the theoretical

integration of the SP aromatic hydrogens. The percent incorporations were calculated by

dividing each ratio by the total of the two, as shown below.

𝑇𝑃𝑇 𝑟𝑎𝑡𝑖𝑜 =61.83 − 15

16= 2.93; 𝑀𝑀𝐴 𝑟𝑎𝑡𝑖𝑜 =

413.63

3= 137.88; % 𝑇𝑃𝑇 =

2.93

2.93 + 137.88 + 1

= 2.07%; % 𝑀𝑀𝐴 =137.88

2.93 + 137.88 + 1= 97.2%; % 𝑆𝑃 = 100 − (2.07 + 97.02) = 0.73%

Representative calculations for other ER-based SCNPs:

TPT-co-SNap-co-MMA

𝑇𝑃𝑇 𝑟𝑎𝑡𝑖𝑜 =60.38 − 13

16= 2.96; 𝑀𝑀𝐴 𝑟𝑎𝑡𝑖𝑜 =

436.29

3= 145.43; % 𝑇𝑃𝑇 =

2.96

2.96 + 145.43 + 1

= 1.98%; % 𝑀𝑀𝐴 =145.43

2.96 + 145.43 + 1= 97.3%; % 𝑆𝑁𝑎𝑝 = 100 − (1.98 + 97.3) = 0.72%

63

TPT-co-SPhen-co-MMA

𝑇𝑃𝑇 𝑟𝑎𝑡𝑖𝑜 =68.29 − 15

16= 3.33; 𝑀𝑀𝐴 𝑟𝑎𝑡𝑖𝑜 =

516.58

3= 172.19; % 𝑇𝑃𝑇 =

3.33

3.33 + 172.19 + 1

= 1.89%; % 𝑀𝑀𝐴 =172.19

3.33 + 172.19 + 1= 97.5%; % 𝑆𝑃ℎ𝑒𝑛 = 100 − (1.89 + 97.5) = 0.61%

SCNP (14) 13 (23.3 mg) was dissolved in MeCN (2.33 mL) in a foil wrapped vial. The

polymer was allowed to completely dissolve and then the foil was removed. The vial was

placed about 6 in. in front of a white CFL light with a cooling fan above it. The vial was

irradiated without stirring for 1 hour and then immediate wrapped in foil. The mixture was

concentrated in vacuo in the dark to yield the nanoparticle.

Homopolymers (14, 15) Either the TPT (341 mg, 0.74 mmol) or SP (118 mg, 0.23 mmol)

monomer was combined with CTA (49.2 mg, 0.122 mmol) and AIBN (4 mg, 0.024 mmol)

and dissolved in MMA (3.5 mL, 36.54 mmol) in the dark. DMF (5.3 mL) was added to the

reaction mixture and it was sparged with N2 for 30 minutes. The polymerization was stirred

at 80 °C for 24 hours under N2. The reaction was cooled to room temperature and then

64

precipitated into MeOH (150 mL). The polymer was filtered off and washed with MeOH (2

x 30 mL) and Et2O (2 x 30 mL) to yield the homopolymer as a yellow powder.

Dimer The desired alkene (2 equiv., 0.1 mmol), and the SCNP stock solution (2 mol %

TPT at 10 mg/mL) were added to a scintillation vial in the dark. Solid alkenes were added

before the SCNP and liquid alkenes were added after. The vial was then sealed with

electrical tape and sparged with a nitrogen needle and a vent needle for 10 minutes. The

needles were removed, and the top of the vial was promptly covered with electrical tape.

The vial was then placed between two 427nm Kessil lamps at 25% intensity and stirred

for 24 hrs.

65

Table S-1. Optimization of Cyclodimerization

21 The SNCP stock solution (2 mol% at 10 mg/mL), styrene (0.18 mL, 1.5 mmol), and

trans-anethole (0.15 mL, 1.0 mmol), were added to a foil wrapped scintillation vial. The

vial was then sealed with electrical tape and sparged with a nitrogen needle and a vent

66

needle for 30 minutes. After sparging the top of the vial was also sealed with electrical

tape. The vial was then placed under 427nm Kessil lamps at 25% intensity and stirred for

24 hrs. This afforded the desired product 21 in 44% yield. 1H NMR (500MHz, CDCl3) δ

7.33 (d, J = 8.5, 2H), 7.19 – 7.15 (m, 5H), 6.77-6.75 (m, 2H), 3.69 (s, 3H), 3.30 (q, J =

8.16, 1H), 2.86 (t, J = 9.51, 1H), 2.45-2.42 (dt, J = 10.16, 7.77, 1H), 1.75 (m, 1H), 1.61 (q,

J = 10.14, 1H), 1.10 (d, J = 6.43, 3H)

General procedure: The benzyl alcohol (0.1mmol) was added to a 20mL foil wrapped

scintillation vial containing the nanoparticle (0.0075mmol). DCM (3.75mL) was added in

the dark. The foil was removed and the vial was then irradiated with 427nm Kessil lamps

for 1 hour. The sample was then concentrated in the dark. Trimethoxybenzene (0.1mmol)

was added and yield was then calculated by 1H NMR spectroscopy.

4-bromophenyl)(pyrrolidin-1-yl)methanone (21) The nanoparticle (33.3mg, 0.005

mmol) in a 10mg/mL solution of MeCN was added to a 20mL scintillation vial and

concentrated. 19 (18.5mg, 0.1mmol) was added followed by 20 (0.025mL, 0.3mmol). The

67

contents of the vial were dissolved in MeCN (1mL) and then the vial was stirred under

427nm Kessil lamps for 24 hrs with a cooling fan. The vial was concentrated and

Trimethoxybenzene (0.1mmol) was added. The yield was then calculated by 1H NMR to

by 64% of 21. 1H NMR (400MHz, CDCl3) δ 7.5 (d, J = 8.56, 2 ), 7. 9 (d, J = 8.58, 2 ),

3.64-3.62 (m, 2H), 3.42-3.39 (m, 2H).

68

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