DESIGN AND SYNTHESIS OF SEQUENCE-DEFINED PEPTOID 

PHOTORESISTS AND PEPTOID-PMMA BLOCK COPOLYMERS FOR NEXT-

GENERATION EUV LITHOGRAPHY 

 

 

 

 

 

 

 

A Thesis 

Presented to the Faculty of the Graduate School 

of Cornell University 

In Partial Fulfillment of the Requirements for the Degree of 

Master of Science 

 

 

 

 

 

 

by 

Danya Liu 

August 2025



 

 

 

 

 

 

 

 

 

 

 

 

 

© 2025 

 

Danya Liu 



 

ABSTRACT 

 

Extreme-ultraviolet (EUV) lithography underpins continued device miniaturization, 

yet conventional photoresists suffer from stochastic issues and the resolution-

sensitivity-roughness trade-off at sub-10 nm dimensions. Herein, we present a 

modular synthetic platform based on sequence-defined peptoids to overcome these 

limitations. In this work, two distinct oligopeptoid architectures were explored. The 

first employs a chemical amplification mechanism, using Boc-protected side chains to 

trigger solubility switching upon acid-catalyzed deprotection. Their lithographic 

performance, using either ionic or non-ionic photoacid generators (PAGs), was 

evaluated under deep-ultraviolet (DUV) exposure. The second is a creative innovation 

in which non-ionic PAGs were covalently tethered onto peptoid backbones via copper-

catalyzed azide-alkyne cycloaddition, making the PAG itself the solubility-switch 

moiety and ensuring uniform acid distribution. We further extent the platform to 

peptoid-b-PMMA block copolymers for directed self-assembly (DSA) lithography via 

ATRP “grafting-from” and RAFT-amidation routes, addressing polymerization 

control and purification challenges. Together, these studies provide a foundation for a 

highly tunable, molecularly uniform photoresist framework and demonstrate initial 

compatibility with both EUV patterning and DSA process, although further 

optimization remains necessary. 



 

iv 

BIOGRAPHICAL SKETCH 

Danya Liu was born in Dalian, China on July 10, 2001. After completing her primary 

and secondary education in Dalian, she earned a Bachelor of Engineering in Materials 

Science and Engineering from Nankai University. During her undergraduate studies, 

she contributed to several photovoltaic research projects, where she discovered her 

passion for scientific inquiry. In 2023, she enrolled at Cornell University to pursue a 

Master of Science degree, focusing on polymeric materials for diverse applications. 

Under the mentorship of Professor Christopher Ober, she conducted research in next-

generation EUVL photoresists. Upon completing her M.S. in 2025, she decided to 

continue her academic journey toward a Ph.D. in the polymeric materials. 



 

v 

ACKNOWLEDGMENTS 

First, I would like to express my deepest gratitude to my advisor, Prof. Christopher 

Ober, for providing me with this invaluable opportunity to conduct research in his 

group. His exceptional mentorship, patience, and insightful guidance have profoundly 

shaped my development as a researcher and scholar. I am also indebted to my 

committee member, Prof. Yu Zhong, for his insightful discussions and unwavering 

support. Their guidance was instrumental in the success completion of my M.S. thesis. 

I am grateful to all of my colleagues in the Ober group, especially Dr. Chaoqiuyu 

(Rachel) Wang, who generously shared her extensive practical expertise and offered 

invaluable assistance both in the laboratory and in preparing presentations. Her 

continued encouragement and insights, even after her graduation, were crucial to my 

progress. I also thank Seungjun Kim, Dr. Madan Biradar, Chenyun Yuan, and the rest 

of the group for their assistance and collaboration. 

My heartfelt thanks go to my parents, my roommate, and my friends for their enduring 

love, care, and encouragement throughout my graduate studies. Their support gave me 

the confidence and strength to overcome challenges and pursue my research goals. 

Lastly, I would like to acknowledge my own perseverance and dedication. Although 

there is always more to learn and achieve, I am proud of how far I have come. 



 

vi 

 

TABLE OF CONTENTS 

BIOGRAPHICAL SKETCH  ............................................................................. iv 

ACKNOWLEDGMENTS  .................................................................................. v 

TABLE OF CONTENTS  ................................................................................... vi 

TABLE OF FIGURES  ....................................................................................... viii 

CHAPTER 1: INTRODUCTION  ............................................................................. 10 

1.1 Prospects and background of photolithography  ........................................... 10 

1.2 DUV, EUV, and electron beam lithography  .................................................. 11 

1.3 Evaluating photoresist performance  ............................................................... 13 

1.4 Peptoid as a candidate photoresist  .................................................................. 15 

REFERENCES  ......................................................................................................... 19 

CHAPTER 2: DESIGN AND SYNTHESIS OF SEQUENCE-DEFINED 

OLIGOPEPTOIDS FOR POTENTIAL LITHOGRAPHIC USE  ............................ 22 

2.1 Introduction  ...................................................................................................... 22 

2.2 Experimental methods  ..................................................................................... 26 

2.3 Material design and synthesis  .......................................................................... 28 

2.3.1 Non-ionic PAG  ............................................................................................... 28 

2.3.2 Boc-protected oligopeptoids employing the solubility-switch mechanism in a 

chemically amplified resist  ..................................................................................... 30 

2.3.3 Unprotected oligopeptoids employing non-ionic PAG tethered as the 

solubility switch group  ........................................................................................... 32 

2.3.4 Lithographic patterning  ................................................................................ 33 

2.4 Results and discussion  ...................................................................................... 34 

2.4.1 TGA analysis  .................................................................................................. 34 

2.4.2 Optimization of baking and developing process  ......................................... 35 



 

vii 

2.4.3 AFM characterization of patterns for DUV lithography  ........................... 37 

2.4.4 LC-MS characterization of click reaction product  .................................... 38 

2.5 Conclusion  ......................................................................................................... 40 

REFERENCES  ......................................................................................................... 42 

CHAPTER 3: TOWARDS THE SYNTHESIS OF PEPTOID-HYDROCARBON 

BLOCK COPOLYMERS VIA ATRP AND RAFT POLYMERIZATION  ............ 44 

3.1 Introduction  ...................................................................................................... 44 

3.1.1 Block copolymer design and directed self-assembly  .................................. 44 

3.1.2 Polymerization methods  ................................................................................ 46 

3.2 Experimental methods  ..................................................................................... 49 

3.3 Material design and synthesis  .......................................................................... 50 

3.3.1 Peptoid design and synthesis  ........................................................................ 50 

3.3.2 ATRP grafting-from  ...................................................................................... 51 

3.3.3 RAFT and amidation  .................................................................................... 54 

3.4 Results and discussion  ...................................................................................... 56 

3.4.1 Optimization of ATRP conditions  ................................................................ 56 

3.4.2 RAFT and amidation route  .......................................................................... 58 

3.5 Conclusion  ......................................................................................................... 60 

REFERENCES  ......................................................................................................... 62 

CHAPTER 4: FUTURE WORK  .............................................................................. 64 

4.1 Sequence-defined and length-controlled oligopeptoids  ................................. 64 

4.2 Polypeptoid-based block copolymers for directed self-assembly lithography    .. 65 

4.3 Conclusion  ......................................................................................................... 66 



8 

LIST OF FIGURES 

Figure 1.1 Process flow of general photolithography  .............................................. 11 

Figure 1.2 Schematic of a EUV photolithography machine  .................................... 12 

Figure 1.3 RLS trade-off  ......................................................................................... 15 

Figure 1.4 (a) Comparison of conventional polymer-based resists vs. sequence-

defined polymers, (b) Molecular structures of peptoids and peptides  ...................... 16 

Figure 2.1 CAR process flow  .................................................................................. 23 

Figure 2.2 (a) Reaction scheme of Huisgen’s 1,3-dipolar cycloaddition and CuAAC, 

(b) deprotection of chemically amplified resists  ...................................................... 25 

Figure 2.3 Synthesis scheme of non-ionic PAGs for (a) PAGs functioning as a 

solubility switch and (b) chemically amplified photoresist  ...................................... 29 

Figure 2.4 Peptoid structure and synthetic scheme (a) protected P_8T_P 10-mer in 

which tyramines serve as solubility switch groups and propargyl amines function as 

clickable sites (b) PTTPTTPTTP 10-mer, designed with a distinct distribution and 

number of propargyl amines and (c) typical synthetic steps for peptoid assembly on 

CTC resin  .................................................................................................................. 30 

Figure 2.5 Peptoid structure of PMFMPMFMP 9-mer, designed with propargyl 

amines as potential sites of click reaction  ................................................................ 32 

Figure 2.6 Peptoid structure after click reaction  ...................................................... 33 

Figure 2.7 TGA measurement of peptoid tBoc protected PTTPTTPTTP. 2% weight 

loss at 114 ˚C  ............................................................................................................ 35 

Figure 2.8 TGA measurement of non-ionic PAG NI-Ts-Br. 2% weight loss at 144 ˚C 

 ................................................................................................................................... 35 

Figure 2.9 DUV (248 nm) 1:1 Line space pattern; dose 60 mJ/cm2; post-apply and 

post-exposure bake temperature 110 ˚C; 40 wt.% TPS-TF, developed in (a) undiluted 



 

9 

AZ 726 for 3 seconds and (b) 50× diluted AZ 726 for 45 seconds, observed under 

AFM  ......................................................................................................................... 37 

Figure 2.10 LC-MS analysis of products following 3 purification methods: (a) direct 

precipitation in hexane, (b) alumina column purification followed by precipitation, and 

(c) alumina column purification followed by vacuum drying  .................................. 39 

Figure 3.1 (a) process flow of DSA, (b) design formula of BCP  ............................ 46 

Figure 3.2 (a) mechanism of conventional ATRP, (b) widely used initiators, ligands 

and (c) monomers  ..................................................................................................... 47 

Figure 3.3 (a) mechanism scheme of RAFT polymerization, (b) typical structures of 

CTAs  ......................................................................................................................... 49 

Figure 3.4 Peptoid structure of (FM)10-R 20-mer or 21-mer (named as (FM)10 20-mer, 

(FM)10-2C 21-mer, (FM)10-4C 21-mer and (FM)10-bis-2CCO 21-mer, respectively) 

 ................................................................................................................................... 51 

Figure 3.5 Functionalization of peptoid to a macroinitiator and ATRP polymerization 

 ................................................................................................................................... 51 

Figure 3.6 Synthetic scheme for amine functionalized as an initiator to be attached to 

peptoid  ...................................................................................................................... 53 

Figure 3.7 FTIR of N-(2-aminoethyl)-2-bromo-2-methylpropanamide and its TFA salt 

 ................................................................................................................................... 53 

Figure 3.8 Structure of (a) 21-mer peptoid(I) (FM)10-amino-initiator and (b) 21-mer 

peptoid(I)-b-PMMA block copolymer  ..................................................................... 54 

Figure 3.9 Synthetic scheme of RAFT polymerization and amidation  ................... 55 

Figure 3.10 NMR analysis of 21-mer peptoid (I)-b-PMMA confirmed the successful 

polymerization  .......................................................................................................... 58 

Figure 3.11 NMR analysis of PMMA synthesized via RAFT polymerization indicated 

m≈30 (90.17/3≈30) for 45 eq of MMA added  ......................................................... 59 



 

10 

 

CHAPTER 1 

Introduction 

1.1 Prospects and background of photolithography 

 

The semiconductor industry plays a pivotal role in the development of integrated 

circuit (IC) devices, which are used in microelectronics and are the basis of computing, 

signal processing, and data storage. The origins of this industry can be traced back to 

the invention of the first transistor in 1947, marking the beginning of a technological 

revolution.1 Since then, semiconductor devices have undergone remarkable 

advancements in both compact size and functionality.2 This rapid progression is well 

represented by Moore’s Law, which predicts that the number of transistors per unit 

area doubles approximately every two years.3-5 

In recent years, however, maintaining the scaling trend predicted by Moore’s Law has 

posed increasing challenges, particularly in terms of resolution limitations in current 

lithography tools.6-9 The fabrication of nanometer-scale semiconductor devices relies 

on photolithography, a process in which light selectively passes through a photomask 

and transfers the designed patterns onto photoresist-coated wafer substrates. Following 

exposure, the wafer undergoes chemical development, where localized chemical 

reactions occur in the exposed regions of the resist layer, leading to the selective 

removal of either the exposed (positive resist) or unexposed (negative resist) regions. 

The developed resist pattern is then transferred onto the substrate via etching or 

deposition, after which the resist layer is removed, completing the patterning process. 



 

11 

Figure 1.1 Process flow of general photolithography10 

 

1.2 DUV, EUV, and electron beam lithography 

 

In optical lithography, achieving higher resolution is generally facilitated by the use of 

shorter-wavelength light. This principle is rooted in the diffraction effects of optics: 

when an electromagnetic wave encounters an aperture or obstacle comparable in size 

to its wavelength, it deviates from straight-line propagation. As a result, the 

wavelength of the light source in photolithography must be shorter than the smallest 

feature size intended to be patterned on the photomask. Quantitatively, the resolution 

of optical lithography can be described by Rayleigh’s equation: 

 

Where k is the Rayleigh coefficient dictated by processing condition, coefficient of the 

light, and NA is the numerical aperture determined by imaging systems. This equation 



 

12 

establishes a relationship between wavelength, numerical aperture, and process factors, 

providing a fundamental limit to the minimum feature size that can be reliably printed. 

The wavelength used in photolithography has progressively shortened from 436 nm 

visible g-line to 13.5 nm extreme ultraviolet (EUV) light, enabling ever-smaller 

feature sizes in semiconductor manufacturing.11-13 The modern EUV photolithography 

system is regarded as the key technology to sustaining Moore’s Law, allowing the 

continued scaling of transistor dimensions. Below is a brief overview of the 

mechanism behind EUV photolithography tools.14 

Figure 1.2 Schematic of a EUV photolithography machine14 

 

As of 2025, the most established EUV light source is tin plasma.15-18 Unlike traditional 

lithography, EUV lithography cannot use lenses, as no known material is transparent 

to such short-wavelength radiation. Instead, mirrors are employed to direct the light 

from the source to the wafer. These mirrors are composed of alternating layers of 



 

13 

molybdenum and silicon, engineered to enhance constructive interference and 

maximize reflectivity. The EUV photomask operates similarly—unlike conventional 

masks that block light, the EUV mask functions as a reflective optical component, 

utilizing Bragg diffraction through alternating metal layers to control pattern transfer. 

The mask pattern is then reduced through a projection optical system and imprinted 

onto the wafer. 

Another approach to overcoming the diffraction limit is electron beam lithography 

(EBL).19,20 High-energy electrons are emitted under high voltage (typically tens of kV) 

in a vacuum, guided and focused by magnetic lenses, and deposit energy onto E-beam 

resist layers. EBL offers exceptional resolution, with spot sizes below 0.5 nm and 

feature sizes around 10 nm. Unlike photolithography, EBL is maskless, providing 

design flexibility. However, its sequential scanning process significantly limits 

throughput, making it impractical for large-scale semiconductor manufacturing. To 

address this, mask-based electron beam lithography has been explored, where a mask 

scatters electrons, transferring a pattern onto the substrate. However, this method faces 

critical challenges: high-energy electrons generate excessive heat, potentially 

damaging the mask, while low-energy beams compromise pattern fidelity, making it 

less viable for high-resolution patterning.21 

 

1.3 Evaluating Photoresist Performance 

 

The resolution in photolithography is influenced by both the lithographic tool and the 

chemical properties of the photoresist. Several key factors must be considered in the 

design of photoresist materials: 

(1) Film Formation: The photoresist must be capable of uniformly coating the 

substrate wafer while ensuring strong adhesion to the silicon substrate.12 



 

14 

(2) Sensitivity: The resist must exhibit sufficient sensitivity to the specific radiation 

wavelength used in the lithographic process. 

(3) High Glass Transition Temperature (Tg): In processes requiring post-exposure 

bake (PEB), the resist must maintain structural integrity. If the Tg is lower than the 

baking temperature, pattern collapse may occur. 

(4) Selectivity to Etching Processes: The resist must effectively protect the underlying 

substrate during etching. Ideally, it should be etched at a significantly slower rate than 

the exposed substrate to ensure pattern fidelity. 

(5) Low Line Edge Roughness (LER): LER represents deviations of the actual feature 

edge from the ideal smooth contour, affecting pattern resolution and fidelity. 

In the context of chemically amplified resists (CARs)—which will be further 

discussed later—the resolution-line edge roughness-sensitivity (RLS) trade-off 

emerges as a key limitation. This trade-off, often visualized as the “triangle of death,” 

highlights the inherent incompatibility between resolution, sensitivity, and LER. The 

RLS trade-off dictates that these three properties cannot be simultaneously optimized. 

A widely used metric for evaluating photoresist performance is the Z parameter, which 

is mathematically defined as: 

 

where R represents resolution, L denotes LER, and D is the minimum dose required to 

completely remove the resist film from the substrate (a measure of resist sensitivity). 

A lower Z value indicates a higher-quality resist. 



 

15 

 

Figure 1.3 RLS trade-off22 

 

1.4 Peptoid as a candidate photoresist 

 

Traditional polymer-based photoresists typically exhibit polydispersity, containing a 

broad distribution of molecular weights. As photolithography advances toward sub-10 

nm resolution, this polydispersity worsens LER due to stochastic variations and non-

uniform copolymerization at the molecular scale.23-25 

In contrast, sequence-defined polymers offer superior control, minimizing stochastic 

effects while maintaining nearly perfect uniformity in terms of composition, chain 

length, and functional group placement.3 Peptoids, in particular, have gained 

increasing interest as potential high-performance photoresists. 

Peptoids are synthetic polymers that mimic peptides—essential structural components 

of proteins—while offering enhanced sequence control and chemical stability.26-30 

Unlike peptides, which are composed of amino acid monomers, peptoids are built 

from N-substituted glycine oligomers, with side chains attached to the nitrogen atom 



 

16 

of the backbone. Beyond their uniformity, peptoid-based photoresists offer several 

advantages: 

(1) High Production Efficiency: Peptoids can be synthesized with high precision using 

automated peptide synthesizers, enabling scalable manufacturing. 

(2) Enhanced Sensitivity: It’s been demonstrated that incorporating EUV-absorbing 

elements (e.g., metals and halogens) into peptoid-based resists significantly improves 

sensitivity.31 

(3) Tunable Functionality: A diverse range of functional groups can be incorporated 

into peptoids, allowing fine-tuning of properties such as adhesion, solubility switches, 

glass transition temperature, and etching resistance.32,33 

(a) (b) 

Figure 1.4 (a) Comparison of conventional polymer-based resists vs. sequence-

defined polymers,3 (b) Molecular structures of peptoids and peptides33 

 

This study focuses on two main directions: the development of well-defined 

oligopeptoids used directly as photoresists, and the construction of peptoid-PMMA 

block copolymers (BCPs) for directed self-assembly (DSA). The first approach 

explores oligopeptoids as standalone photoresist materials. Two architectures were 

explored, one design functions as a chemically amplified resist with the presence of 

physically blended ionic or non-ionic photoacid generators (PAGs). In the other, non-



 

17 

ionic PAGs were incorporated covalently. These two different mechanisms of resists 

were designed to systematically assess and compare their lithographic performance. 

The second aspect of this work involves the design of block copolymers in which the 

peptoids serve as a structurally programmable segment. When coupled with a polymer 

like poly(methyl methacrylate) (PMMA), the resulting BCP can be tailored to exhibit 

favorable phase separation behavior for DSA applications. Two synthetic strategies 

were employed to construct well-defined architectures: a grafting-from method using 

atom transfer radical polymerization (ATRP), and a grafting-to method based on 

reversible addition-fragmentation chain transfer (RAFT) polymerization followed by 

amidation. Both approaches aim to achieve precise control over block length and 

interfacial properties, which are critical to producing high-resolution nanostructures. 

Together, these two systems represent complementary pathways to address key 

challenges in next-generation EUV lithography materials, including molecular-level 

uniformity, functional tunability and process compatibility. 

The remainder of this thesis is organized as follows. In Chapter 2, we present the 

design, solid-phase synthesis, purification and preliminary DUV lithographic 

evaluation of sequence-defined, length-controlled oligopeptoids-comparing 

chemically amplified and click-functionalized architectures-and establish how film 

thickness, bake temperatures and developer strength influence the observed 

positive/negative tone-switch behavior. Chapter 3 focuses on the construction of 

peptoid-PMMA block copolymers for directed self-assembly, detailing both ATRP 

‘grafting-from’ and RAFT-amidation routes, the optimization of macroinitiator design 

and polymerization conditions, and the challenges encountered in block copolymer 

purification and characterization. Finally, Chapter 4 outlines future work: systematic 

mapping of thickness-dependent tone switching under EUV conditions, further 



 

18 

investigation in lithographic performance of click-modified peptoids, and further 

refinement of block copolymer synthesis and analysis techniques. 



 

19 

REFERENCES 

 

[1] Bardeen, J.; Brattain, W. H. The Transistor, a Semi-Conductor Triode. Phys. Rev. 
1948, 74, 230-231. 
 
[2] Gilbert, H. D., Ed. Miniaturization; Reinhold Publishing: New York, 1961. 
 
[3] Meng, X. Z.; Käfer, F. H.; Wallraff, G. M.; Ober, C. K.; Segalman, R. A. 
Controlled Sequence Peptoids as Photoresist Platforms for High-Resolution 
DUV/EUV Photoresists. Proc. SPIE 2022, 12292, 122920Q. 
 
[4] Moore, G. E. Cramming More Components onto Integrated Circuits. Electronics 
1965, 38 (8), 1-14. 
 
[5] Moore, G. E. Progress in Digital Integrated Electronics. Tech. Dig. Int. Electron 
Devices Meet. 1975, 21, 11-13. 
 
[6] Meng, L.; Xin, N.; Hu, C.; et al. Dual-Gated Single-Molecule Field-Effect 
Transistors beyond Moore’s Law. Nat. Commun. 2022, 13, 1. 
 
[7] Shalf, J. M.; Leland, R. Computing beyond Moore’s Law. Computer 2015, 48 (12), 
14-23. 
 
[8] Sui, C. Semiconductor Physics. In Electronic Devices, Circuits, and Applications 
2022, 35-39. 
 
[9] Mack, C. A. Fifty Years of Moore’s Law. IEEE Trans. Semicond. Manuf. 2011, 24 
(2), 202-207. 
 
[10] What Is Photolithography? GeeksforGeeks. https://www.geeksforgeeks.org/what-
is-photolithography/. 
 
[11] Subramanian, A.; Tiwale, N.; Lee, W.-I.; et al. Vapor-Phase Infiltrated Organic–
Inorganic Positive-Tone Hybrid Photoresist for Extreme UV Lithography. Adv. Mater. 
Interfaces 2023, 10 (28), 2300420. 
 
[12] Goldfarb, D. L. Evolution of Patterning Materials towards the Moore’s Law 2.0 
Era. Jpn. J. Appl. Phys. 2022, 61 (SD), SD0802. 
 
[13] De Silva, A.; Guo, J.; Dutta, A.; Goldfarb, D. L.; Church, J.; et al. Patterning 
Material Challenges for Improving EUV Stochastics. J. Photopolym. Sci. Technol. 
2019, 32, 169-177. 
 
[14] https://www.elecfans.com/d/659556.html 
 
[15] Versolato, O. O. Atomic and Molecular Physics Aspects of EUV Light Sources 
for Lithography. Plasma Sources Sci. Technol. 2019, 28, 083001. 
 
[16] Banine, V. Y.; Koshelev, K. N.; Swinkels, G. H. P. M. Physical Processes in 
EUV Sources for Lithography. J. Phys. D: Appl. Phys. 2011, 44, 253001. 

https://www.geeksforgeeks.org/what-is-photolithography/
https://www.geeksforgeeks.org/what-is-photolithography/


 

20 

[17] Bakshi, V., Ed. EUV Sources for Lithography; SPIE Press: Bellingham, WA, 
2006. 
 
[18] Bakshi, V., Ed. EUV Lithography, 2nd ed.; SPIE Press: Bellingham, WA, 2018. 
 
[19] Li, L.; Liu, X.; Pal, S.; Wang, S.; Ober, C. K.; Giannelis, E. P. Directed Assembly 
of Polymer Nanostructures for Lithography. Chem. Soc. Rev. 2017, 46, 4855-4866. 
 
[20] Pimpin, A.; Srituravanich, W. Review on Micro- and Nanolithography 
Techniques and Their Applications. Eng. J. 2011, 16 (1), 37-56. 
 
[21] Shamoun, B.; Sprague, M. A.; Engelstad, R. L.; Cerrina, F. Photomask In-Plane 
Distortion Induced during E-Beam Patterning. Proc. SPIE 1998, 3331. 
 
[22] BRG - A Brief Overview of Nanotechnology. Barrett-group.mcgill.ca. 
https://barrett-group.mcgill.ca/tutorials/nanotechnology/nano05.htm. 
 
[23] Ober, C. K.; Xu, H.; Kosma, V.; et al. EUV Photolithography: Resist Progress 
and Challenges. Proc. SPIE 2018, 10583. 
 
[24] Ashby, P. D.; Olynick, D. L.; Ogletree, D. F.; et al. Resist Materials for Extreme 
Ultraviolet Lithography: Toward Low-Cost Single-Digit-Nanometer Patterning. Adv. 
Mater. 2015, 27 (38), 5813-5819. 
 
[25] Mojarad, N.; Gobrecht, J.; Ekinci, Y. Beyond EUV Lithography: A Comparative 
Study of Efficient Photoresists’ Performance. Sci. Rep. 2015, 5, 9235. 
 
[26] Yu, B.; Chang, B. S.; Loo, W. S.; et al. Nanopatterned Monolayers of Bioinspired, 
Sequence-Defined Polypeptoid Brushes for Semiconductor/Bio Interfaces. ACS Nano 
2024, 18 (10), 7411-7423. 
 
[27] Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; et al. Peptoids: A Modular 
Approach to Drug Discovery. Proc. Natl. Acad. Sci. U.S.A. 1992, 89 (20), 9367-9371. 
 
[28] Nyembe, P. L.; Ntombela, T.; Makatini, M. M. Structure-Activity Relationship of 
Antimicrobial Peptoids: A Review. Pharmaceutics 2023, 15 (5). 
 
[29] Lee, B. C.; Connolly, M. D.; Zuckermann, R. N. Bio-Inspired Polymers for 
Nanoscience Research. Proc. NSTI Nanotech. 2007, 2, 28-31. 
 
[30] Gao, C. M.; Yam, A. Y.; Wang, X.; et al. Aβ40 Oligomers Identified as a 
Potential Biomarker for the Diagnosis of Alzheimer’s Disease. PLOS ONE 2011, 5 
(12), e15725. 
 
[31] Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. Efficient Method 
for the Preparation of Peptoids [Oligo(N-Substituted Glycines)] by Submonomer 
Solid-Phase Synthesis. J. Am. Chem. Soc. 1992, 114 (26), 10646-10647. 
 
[32] Tran, H.; Gael, S. L.; Connolly, M. D.; Zuckermann, R. N. Solid-Phase 
Submonomer Synthesis of Peptoid Polymers and Their Self-Assembly into Highly-
Ordered Nanosheets. J. Vis. Exp. 2011, (57), e3373. 

https://barrett-group.mcgill.ca/tutorials/nanotechnology/nano05.htm


 

21 

[33] Butterfoss, G. L.; Yoo, B.; Jaworski, J. N.; et al. De Novo Structure Prediction 
and Experimental Characterization of Folded Peptoid Oligomers. Proc. Natl. Acad. Sci. 
U.S.A. 2012, 109 (36), 14320-14325. 



 

22 

CHAPTER 2 

 

Design and Synthesis of Sequence-Defined Oligopeptoids for Potential Lithographic 

Use 

2.1 Introduction 

 

The next generation photoresist system for EUVL must overcome the inherent 

stochastic effects that limit resolution, line edge roughness, and pattern fidelity at the 

nanoscale. One promising approach to address these challenges is the use of sequence-

defined and length-controlled peptoids. Unlike conventional polymeric resists, which 

exhibit broad molecular weight distributions and compositional randomness, peptoids 

synthesized via automated solid-phase peptide synthesizer exhibit precise control over 

chain length, sequence, and functionality so that they have identical chains with each 

other. Furthermore, their unique backbone structure, featuring side chains attached to 

the nitrogen atom rather than the α-carbon, eliminates main chain chirality and 

reduces the likelihood of strong intermolecular hydrogen bonding. These 

characteristics help suppress stochastic variation, leading to more predictable and 

uniform pattern formation. 

One of the two types of photoresists investigated in this study functioned as CARs. 

CARs have emerged as a promising approach for high-resolution patterning in 

nanolithography, particularly for semiconductor manufacturing.1 Unlike conventional 

photoresists,2-4 CARs utilize a chemical amplification mechanism to enhance both 

sensitivity and resolution. The CAR system typically consists of the following 

components: a polymer matrix, PAG and developer solvent. The key principle of 

CARs is the photoacid-catalyzed reaction. A second major contributor to stochastic 

variation arises from the photoacid generator, a key component in CAR systems. Upon 



 

23 

EUV exposure, a single photon generates photoelectrons and secondary electrons, 

which activate PAG molecules to release strong acids. These acids then catalyze 

solubility-altering reactions—such as side chain deprotection—during the post-

exposure bake (PEB), changing the solubility of polymer backbone in developer. The 

energy needed to activate PAG is significantly lower than that needed for polymer, 

enabling pattern formation with dramatically reduced exposure dose, which is crucial 

for achieving sub-10 nm patterning.1 

 

Figure 2.1 CAR process flow1 

 

However, traditional CAR systems,1,5,6 originally optimized for 193 nm DUV 

lithography, exhibit performance limitations under 13.5 nm EUV exposure. Key 

challenges include: (1) acid diffusion lengths that approach the target feature size, 

compromising resolution, and (2) non-selective ionization by low-energy secondary 

electrons, leading to variability in acid generation.7,8 PAGs themselves play a central 

role in these challenges. Continued development of high-efficiency, low-stochastic 

PAG systems remains critical for advancing EUV photoresist technology. They are 

typically categorized as onium salts9-12 (e.g., iodonium or sulfonium-based PAGs) or 



 

24 

non-ionic species,13,14 each with distinct properties in terms of acid yield and thermal 

stability. Previously, ionic PAGs were widely favored due to their reliable sensitivity 

to EUV radiation.15 To improve patterning efficiency and reduce line-edge roughness, 

a common strategy involved increasing the PAG loading within the resist formulation. 

However, this approach introduced a critical drawback: the tendency of PAGs to 

segregate within the resist matrix, leading to inhomogeneous acid generation and 

reduced pattern fidelity. On the contrary, non-ionic PAGs have been proven to 

outperform ionic PAGs in several respects, including reduced dark loss, lower 

outgassing, and prevention of PAG phase separation.16 For EUV lithography, PAGs 

face the same additional challenges with CARs. Strategies such as incorporating PAGs 

into the polymer backbone or designing low-diffusion PAGs are being explored to 

address these issues. 

To address these challenges, click chemistry has been employed to covalently attach 

PAGs onto peptoid backbones. This approach offers a highly efficient and modular 

strategy for constructing macromolecular architecture, making it especially valuable in 

the development of functional materials such as photoresists for advanced lithographic 

applications. Drawing inspiration from nature's method of assembling complex 

biomolecules through simple, repetitive linkages—typically carbon–heteroatom 

bonds—click reactions enable the formation of robust covalent bonds under mild 

conditions, with high selectivity and yield. This versatility makes click chemistry a 

powerful tool for post-synthetic modification and precise architectural control.17 

Several reactions fall under the umbrella of click chemistry; among them, the copper-

catalysed azide–alkyne cycloaddition (CuAAC) and the Diels-Alder reaction are two 

of the most widely utilized. These reactions facilitate the modular attachment of 

functional side chains, allowing for the fine-tuning of key material properties such as 

solubility, adhesion, and etch resistance. The CuAAC reaction, in particular, is 



 

25 

renowned for its simplicity, reliability, and broad functional group compatibility. It 

exemplifies click chemistry due to the accessibility and stability both azide and alkyne 

groups, along with their tolerance to a variety of solvents and reaction conditions. 

Unlike the uncatalyzed Huisgen 1,3-dipolar cycloaddition, which produces a mixture 

of 1,4 and 1,5-disubstituted triazoles, the CuAAC reaction, catalyzed by Cu(I), 

proceeds with complete regioselectivity to afford only the 1,4-disubstituted triazole 

product (as illustrated in Figure 2.2(a)). This level of control is crucial for addressing 

the limitations of traditional resists, which often exhibit compositional inhomogeneity 

and inconsistent patterning performance at the nanometer scale. 

(a) (b) 

Figure 2.2 (a) Reaction scheme of Huisgen’s 1,3-dipolar cycloaddition and 

CuAAC, (b) deprotection of chemically amplified resists 

 

In this study, two distinct types of peptoid-based photoresist sequences were designed 

to investigate the influence of PAG architecture on lithographic performance. The first 

type follows a traditional CAR mechanism. These sequences consist of an 

oligopeptoid backbone functionalized with acid-labile groups—specifically, tert-

butyloxycarbonyl (tBoc) protecting groups. Upon DUV exposure, the PAGs produce 

acid, which catalyzes the deprotection of the tBoc groups, as illustrated in Figure 

2.2(b). This reaction transforms the resist material from hydrophobic to hydrophilic, 

thereby functioning as a solubility switch. Building on prior studies demonstrating the 



 

26 

value of sequence-controlled peptoids as a versatile platform for designing modular, 

high-resolution, and low-line-edge-roughness resists suitable for EUVL, this work 

specifically examines how replacing conventional ionic PAGs with non-ionic 

alternatives affects the performance of peptoid-based resist systems. To that end, the 

designed sequences were mixed with either synthesized non-ionic PAGs or 

commercially available ionic PAGs, and their lithographic outcomes were 

systematically compared. 

In contrast, the second type of sequence was invented to incorporate non-ionic PAGs 

directly into the peptoid backbone via covalent attachment, using click chemistry as 

the coupling strategy. To enable this, propargylamine was included in the peptoid 

sequence to serve as a clickable alkyne-functionalized monomer. Correspondingly, a 

non-ionic PAG bearing an azide group at its terminus was synthesized. The click 

reaction between the azide-functionalized PAG and the alkyne groups in the peptoid 

chain results in covalently tethered PAGs that are uniformly distributed along the 

polymer backbone. This architecture design is intended to enhance the spatial 

distribution of acid generation, thereby mitigating stochastic effects and promoting 

uniform feature development, especially at the nanometer scale. 

 

2.2 Experimental methods 

 

Synthesis of peptoids: All reagents and solvents were purchased from Sigma–Aldrich 

and used without further purification. Oligopeptoids were synthesized using a CSBio 

Peptide Synthesizer, Model CS336X. The oligopeptoids photoresist designed to use 

attached non-ionic PAG molecules as solubility switch groups were synthesized at 

California NanoSystems Institute (CNSI) at UCSB using a Prelude X peptide 

synthesizer. 



 

27 

Peptoid purification: The peptoids were cleaved from the solid-phase resin using 

either a 30% (v/v) solution of hexafluoroisopropanol (HFIP) in dichloromethane 

(DCM) for those synthesized on CTC resins, or a 50% (v/v) solution of trifluoroacetic 

acid (TFA) in DCM for those synthesized on RA resins. After cleavage, the resin was 

filtered, and solvent was evaporated. The resulting solid was dissolved in acetonitrile 

at a concentration of approximately 70 mg/mL, filtered through a hydrophilic PTFE 

membrane, and purified using a preparative high-performance liquid chromatography 

(HPLC) system (Agilent 1100) equipped with a Waters XBridge BEH C18 OBD Prep 

Column (130Å, 10 μm, 30 mm × 150 mm). Purification was performed using an 

acetonitrile/water mobile phase, employing a gradient elution where the acetonitrile 

content was increased from 30% to 95% over 30 minutes. Finally, the solution was 

evaporated and freeze dried. 

Liquid chromatography-mass spectrometry (LC–MS): LC-MS characterization 

was performed using a Shimadzu Nexera Analytical HPLC system equipped with C18 

columns featuring pore sizes of 100 Å and 300 Å. The system was coupled to an 

LCMS-2050 mass spectrometer, which supports electrospray ionization (ESI) and 

covers a mass range of 10–3000 m/z. 

Nuclear magnetic resonance spectrometer (NMR): The structural characterization 

of small-molecule non-ionic photoacid generators (PAGs) was confirmed by 1H NMR 

spectroscopy at room temperature using a Bruker AV-500 spectrometer. 

Fourier-transform infrared spectroscopy (FTIR): The chemical bonding 

characteristics of small-molecule PAGs were analyzed and identified using a Bruker 

Hyperion FT-IR spectrometer, providing detailed insights into their functional groups 

that could not be conclusively confirmed through NMR. 

Thermogravimetric Analysis (TGA): The thermal stability of the peptoids and 

small-molecule PAGs were evaluated by monitoring weight loss as a function of 



 

28 

temperature using a TA Instruments 5500 Thermogravimetric Analyzer, providing 

insights into their thermal degradation behavior. 

Differential Scanning Calorimeter (DSC): The glass transition, crystallization, and 

melting temperatures of the peptoids were determined using a TA Instruments DSC 

Auto 2500 Differential Scanning Calorimeter. 

Atomic Force Microscope (AFM): The performance of peptoids as photoresists was 

characterized using AFM-Veeco Icon in Cornell NanoScale Science and Technology 

Facility (CNF). 

DUV Wafer Stepper: All the samples were patterned using ASML PAS 5500/300C 

DUV Wafer Stepper in CNF. 

Spectroscopic ellipsometry: The film thickness of all samples were measured by 

Woollam RC2 Spectroscopic Ellipsometer in CNF. 

 

2.3 Material design and synthesis 

 

2.3.1 Non-ionic PAG 

Non-ionic PAGs were designed with active moieties, including naphthalimide, 

iminosulfonates, and aryl groups, to ensure sensitivity under DUV exposure, with the 

expectation that they would also exhibit high efficiency under EUV conditions. 

Additionally, azido groups were incorporated as clickable groups, enabling their 

chemical attachment to photoresist polymers. 



 

29 

Figure 2.3 Synthesis scheme of non-ionic PAGs for (a) PAGs functioning as a 

solubility switch and (b) chemically amplified photoresist 

 

Synthesis of 1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl 4-

(bromomethyl)benzenesulfonate (NI-Ts-CH2Br) 

N-Hydroxy-1,8-naphthalimide (1.0 eq, 4.46 mmol) and 4-

bromomethylbenzenesulfonyl chloride (1.5 eq, 6.68 mmol) were added to 90 mL of 

anhydrous DCM in a round-bottom flask. The mixture was purged with argon and 

cooled to 0 °C using an ice bath. N,N-Diisopropylethylamine (2.0 eq, 8.92 mmol) was 

then added slowly under vigorous stirring. After 1 hour of reaction, the reaction 

progress was monitored by thin-layer chromatography (TLC). Upon completion, the 

solvent was evaporated, and the resulting solid was washed with 20% (v/v) DCM in 

hexane, yielding a white powder. 

1H NMR (500 MHz, CDCl3) δ 8.67 (dd, J = 7.3, 1.1 Hz, 2H), 8.32 (dd, J = 8.3, 1.1 Hz, 

2H), 8.19 – 8.14 (m, 2H), 7.83 (dd, J = 8.2, 7.3 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 

4.575 (s, 2H). 

Synthesis of 1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl 4-

(azidomethyl)benzenesulfonate 

NI-Ts-CH₂Br (1.0 eq, 2.70 mmol) was dissolved in 200 mL of tetrahydrofuran (THF) 

at room temperature. Sodium azide (10 eq, 26.96 mmol) was added portion-wise, and 

the reaction mixture was stirred for 24 hours. After solvent evaporation, the resulting 



 

30 

solid was dissolved in 150 mL of DCM and extracted with water four times. The 

organic phase was dried over MgSO₄, concentrated, and purified by washing with 

diethyl ether, yielding a pale-yellow product. 

1H NMR (500 MHz, CDCl3) δ 8.65 (dd, J = 7.3, 1.2 Hz, 2H), 8.32 (dd, J = 8.2, 1.2 Hz, 

2H), 8.22 – 8.19 (m, 2H), 7.83 (dd, J = 8.2, 7.3 Hz, 2H), 7.65 – 7.60 (m, 2H), 4.577 (s, 

2H). 

Synthesis of 1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl 4-

(bromomethyl)benzenesulfonate (NI-Ts-Br) 

The synthesis of NI-Ts-Br followed the same procedure and equivalency of reactants 

as the synthesis of NI-Ts-CH₂Br, with the only difference being the use of 

triethylamine (TEA) in place of DIEA. 

 

2.3.2 Boc-protected oligopeptoids employing the solubility-switch mechanism in a 

chemically amplified resist 

Oligopeptoid synthesis 

(a) (b) 

(c) 

Figure 2.4 Peptoid structure and synthetic scheme (a) protected P_8T_P 10-mer in 

which tyramines serve as solubility switch groups and propargyl amines function as 



 

31 

clickable sites (b) PTTPTTPTTP 10-mer, designed with a distinct distribution and 

number of propargyl amines and (c) typical synthetic steps for peptoid assembly on 

CTC resin18 

 

Solid-phase peptoid synthesis follows a repetitive two-step cycle: acylation and 

nucleophilic displacement of primary amines (Figure 2.4(c)). Typically, 1 g of CTC 

resin was swelled and well dispersed in dimethylformamide (DMF), followed by the 

addition of 10 mL of 1.3 M bromoacetic acid (BrAA) solution in DMF and 10 mL of 

1.3 M N,N'-diisopropylcarbodiimide (DIC) solution in DMF. The mixture was shaken 

for 30 minutes before draining. After four washes with DMF, 10 mL of 1.5 M 

propargyl amine (P) in DMF or 1.0 M tyramine (T) in N-methyl-2-pyrrolidone (NMP) 

was added to the reaction vessel, followed by continuous nitrogen bubbling and 

shaking for 1 hour per step. The solution was then drained, and the resin was washed 

with DMF four times. This process was repeated until all programmed amines were 

reacted and attached to the chain end. Peptoids containing tyramines in their sequences 

were protected using 5.0 eq of di-tert-butyl decarbonate (Boc2O) and 0.05 eq of 4-

dimethylaminopyridine (DMAP) per tyramine unit. The reaction mixture was shaken 

overnight, followed by sequential washing with DMF and DCM. After cleavage using 

HFIP solution and purification, the structures corresponded to Figure 2.4 (a) and (b), 

where the protected tyramines were specifically designed to act as solubility switch 

groups upon exposure, while the propargyl amines served as clickable sites. The two 

synthesized sequences, which differed in the distribution and quantity of propargyl 

amines, resulting in 32 wt.% and 75 wt.% of PAG, respectively, in the resist system, 

were further evaluated to determine their influence on photoresist efficiency. The 

sequences were characterized with LC-MS and proven to be successfully synthesized. 

 



 

32 

2.3.3 Unprotected oligopeptoids employing non-ionic PAG tethered as the 

solubility switch group 

Oligopeptoid synthesis 

Figure 2.5 Peptoid structure of PMFMPMFMP 9-mer, designed with propargyl 

amines as potential sites of click reaction 

 

The synthesis and purification followed the same procedure as that of Boc-protected 

oligopeptoids, with the key difference being the use of RA resin as the solid phase. 

Consequently, the cleavage process was performed using a TFA solution. In the 

synthesized sequence shown in Figure 2.5, propargyl amines remained the designated 

clickable sites. The PAGs attached to the sequence function as the solubility switch 

groups—upon exposure, the tethered PAGs undergo dissociation, rendering the 

oligopeptoid soluble in aqueous base. Phenylethylamine (F) has been widely favored 

for its robustness during peptoid synthesis. Initially, (PF2)3 was designed; however, its 

high hydrophobicity posed significant challenges during purification, where a water-

acetonitrile solvent system was employed. To address this issue, 2-methoxyethylamine 

(M) was introduced to incorporate a neutral, polar side chain into the sequence, 

enhancing its suitability for application as an aqueous solution developable organic 

photoresist thin film. 

CuAAC Click reaction 



 

33 

Figure 2.6 Peptoid structure after click reaction 

 

PMFMPMFMP peptoid (1.0 eq, 0.046 mmol) and NI-Ts-CH2Br PAG (4.5 eq, 0.21 

mmol) were dissolved in 15 mL of THF and 0.2 mL of DMF in a three-neck flask, and 

the mixture was purged with Ar. CuBr (0.4 eq, 0.018 mmol) and PMDETA (0.45 eq, 

0.021 mmol) were then added under vigorous stirring while maintaining continuous 

Ar purging. The reaction was carried out overnight at room temperature, during which 

the solution gradually turned dark green—an indication of successful complex 

formation. Upon completion, the reaction was quenched by exposure to air and diluted 

with THF. The crude product was then precipitated in hexane, followed by 

centrifugation and drying in a vacuum oven for 24 hours. 

 

2.3.4 Lithographic patterning 

To evaluate the performance of our peptoid as a chemically amplified resist, we 

initially employed triphenylsulfonium trifluorosulfonate (TPS-TF), a widely used 

commercial ionic PAG. The spin-coating solution for the photoresist film was 



 

34 

prepared by dissolving 10 mg of Boc-protected PTTPTTPTTP and 40 wt.% of TPS-

TF (relative to the peptoid) in 1 mL of propylene glycol methyl ether (PGME). A 

separate solution containing the peptoid and the synthesized non-ionic PAG was 

prepared at the same concentration in acetone. Once fully dissolved, the solution was 

filtered and spin-coated onto a UV-ozone (UVO) cleaned silicon wafer. The post-

apply bake was conducted at 110 ˚C for 60 seconds, based on the Td determined from 

TGA results. The film was then exposed under DUV condition at a dose of 60 mJ/cm2, 

followed by a post-exposure bake at 110 ˚C for 60 seconds. Previously, our group 

attempted to develop the resist using isopropyl alcohol (IPA);18 however, the Boc-

protected PTTPTTPTTP proved to be soluble in IPA, leading to undesired dissolution 

of the whole film. As an alternative, we explored the use of diluted 

tetramethylammonium hydroxide (TMAH) aqueous solution as a potential developer. 

 

2.4 Results and discussion 

 

2.4.1 TGA analysis 

Approximately 5 mg of each sample was loaded at room temperature and heated to 

400 °C at a rate of 10 °C/min under a nitrogen atmosphere. The thermal 

decomposition temperature (Td) was a key parameter for determining the appropriate 

baking temperature. 



 

35 

Figure 2.7 TGA measurement of peptoid tBoc protected PTTPTTPTTP. 2% weight 

loss at 114 ˚C 

Figure 2.8 TGA measurement of non-ionic PAG NI-Ts-Br. 2% weight loss at 144 ˚C 

 

2.4.2 Optimization of baking and developing process 

Although photoresists exposed to DUV light exhibit fundamentally different behaviors 

under EUV light due to distinct acid generation mechanisms, DUV exposure was 



 

36 

utilized as a preliminary screening method to evaluate the resist systems and optimize 

processing conditions. 

Using tBoc protected PTTPTTPTTP and ionic PAG TPS-TF: Initially, a post-

apply bake and post-exposure bake temperature of 90 °C was tested, as peptoids 

exhibit limited thermal stability, beginning to degrade at 114 °C, with significant 

weight loss occurring above 150 °C (shown in Figure 2.7). However, under this 

condition, no discernible pattern was observed using any developing method. 

Consequently, the temperature was increased to 110 ˚C, a value previously employed 

by our group.18 Regarding the choice of developer solution, prior studies indicated that 

isopropyl alcohol (IPA) typically provides the highest selectivity.19 However, even 

after just 1 second of development in IPA, the entire film-both exposed and unexposed 

areas-was completely removed. Given that deprotection of the peptoids side chains 

renders them acidic and theoretically soluble in aqueous base solutions, different 

dilutions of TMAH aqueous solution were evaluated as alternative developers. A 

systematic screening was conducted, varying both TMAH concentration and 

development time, ranging from 10× to 100× diluted AZ® 726 MIF Developer (AZ® 

726 is an aqueous 2.38% TMAH solution with a surfactant for uniform substrate 

wetting) and development times spanning from 2 seconds to 1 hour. Another crucial 

factor affecting pattern formation was the film thickness deposited on the silicon wafer. 

Despite maintaining constant spin speed and spin time, the film thickness varied from 

16.43 nm to 31.74 nm. Notably, a development recipe that performed optimally on one 

thickness might not work for another. To address this, each wafer was sectioned into 

smaller pieces to determine the most effective development conditions. Among the 

tested conditions, two specific samples yielded the most distinct patterns, which had 

film thicknesses of 23.01 nm and 31.74 nm respectively. The first sample was 

developed in undiluted AZ 726 for 3 seconds, while the second was developed in 50× 



 

37 

diluted AZ 726 for 45 seconds. The detailed analysis of these results will be discussed 

in the following section. 

Using tBoc protected PTTPTTPTTP and non-ionic PAG NI-Ts-Br: Since the click 

reaction between peptoids and azido-functionalized PAGs remains to be optimized, an 

alternative approach was explored by simply mixing the peptoid with the non-ionic 

PAG NI-Ts-Br in acetone. NI-Ts-Br was chosen due to its structural similarity to the 

target clickable azido-PAG. This method aimed to simulate the behavior of the peptoid 

after undergoing the click reaction. However, after the post-apply bake, the resulting 

film was noticeably inhomogeneous significantly thicker than expected, measuring 

131.29 nm. Despite testing various exposure and development conditions, no distinct 

patterns were successfully generated. This suggests that further optimization of the 

click reaction is essential to achieving a uniform film and ensuring effective pattern 

formation. 

 

2.4.3 AFM characterization of patterns for DUV lithography 

(a) (b) 

Figure 2.9 DUV (248 nm) 1:1 Line space pattern; dose 60 mJ/cm2; post-apply and 



 

38 

post-exposure bake temperature 110 ˚C; 40 wt.% TPS-TF, developed in (a) undiluted 

AZ 726 for 3 seconds and (b) 50× diluted AZ 726 for 45 seconds, observed under 

AFM 

 

From AFM images presented above, the developed patterns exhibited imperfections, 

with some areas appearing overdeveloped. However, a fascinating tone-switch 

phenomenon was observed. In the case of the thinner film (Figure 2.9(a)), the 

photoresist behaved as a positive-tone resist, consistent with our initial hypothesis: 

upon exposure, the tyramine side chains undergo deprotection, rendering the exposed 

areas soluble in basic developer, leading to their removal. Surprisingly, in the thicker 

film scenario (Figure 2.9(b)), the resist exhibited characteristics of a negative-tone 

resist, as indicated by the higher height of the exposed areas in the AFM images. This 

unexpected behavior suggests that film thickness plays a critical role in determining 

the peptoid resist tone. While we hypothesize that this tone-switch effect is driven by 

changes in film thickness, the underlying mechanism behind the negative-tone 

behavior remains an open question and requires further investigation. 

 

2.4.4 LC-MS characterization of click reaction product 

Three different work-up procedures were evaluated. In the first approach, the crude 

product was directly precipitated in hexane. In the second method, the product was 

passed through an alumina column; however, significant retention of the peptoids was 

observed, suggesting strong interaction with the stationary phase. To recover the 

material, the column was washed with DMF, followed by precipitation in water. In the 

third method, the crude product was again passed through an alumina column, washed 

with DMF, and subsequently dried under vacuum. 



 

39 

Assuming full conversion at the clickable sites, the theoretical molecular weights of 

the modified peptoids are 2310.43 g/mol for 3 reacted sites, 1902.05 g/mol for 2 sites, 

and 1493.66 g/mol for a single site. LC-MS analysis of three product batches revealed 

dominant peaks at approximately 2310 and 408 Da (Figure 2.10), corresponding to the 

fully clicked product and PAG fragments, respectively. These results confirm that all 

three clickable sites were effectively reacted. 

Figure 2.10 LC-MS analysis of products following 3 purification methods: (a) direct 

precipitation in hexane, (b) alumina column purification followed by precipitation, and 

(c) alumina column purification followed by vacuum drying 

 

Notably, both samples subjected to alumina column purification showed a significant 

reduction in the intensity of the clicked product peak, indicating product loss during 

this step. The only observable difference after additional precipitation with water was 

a slight decrease in impurity peaks. To improve overall yield without compromising 

purity, the alumina column step may therefore be omitted, especially considering that 

only a minimal amount of copper catalyst was used in the reaction. To address residue 

PAG, the crude product was treated with a DCM/hexane mixture, which selectively 

dissolved the product while leaving PAG undissolved. 



 

40 

 

2.5 Conclusion 

In this work, we successfully designed and synthesized bioinspired, sequence-defined 

and length-controlled oligopeptoids incorporating both clickable sites and solubility-

switch functional groups. Two distinct strategies were explored: one employing Boc-

protected tyramines as acid-labile switches in a chemically amplified resist system, 

and the other utilizing tethered non-ionic PAGs directly integrated into the peptoid 

backbone. Solid-phase synthesis protocols were carefully optimized, enabling the 

construction of oligopeptoid sequences with controlled length and composition. In 

parallel, the HPLC purification profile was refined to enhance the isolation of high-

purity peptoid products, facilitating downstream processing. 

Thermal stability studies of both the oligopeptoids and PAG components helped 

determining the suitable post-apply and post-exopsure bake temperatures. Through 

systematic evaluation of key lithographic parameters—including developer 

composition, TMAH dilution ratios, and film thickness—a set of processing 

parameters was established to generate discernible patterns under DUV exposure. 

Intriguingly, a tone-switch behavior was observed in peptoid films formulated with 

ionic PAGs, wherein thinner films behaved as positive-tone resists while thicker films 

as negative-tone, highlighting the complex interplay between film morphology and 

development responses. 

Furthermore, a brand new type of resist using PAG tethered as the solubility switch 

was invented. The CuAAC click reaction was used to tether azide-functionalized 

PAGs onto peptoid backbones, with LC-MS confirming efficient tri-site conjugation 

under optimized reaction conditions. Comparative evaluation of purification methods 

revealed that bypassing the alumina column step significantly improved overall yield 

particularly due to the low amount of copper catalyst content. 



 

41 

Overall, this study demonstrates a modular synthetic framework for peptoid-based 

photoresists with tunable chemical functionality and processibility, paving the way for 

further investigations into their performance under EUV and electron beam 

lithographic conditions, advancing the development of next-generation organic resist 

materials. 



 

42 

REFERENCES 

 

[1] Reichmanis, E.; Houlihan, F. M.; Nalamasu, O.; Neenan, T. X. Chemically 
Amplified Resists: Chemistry and Processes. Adv. Mater. Opt. Electron. 1994, 4, 83-
93. 
 
[2] Reichmanis, E.; Thompson, L. F. Polymer Materials for Microlithography. Chem. 
Rev. 1989, 89 (6), 1273-1289. 
 
[3] Willson, C. G. Introduction to Microlithography-Chemically Amplified Resist 
Systems; in Introduction to Microlithography; Thompson, L. F.; Willson, C. G.; 
Bowden, M. J., Eds.; ACS Symposium Series 219; American Chemical Society: 
Washington, DC, 1983; pp 88-159. 
 
[4] Thompson, L. F.; Willson, C. G.; Bowden, M. J. Overview of Chemically 
Amplified Resist Systems; in Introduction to Microlithography; Thompson, L. F.; 
Willson, C. G.; Bowden, M. J., Eds.; ACS Symposium Series 219; American 
Chemical Society: Washington, DC, 1983; pp 1-87. 
 
[5] Moon, S.-Y.; Kim, J.-M. Chemistry of Photolithographic Imaging Materials Based 
on the Chemical Amplification Concept. J. Photochem. Photobiol. C Photochem. Rev. 
2007, 8 (4), 157-173. 
 
[6] Reichmanis, E.; Nalamasu, O.; Houlihan, F. M. Organic Materials Challenges for 
193 nm Imaging. Acc. Chem. Res. 1999, 32 (8), 659-667. 
 
[7] Torok, J.; Re, R. D.; Herbol, H.; Das, S.; Bocharova, I.; Paolucci, A.; Ocola, L. E.; 
Ventrice Jr, C.; Lifshin, E.; Denbeaux, G.; Brainard, R. L. Secondary Electrons in 
EUV Lithography. J. Photopolym. Sci. Technol. 2013, 26 (5), 625-634. 
 
[8] Martin, C. J.; Rapenne, G.; Nakashima, T.; Kawai, T. Recent Progress in 
Development of Photoacid Generators. J. Photochem. Photobiol. C Photochem. Rev. 
2018, 34, 41-51. 
 
[9] Crivello, J. V. Photopolymerization Mechanisms in Chemically Amplified 
Systems. In Polymers in Electronics, ACS Symposium Series 242; Davidson, T., Ed.; 
American Chemical Society: Washington, DC, 1984; pp 3-10. 
 
[10] Crivello, J. V.; Lee, J. L.; Conlon, D. A. Gel Formation in Cationic 
Polymerization of Divinyl Ethers. Makromol. Chem., Makromol. Symp. 1988, 13-14, 
145-160. 
 
[11] Crivello, J. V.; Lam, J. H. W. Photochemical Initiation of Cationic and 
Concurrent Radical-Cationic Polymerization. Macromolecules 1977, 10, 1307-1315. 
 
[12] Crivello, J. V.; Lam, J. H. W. Photoinitiated Cationic Polymerization with 
Triarylsulfonium Salts. J. Polym. Sci., Polym. Chem. Ed. 1996, 34, 3231-3253. 
 



 

43 

[13] Houlihan, F. M.; Shugard, A.; Gooden, R.; Reichmanis, E. Photo- and 
Thermochemistry of Select 2,6-Dinitrobenzyl Esters in Polymer Matrices: Studies 
Pertaining to Chemical Amplification. Macromolecules 1988, 21, 2001-2006. 
 
[14] Neenan, T. X.; Houlihan, F. M.; Reichmanis, E.; Kometani, J. M.; Bachman, B. J.; 
Thompson, L. F. Photo-Generated Acid-Catalyzed Chemical Amplification in 
Chemically Amplified Resists. Macromolecules 1990, 23, 145-150. 
 
[15] Higgins, C. D.; Szmanda, C. R.; Antohe, A.; Denbeaux, G.; Georger, J.; Brainard, 
R. L. Resolution, Line-Edge Roughness, Sensitivity Tradeoff, and Quantum Yield of 
High Photoacid Generator Resists for Extreme Ultraviolet Lithography. Jpn. J. Appl. 
Phys. 2011, 50 (3R), 036504. 
 
[16] Richard, A. L.; David, E. N.; Laren, M. T.; Clifford, L. H. Non-ionic PAG 
Behavior under High Energy Exposure Sources. In Proc. SPIE, 2009; 7273, 72731R. 
 
[17] Moses, J. E.; Moorhouse, A. D. The Growing Applications of Click Chemistry. 
Chem. Soc. Rev. 2007, 36 (8), 1249–1262. 
 
[18] Käfer, F.; Wang, C.; Huang, Y.; Bard, F.; Segalman, R.; Ober, C. K. 
Polypeptoids: Exploring the Power of Sequence Control in a Photoresist for Extreme-
Ultraviolet Lithography. Adv. Mater. Technol. 2023, 8, 2301104. 
 
[19] Deng, J.; Bailey, S.; Jiang, S.; Ober, C. K. High-Performance Chain Scissionable 
Resists for Extreme Ultraviolet Lithography: Discovery of the Photoacid Generator 
Structure and Mechanism. Chem. Mater. 2022, 34 (13), 6170–6181. 



44 

CHAPTER 3 

 

Towards the Synthesis of Peptoid-Hydrocarbon Block Copolymers via ATRP and 

RAFT Polymerization 

3.1 Introduction 

 

3.1.1 Block copolymer design and directed self-assembly 

Block copolymers, composed of covalently linked polymer segments with distinct 

chemical compositions, have emerged as promising materials for nanoscale patterning 

via directed self-assembly. Molecular directed self-assembly refers to the spontaneous 

aggregation of molecules into thermodynamically stable structures. This process, as 

illustrated in Figure 3.1(a), begins with the chemical patterning of a substrate, creating 

regions with distinct surface chemistries through conventional lithography and etching 

techniques.1,2 This patterned surface guides the spontaneous organization of BCPs into 

periodic nanostructures, driven by microphase separation and surface energy 

minimization. After self-assembly, one of the blocks is selectively removed, leaving 

behind a polymer mask that guides the patterning of the underlying substrate, enabling 

pattern rectification as well as a multiple-fold reduction in the pattern feature size 

beyond the resolution limit of conventional photolithography. 

The effectiveness of DSA critically depends on the physical and chemical properties 

of the BCP. Two primary thermodynamic parameters govern the self-assembly 

process: surface energy difference ( ) and Flory-Huggins interaction parameter (χ) 

of the polymer components.3-8 

Surface energy (SE) quantifies the excess energy at a material’s surface relative to its 

bulk. In a BCP with a significant surface energy difference, the lower-SE block 

preferentially localizes at the surface, while the higher-SE block forms the bulk. This 



 

45 

imbalance affects film quality and self-assembly. Ideally, the surface energy 

difference should be minimized to . 

Flory-Huggins interaction parameter, which quantifies the incompatibility between 

blocks and segregation strength, also plays a crucial role in DSA. A higher χ promotes 

phase separation, forming well-defined domains. However, excessive segregation can 

introduce defects. To balance self-assembly and defect minimization, χN (where N is 

the degree of polymerization) typically needs to fall within a narrow range of 20-25, 

ensuring effective pattern formation without compromising structural integrity.9-12 In 

general, BCP with high χN tends to have blocks with very different polarity, which in 

turn increases , illustrating a fundamental trade-off between phase separation and 

interfacial compatibility. 

To resolve this, H. Feng et al. proposed an optimized design strategy using 

asymmetric BCPs with the architecture A-b-(B-r-C), where B and C are statistically 

copolymerized to form a tunable hybrid block.13 By adjusting the C composition ( ), 

the χ parameter and surface energy of the B-r-C block can be modulated 

simultaneously, allowing independent control of thermodynamic and interfacial 

properties. As shown in Figure 3.1(b),13 the χ value of A-b-(B-r-C) follows a parabolic 

trend between that of A-b-B and A-b-C, enabling precise tuning toward an optimal 

condition where surface energy mismatch is minimized while maintaining sufficient 

segregation strength for microphase separation. 



 

46 

Figure 3.1 (a) process flow of DSA, (b) design formula of BCP13 taken with 

permission from Nat Mater. 2022;21(12):1426-1433. 

 

Building on this concept, we designed a novel BCP system in which PMMA serves as 

the A block and a sequence-defined oligopeptoid as the B-r-C segment. The peptoid 

was designed with alternating polar monomers M and non-polar monomers F to 

modulate polarity and surface interactions in a programmable manner. Spacer units 

were further incorporated at the chain end to reduce inter-block steric interference and 

improve polymerization efficiency. This molecular design aims to provide a favorable 

balance between χ and SE, thereby facilitating the formation of well-aligned 

nanodomains with high pattern fidelity. 

 

3.1.2 Polymerization methods 

To realize the architecture mentioned above, synthetic precision is essential—

particularly for controlling block lengths and end-group functionalities. Therefore, two 

living/controlled radical polymerization strategies were explored in this study: atom 

transfer radical polymerization and reversible addition-fragmentation chain transfer 

polymerization. Both methods enable the preparation of polymers with narrow 



 

47 

molecular weight distribution and well-defined structures, making them suitable for 

constructing block copolymers with peptoids. 

Atom transfer radical polymerization: ATRP is a type of controlled/living radical 

polymerization that allows for precise control over polymer chain length, dispersity 

and end-group functionality. Unlike conventional radical polymerization, where chain 

termination is frequent and uncontrolled,15,16 ATRP relies on a reversible activation-

deactivation mechanism mediated by a transition metal complex.17 In a typical ATRP 

process, a halogen-capped dormant chain end is reversibly activated by a metal 

catalyst (e.g., Cu(I)) to form a propagating radical. After addition of a monomer unit, 

the growing radical is quickly deactivated by re-capping with the halogen, 

regenerating the dormant species.18 This fast and reversible cycle between active and 

dormant states allows polymer chains to grow uniformly, as most chains are dormant 

rather than active at any given time, thus reducing side reactions and broad molecular 

weight distribution.19 A distinct scheme and some widely used monomers, initiators 

and ligands to form metal complexes are shown in Figure a,b,c.17 

(a) (b) 

(c) 



 

48 

Figure 3.2 (a) mechanism of conventional ATRP, (b) widely used initiators, ligands 

and (c) monomers17 

 

In this study, ATRP was carried out using a Cu(I)/(Me6TREN) complex as the 

catalyst, with tin(II) 2-ethylhexanoate serving as the reducing agent. This system was 

selected for its ability to enable efficient initiation and maintain control over the 

polymerization of methyl methacrylate. A grafting-from strategy was employed, 

wherein the peptoid acts as a macroinitiator to allow direct growth of the PMMA 

block from the peptoid chain end. This approach offers a streamlined synthetic route 

and a simple purification process, giving rise to minimal loss of material while 

ensuring the formation of block copolymers with well-defined architecture. Overall, 

ATRP was chosen in this work for its reliability, broad monomer compatibility, and 

suitability for synthesizing the PMMA block with a targeted molecular weight—key to 

achieving the desired BCP architecture required for DSA. 

 

Reversible addition-fragmentation chain transfer: RAFT polymerization is another 

versatile and widely adopted controlled radical polymerization technique that enables 

the synthesis of polymers with well-defined molecular weights, low dispersity, and 

high end-group fidelity.20 The mechanism scheme is shown in Figure 3.3(a). The 

process operates through a degenerative chain transfer mechanism,21 wherein after 

activation (step I), a chain transfer agent (CTA) mediates an equilibrium between 

dormant and propagating chains (steps II and IV).22 The basic chain transfer steps of 

RAFT is degenerative due to the reversibility of the functional chain end-group, 

(typically a thiocarbonylthio group, Z-C(=S)S-R) between the dormant chains and the 

propagating radicals.23 Some typical RAFT agent structures are shown in Figure 3.3(b). 

In the meantime, the rate of addition/fragmentation equilibrium is higher than that of 



 

49 

the propagation, meaning that less than one monomer unit added per activation cycle, 

allowing precise control over polymer growth even at high monomer conversion. 

(a) (b) 

Figure 3.3 (a) mechanism scheme of RAFT polymerization, (b) typical structures of CTAs22 

 

Unlike reversible deactivation systems such as ATRP or NMP, the living character in 

RAFT is governed not by radical suppression but by the stoichiometric balance 

between initiator-derived radicals and CTAs. This makes RAFT an ideal method when 

it comes to synthesizing low-molecular-weight polymers or multiblock copolymers, 

where each chain’s uniform growth is critical. Furthermore, RAFT is compatible with 

a broad range of vinyl monomers, including methacrylates, acrylates, and styrenics, 

and offers tunability via structural modification of the R- and Z-groups on the CTA. 

The RAFT method was employed as another key strategy for constructing sequence-

defined peptoid-PMMA block copolymers. The NHS-functionalized chain transfer 

agent enabled post-polymerization amidation with amine-terminated peptoids, 

providing an efficient route for conjugation. RAFT should afford superior control over 

PMMA molecular weight and avoid the early termination compared to ATRP. 

 

3.2 Experimental methods 



 

50 

 

Synthesis and purification of peptoids: The peptoid sequences used in this chapter 

were synthesized and purified using the same methods as the previous chapter. 

Liquid chromatography-mass spectrometry (LC–MS): The molecular weight (MW) 

of prptoids were confirmed with the same LC-MS mass spectrometer as the previous 

chapter. 

Nuclear magnetic resonance spectrometer (NMR): The structural characterization 

of the small-molecule amine functionalized as an initiator, as well as the degree of 

polymerization of the polymers, was confirmed by ¹H NMR spectroscopy at room 

temperature using a Bruker AV-500 spectrometer. 

Fourier-transform infrared spectroscopy (FTIR): The chemical bonding 

haracteristics of small-molecule amine were analyzed and identified using a Bruker 

Hyperion FT-IR spectrometer, providing detailed insights into its functional group that 

couldn’t be confirmed with NMR. 

Gel Permeation Chromatography (GPC): The molecular weight and polydispersity 

of polymers and block copolymers synthesized via ATRP or RAFT were assessed 

using an Agilent 1200 GPC HPLC System, providing critical insights into their 

molecular distribution and uniformity. 

 

3.3 Material design and synthesis 

 

3.3.1 Peptoid design and synthesis 



 

51 

Figure 3.4 Peptoid structure of (FM)10-R 20-mer or 21-mer (named as (FM)10 20-mer, 

(FM)10-2C 21-mer, (FM)10-4C 21-mer and (FM)10-bis-2CCO 21-mer, respectively) 

 

The synthesis and purification followed the same procedure as that of unprotected 

oligopeptoids, utilizing RA resin as the solid phase. In accorfance with the design 

principles for directed self-assembly block copolymers, ensuring that the two building 

blocks possess similar surface energies, the first block, a 20-mer or 21-mer peptoid, 

was designed with alternating monomers of differing polarity: F and M (as illustrated 

in Figure). Additionally, spacer units were introduced at the end of the sequence to 

minimize potential inter-block interference and evaluate their impact on 

polymerization efficiency. 

 

3.3.2 ATRP grafting-from 

For the synthesis of block copolymers intended for directed self-assembly, two 

approaches were considered, with one being the ATRP grafting-from method. 

Figure 3.5 Functionalization of peptoid to a macroinitiator and ATRP polymerization 

 



 

52 

Since the block copolymer was designed with the goal of directed self-assembly, the 

two blocks should ideally have similar volumes.13 However, at this stage, measuring 

the volume is challenging. As a result, we initially designed the two blocks to have 

similar molecular weights as a reference, which means that degree of polymerization 

m in Figure 3.5 should be around 29. 

Synthesis of peptoid macroinitiator 

Peptoid (20-mer, 1.0 eq, 0.047 mmol) was dissolved in 12 mL of anhydrous DCM in a 

round-bottom flask under continuous Ar purging. Separately, TEA (5.0 eq, 0.24 mmol) 

was dissolved in 400 uL of DCM, while 2-Bromoisobutyryl bromide (BIBB) (2.5 eq, 

0.12 mmol) was prepared in 300 uL of DCM. After adding the TEA solution to the 

reaction mixture, the BIBB solution was introduced slowly. The flask was wrapped in 

aluminum foil and stirred for 48 hrs. Upon reaction completion, the mixture was 

diluted in 50 mL of chloroform, followed by two water extractions. The organic phase 

was then washed with brine, dried over MgSO4 and the solvent was evaporated. 

Finally, the product was purified using HPLC. 

Synthesis of functionalized 20-mer peptoid-b-PMMA by ATRP 

Peptoid macroinitiator (1.0 eq, 0.00724 mmol), inhibitor-free methyl methacrylate 

(MMA, 30 eq, 0.2172 mmol), CuBr2 (0.02 eq, 0.000145 mmol), and the ligand N',N'-

bis[2-(dimethylamino)ethyl]-N,N-dimethylethane-1,2-diamine (Me6TREN, 1 eq, 

0.00724 mmol) were added to 5 mL of toluene in a 40 mL vial and purged with Ar for 

at least 10 minutes. The reaction system was then heated to 70 ℃, followed by the 

addition of the reducing reagent tin(II) 2-ethylhexanoate. The reaction proceeded for 

24 hours before being quenched in air. The mixture was then passed through a neutral 

aluminum oxide column. Finally, the solvent was removed to isolate the product. 

Synthesis of N-(2-aminoethyl)-2-bromo-2-methylpropanamide 



 

53 

 

Figure 3.6 Synthetic scheme for amine functionalized as an initiator to be attached to 

peptoid 

Tert-butyl N-(2-hydroxyethyl)carbamate (1.0 eq, 5 mmol) and TEA (1.5 eq, 7.5 mmol) 

were mixed in 15 mL of anhydrous DCM. An ice bath was employed to cool down the 

system to 0 ℃. Add BIBB was added dropwise at 0 ℃. Removed ice bath after 30 

mins and reacted for 1.5 hrs. The formed salt was filtered off and the filtrate was 

extracted with saturated NaHCO3 aqueous solution. The organic layer was dried over 

MgSO4 and evaporated. The resulting t-Boc-aminoethyl 2-bromoisobutyrate was 

treated with 4 mL TFA and stirred overnight. Finally, the product was added into 70 

mL of NaOH aqueous solution to acquire the product N-(2-aminoethyl)-2-bromo-2-

methylpropanamide. The success of the reaction could not be determined solely from 

NMR data; therefore, FTIR analysis was conducted to confirm the formation of the N–

H bond. 

 

Figure 3.7 FTIR of N-(2-aminoethyl)-2-bromo-2-methylpropanamide and its TFA salt 

 

 



 

54 

(a) (b) 

Figure 3.8 Structure of (a) 21-mer peptoid(I) (FM)10-amino-initiator and (b) 21-mer 

peptoid(I)-b-PMMA block copolymer 

Synthesis of 21-mer peptoid(I) (FM)10-amino-initiator 

The synthesis of this 21-mer peptoid(I) was carried out manually while following the 

same procedure as that used by the peptoid synthesizer. The on-resin 20-mer (FM)10 

was first swelled, then treated with BrAA and DIC solution in DMF. The mixture was 

shaken for 30 minutes before being drained. After four washes with DMF, a 1.5 M 

solution of the previously synthesized N-(2-aminoethyl)-2-bromo-2-

methylpropanamide in DMF (10 mL) was added to the reaction vessel and shaken for 

1 hour to complete the coupling reaction. Finally, the peptoid was cleaved from the 

resin, purified using HPLC, and obtained in the sequence shown in Figure 3.8(a). 

Synthesis of 21-mer peptoid(I)-b-PMMA by ATRP 

Polymerization was carried out following the same ATRP procedure to grow PMMA 

on the macroinitiator to get the structure shown in Figure 3.8(b). 

 

3.3.3 RAFT and amidation 

Another approach employed concurrently for the synthesis of the block copolymer 

involved RAFT polymerization of PMMA, followed by grafting the PMMA block 



 

55 

through amidation. The N-hydroxysuccinimide (NHS)-functionalized CTA was 

selected over 4-cyano-4-(thiobenzoylthio)pentanoic acid due to the superior leaving 

group ability of NHS compared to hydrogen, thereby enhancing the efficiency of the 

amidation reaction with the peptoid. Additionally, a 21-mer peptoid(II) with a primary 

amine at the chain end was chosen over a secondary amine, as primary amines exhibit 

higher reactivity, further improving the efficiency of the amidation process. 

Figure 3.9 Synthetic scheme of RAFT polymerization and amidation 

Synthesis of PMMA block by RAFT polymerization 

4-cyano-4-(phenylcarbonothioylthio)pentanoic acid N-succinimidyl ester (5.0 eq, 0.3 

mmol), inhibitor-free MMA (225 eq, 13.5 mmol), and 2,2'-azobis(2-

methylpropionitrile) (AIBN, 1.0 eq, 1.16 mmol) were dissolved in 3 mL of toluene in 

a Schlenk flask. To ensure complete removal of air and moisture, the solution 

underwent three freeze-pump-thaw cycles before being backfilled with Ar. The 

polymerization was carried out at 70 °C for 24 hours. After the reaction was complete, 

the resulting polymers were precipitated in diethyl ether and isolated by filtration. 

Synthesis of 21-mer peptoid(II)-b-PMMA by amidation 

21-mer peptoid(II) (1.0 eq, 0.024 mmol) and PMMA (with CTA, 1.0 eq, 0.024 mmol) 

were sonicated and dissolved in 1.5 mL of dimethyl sulfoxide (DMSO). The mixture 

was purged with Ar before adding TEA (3.0 eq, 0.072 mmol) and allowed to react for 

24 hours. Following the reaction, 100 mL of DCM was added, and the mixture was 



 

56 

extracted 10 times with 10 mL of water per extraction to remove DMSO. The final 

product was purified using column chromatography. 

 

3.4 Results and discussion 

 

3.4.1 Optimization of ATRP conditions 

In the initial approach to growing PMMA on a 20-mer peptoid, the peptoid was first 

cleaved from the resin, functionalized with BIBB, and then grew MMA on it. 

However, this process required 2 rounds of time-consuming HPLC purification and 

lyophilization--both before and after macroinitiator functionalization. This not only 

led to inefficiencies in time but also resulted in significant loss of valuable peptoid 

material. Given that synthesizing a 20-mer peptoid takes approximately two days 

(with each step requiring around two hours), assuming no clogging issue in the 

instrument’s tubing system or software crashes. Purification using prep-HPLC could 

take 1-2 days, with each round lasting 50 minutes, and processing peptoids from a 

single batch of 500 mg resin requiring 4-5 rounds of purification. Furthermore, 

lyophilization added another 2 days using our local equipment. Despite all this effort, 

the final yield was only 100-200 mg of peptoid, and obtaining LC-MS data often 

required several more days of waiting. Another issue was slow kinetics and early 

termination. In a literature, similar observations were also discussed and mentioned 

that initiator with an ester functional group may work better for ATRP.24 

To streamline the process and maximize the use of synthesized peptoids, a 

bromoisobutyrate-functionalized small molecule, N-(2-aminoethyl)-2-bromo-2-

methylpropanamide, was synthesized and incorporated as the 21st submonomer amine 

at the end of the peptoid sequence. This approach eliminated one trial of purification, 

improving efficiency. 



 

57 

When transitioning to the 21-mer peptoid(I) as the ATRP initiator, it was prudent to 

first optimize the ATRP conditions using a small-molecule initiator, ethyl 2-

bromoisobutyrate, which has a similar chemical environment to the 21-mer peptoid. 

This allowed for systematic screening of polymerization conditions before applying 

them to the valuable peptoid materials. Several conditions were evaluated, including: 

(1) temperature: 70 ℃ vs. 80 ℃, (2) solvent: acetonitrile vs. toluene vs. 

toluene/methanol, and (3) reducing agent: ascorbic acid vs. tin(II) 2-ethylexanoate. 

Samples were collected for GPC analysis after 5 hours and 24 hours of reaction. GPC 

does not provide an exact molar mass but rather a reference for the relative MW of the 

polymers. Based on this evaluation, the optimized ATRP conditions were determined 

to be 70 ℃, with toluene/methanol mixture as the solvent and tin(II) 2-ethylhexanoate 

as the reducing agent, reacting for 24 hours. This combination was assumed to ensure 

reliable ATRP polymerization efficiency while also facilitating the attainment of the 

desired MW for PMMA. GPC analysis of the ATRP reaction mixture on 21-mer 

peptoid(I) revealed no detectable peaks corresponding to block copolymers. However, 

NMR characterization confirmed the presence of PMMA peaks. Due to interference 

from solvent signals, the MW could not be accurately determined, and the yield of the 

resulting block copolymers was disappointingly low. This result highlights the 

limitation of the ATRP route for peptoid-PMMA synthesis under current conditions, 

particularly regarding low polymerization efficiency and product yield. Further 

optimization or alternative strategies were thus deemed necessary. 



 

58 

Figure 3.10 NMR analysis of 21-mer peptoid (I)-b-PMMA confirmed the successful 

polymerization 

Another concern was that TFA, used during the cleavage step, might react with the 

peptoid and hinder subsequent polymerization. However, this possibility was ruled out 

by 19F-NMR analysis, which showed no detectable fluorine signals associated with 

residual TFA. This indicates that TFA was effectively removed and does not interfere 

with the downstream polymerization process. 

 

3.4.2 RAFT and amidation route 

Given the limited yield and purification difficulties in the ATRP pathway, a second 

approach involving RAFT polymerization followed by amidation was investigated. 

In the initial polymerization step, the molar ratio of MMA was adjusted from 40 eq to 

45 eq to achieve a target PMMA MW of approximately 3000. Due to slight deviations 

from theoretical conversion, a higher monomer feed was required to reach the desired 

MW. 1H NMR analysis (Figure 3.11) of the resulting polymers synthesized with 40 eq 

and 45 eq of MMA revealed that the integral ratio of PMMA peaks to the CTA was 

approximately 20:1 and 30:1, respectively. This correlation suggests that the obtained 

polymers had molecular weights of around 2000 and 3000, respectively. 



 

59 

Figure 3.11 NMR analysis of PMMA synthesized via RAFT polymerization indicated 

m≈30 (90.17/3≈30) for 45 eq of MMA added 

 

Based on these findings, the polymer batch with an MW of 3000 was selected for 

subsequent amidation. PMMA and peptoid were reacted in a 1:1 molar ratio, and the 

reaction mixture analyzed using normal-phase TLC. The absence of a distinct PMMA 

spot indicated successful amidation. However, both the peptoid and the resulting 21-

mer peptoid(II)-b-PMMA exhibited a retention factor (Rf) of 0, suggesting that these 

two fractions were not separable via conventional column chromatography. To address 

this challenge, C18 reversed-phase TLC (RP-TLC) was attempted to identify a suitable 

separation profile for HPLC purification. Various eluents, including mixtures of 

acetonitrile/water and acetonitrile/THF, were tested, but none provided effective 

resolution. Despite the challenges in purification, the RAFT-amidation route offered 

improved control over PMMA molecular weight and avoided the early termination 

issues observed in ATRP. Alternative separation strategies and further optimization 

are necessary to achieve efficient fractionation of 21-mer peptoid(II)-b-PMMA. 



 

60 

Potential approaches include exploring different eluent systems, increasing the amount 

of PMMA used in the amidation reaction, and altering the reaction sequence by 

performing amidation first, followed by RAFT polymerization. 

 

3.5 Conclusion 

 

In this study, we systematically designed and synthesized sequence-defined peptoid-

based block copolymers tailored for directed self-assembly applications. The peptoid 

segments were engineered with alternating monomers of differing polarity to balance 

surface energy, aligning with established principles in block copolymer design. 

Incorporation of terminal spacers were designed to further minimize inter-block 

interference and enhanced polymerization compatibility. 

Two synthetic strategies were developed to get peptoid-PMMA block copolymers: (1) 

the ATRP grafting-from method and (2) RAFT polymerization followed by post-

polymerization amidation. Initial efforts using cleaved peptoid macroinitiators for 

ATRP suffered from low efficiency, slow kinetics, and material loss due to multi-step 

purification. To circumvent this process, a bromoisobutyrate-functionalized amine was 

introduced as the final submonomer during on-resin synthesis, effectively minimizing 

purification steps. Systematic optimization of ATRP parameters using a small-

molecule surrogate enabled the identification of conditions conducive to reliable 

PMMA growth, although the block copolymer yield remained modest and separation 

remained challenging. 

In parallel, the RAFT approach offered relatively controlled polymerization and 

facilitated MW tuning of PMMA. Amidation between NHS-functionalized PMMA 

and primary amine-terminated peptoids proceeded smoothly, with NMR and TLC 

analyses confirming successful coupling. However, difficulties in post-reaction 



 

61 

purification—stemming from the similar polarities of the peptoid and resulting block 

copolymer—highlighted the need for alternative separation strategies, such as 

reversed-phase HPLC. 

Collectively, this work establishes a modular and adaptable synthetic framework for 

constructing peptoid-based block copolymers with tunable architectures. While both 

ATRP and RAFT-based routes show promise, further refinements in post-

polymerization processing and analytical separation will be crucial to unlock their full 

potential in nanoscale self-assembly applications. 



 

62 

REFERENCES 

 
[1] Ji, S. X.; Wan, L.; Liu, C. C.; Nealey, P. F. Directed Self-Assembly of Block 
Copolymers on Chemical Patterns: A Platform for Nanofabrication. Prog. Polym. Sci. 
2016, 54-55, 76-127. 
 
[2] Liu, C. C.; Ramirez-Hernandez, A.; Han, E.; Craig, G. S. W.; Tada, Y.; Yoshida, 
H.; Kang, H.; Ji, S.; Gopalan, P.; de Pablo, J. J.; Nealey, P. F. Chemical Patterns for 
Directed Self-Assembly of Lamellae-Forming Block Copolymers with Density 
Multiplication of Features. Macromolecules 2013, 46, 1415-1424. 
 
[3] Lane, A. P.; Sung, P.; Delgadillo, P. A. R.; Nealey, P. F.; de Pablo, J. J. Directed 
Self-Assembly and Pattern Transfer of Five Nanometer Block Copolymer Lamellae. 
ACS Nano 2017, 11, 7656-7665. 
 
[4] Li, X. M.; Deng, H. Poly(2-Vinylpyridine)-b-Poly(Fluorinated Methacrylate) 
Block Copolymers Forming 5 nm Domains Containing Metallocene. ACS Appl. Polym. 
Mater. 2020, 2, 3601-3611. 
 
[5] Sinturel, C.; Bates, F. S.; Hillmyer, M. A. High χ-Low N Block Polymers: How 
Far Can We Go? ACS Macro Lett. 2015, 4, 1044-1050. 
 
[6] Sunday, D.; List, S.; Chawla, J.; Kline, R. Evaluation of Effect of Data Quality on 
the Profile Uncertainty of Critical Dimension Small Angle X-ray Scattering. J. 
Microlithogr. Microfab. Microsyst. 2016, 15, 014001. 
 
[7] Yang, G. W.; Xu, T.; Zhang, C.; Nealey, P. F.; de Pablo, J. J.; Stoykovich, M. P. 
Directed Self-Assembly of Polystyrene-b-Poly(propylene carbonate) on Chemical 
Patterns via Thermal Annealing for Next-Generation Lithography. Nano Lett. 2017, 17, 
1233-1239. 
 
[8] Zhang, X. S.; He, Q. B.; Chen, Q.; Nealey, P. F.; Ji, S. X. Directed Self-Assembly 
of High χ Poly(styrene-b-(lactic acid-alt-glycolic acid)) Block Copolymers on 
Chemical Patterns via Thermal Annealing. ACS Macro Lett. 2018, 7, 751-756. 
 
[9] Khaira, G.; Jones, G. R.; Whitfield, R.; Anastasaki, A.; et al. Derivation of 
Multiple Covarying Material and Process Parameters Using Physics-Based Modeling 
of X-Ray Data. Macromolecules 2017, 50, 7783-7793. 
 
[10] Matsen, M. W.; Bates, F. S. Block Copolymer Microstructures in the 
Intermediate-Segregation Regime. J. Chem. Phys. 1997, 106, 2436-2448. 
 
[11] Hur, S. M.; Sukarieh, R. M.; Nealey, P. F.; de Pablo, J. J. Molecular Pathways for 
Defect Annihilation in Directed Self-Assembly. Proc. Natl. Acad. Sci. U.S.A. 2015, 
112, 14144-14149. 
 
[12] Hur, S. M.; Thapar, V.; Ramirez-Hernandez, A.; Nealey, P. F.; de Pablo, J. J. 
Defect Annihilation Pathways in Directed Assembly of Lamellar Block Copolymer 
Thin Films. ACS Nano 2018, 12, 9974-9981. 



 

63 

[13] Feng, H.; Dolejsi, M.; Zhu, N.; Nealey, P. F.; de Pablo, J. J.; Stoykovich, M. P. 
Optimized Design of Block Copolymers with Covarying Properties for 
Nanolithography. Nat. Mater. 2022, 21, 1426-1433. 
 
[14] Kim, S.; Nealey, P. F.; Bates, F. S. Decoupling Bulk Thermodynamics and 
Wetting Characteristics of Block Copolymer Thin Films. ACS Macro Lett. 2012, 1, 
11-14. 
 
[15] Kato, M.; Kamigaito, M.; Sawamoto, M.; Higashimura, T. Polymerization of 
Methyl Methacrylate with the Carbon 
Tetrachloride/Dichlorotris-(Triphenylphosphine)ruthenium(II)/Methylaluminum 
Bis(2,6-Di-tert-butylphenoxide) Initiating System: Possibility of Living Radical 
Polymerization. Macromolecules 1995, 28, 1721-1723. 
 
[16] Wang, J.-S.; Matyjaszewski, K. Controlled/‘Living’ Radical Polymerization. 
Atom Transfer Radical Polymerization in the Presence of Transition-Metal Complexes. 
J. Am. Chem. Soc. 1995, 117, 5614-5615. 
 
[17] Harrisson, S.; Whitfield, R.; Anastasaki, A.; Matyjaszewski, K. Atom Transfer 
Radical Polymerization. Nat. Rev. Methods Primers 2025, 5, 2. 
 
[18] Matyjaszewski, K.; Patten, T. E.; Xia, J. Controlled/‘Living’ Radical 
Polymerization. Kinetics of the Homogeneous Atom Transfer Radical Polymerization 
of Styrene. J. Am. Chem. Soc. 1997, 119, 674-680. 
 
[19] Harrisson, S. The Chain Length Distribution of an Ideal Reversible Deactivation 
Radical Polymerization. Polymers 2018, 10, 887. 
 
[20] Perrier, S. 50th Anniversary Perspective: RAFT Polymerization—A User Guide. 
Macromolecules 2017, 50 (19), 7433-7447. 
 
[21] Goto, A.; Fukuda, T. Kinetics of Living Radical Polymerization. Prog. Polym. Sci. 
2004, 29, 329-385. 
 
[22] Tian, X.; Ding, J.; Zhang, B.; Qiu, F.; Zhuang, X.; Chen, Y. Recent Advances in 
RAFT Polymerization: Novel Initiation Mechanisms and Optoelectronic Applications. 
Polymers 2018, 10, 318. 
 
[23] Moad, G.; Rizzardo, E.; Thang, S. H. Living Radical Polymerization by the 
RAFT Process? A Third Update. Aust. J. Chem. 2012, 65, 985-1076. 
 
[24] Adams, D. J.; Young, I. Oligopeptide-Based Amide Functional Initiators for 
ATRP. J. Polym. Sci., Part A: Polym. Chem. 2008, 46 (17), 6082–6090. 



64 

CHAPTER 4 

 

Future work 

4.1 Sequence-defined and length-controlled oligopeptoids 

 

In Chapter 2, a tone-switching phenomenon was observed and tentatively linked to 

film thickness, but the reproducibility of this result was limited. For a more definitive 

conclusion, improved consistency across repeated experiments is needed. In particular, 

it remains unclear within which specific thickness ranges the tone-switch occurs. A 

systematic study varying film thickness and development conditions—especially more 

refined concentrations of diluted TMAH—would help clarify this behavior. Although 

identifying a universal developer for all peptoid-based resists may be unrealistic, 

eliminating non-viable combinations of development time and developer strength can 

provide valuable guidelines for future formulation. Furthermore, this work relied 

solely on DUVL. To advance toward practical implementation in high-resolution 

applications, it is essential to investigate performance under EUVL and EBL. EBL 

may serve as a useful intermediate step to bridge current DUV-based results with EUV 

requirements. 

Additionally, although the CuAAC reaction between the synthesized non-ionic PAG 

and the peptoid backbone has succeeded, challenges remain in both purification and 

structural characterization. The lithographic performance of the clicked product also 

remains untested. Importantly, metal-free or low-metal-content photoresists are 

preferred for EUV lithography due to contamination concerns. However, copper 

catalysts are typically required for CuAAc reactions. Conventional purification using 

neutral alumina column proved incompatible with peptoids, and even multiple rounds 

of DMF wash resulted in significant material loss. Therefore, alternative purification 



 

65 

 

strategies are necessary. Dialysis may offer a more suitable approach, especially when 

paired with organic solvents incompatible with most liquid-phase column 

chromatography. Given the size difference between peptoids and copper salts, dialysis

—based on molecular weight exclusion—could provide a more effective, non-

destructive purification method. 

 

4.2 Polypeptoid-based block copolymers for directed self-assembly lithography 

 

In Chapter 3, ATRP conditions were successfully optimized using a small-molecule 

initiator. However, polymerization from peptoid-based macroinitiators—either a 

BIBB-functionalized 20-mer or a 21-mer containing an ester linkage—was not as 

satisfying. To improve outcomes, a broader range of polymerization conditions should 

be explored beyond standard literature values, including varied temperatures and 

reagent stoichiometries (catalyst, ligand, and reducing agent). 

In addition, it may be necessary to reassess the integrity of the 21-mer peptoid 

macroinitiator itself. The final coupling step was carried out manually using resin that 

had been stored in fridge for several months, and LC-MS failed to confirm a molecular 

weight above 3000 Da. As a result, the success of the 21-mer synthesis was not 

thoroughly verified. It is possible that this particular amine coupling step was 

inefficient at room temperature. To address this, trials at elevated temperatures are 

currently underway, and new batches of the same peptoid sequence are being 

synthesized to ensure reproducibility. Once this issue is resolved, ATRP conditions 

can be re-evaluated. However, successful synthesis alone is insufficient—accurate 

characterization of the resulting block copolymer is critical. NMR spectroscopy, 

though widely used, has limitations in determining molecular weight. GPC, while 

useful for assessing relative distribution, lacks absolute precision for novel 



 

66 

 

architecture such as peptoid-b-PMMA systems. Maldi-Tof mass spectrometry could 

be a promising alternative, although suitable matrix and salt combinations are still 

under investigation. 

In the RAFT approach, while molecular weight control was improved, purification 

presented significant challenges. HPLC analysis yielded multiple peaks, but none were 

confirmed as the target product by NMR after freeze-drying. The limited solvent 

compatibility of HPLC may have contributed to these issues. As proposed in Section 

4.1, dialysis may also offer a viable purification strategy for RAFT-amidation-

synthesized block copolymers. 

 

4.3 Conclusion 

 

In future work, we will address several key challenges to advance peptoid resist 

materials and peptoid-b-PMMA block copolymers toward practical lithographic 

applications. For oligopeptoid photoresists, we plan to conduct systematic thickness-

dependent studies under EUV and e-beam exposure to map the tone-switch threshold 

and optimize pattern fidelity. We will also develop gentle, non-destructive purification 

methods (e.g., dialysis) to enable click-modified peptoids free of metal contaminants 

and then evaluate their lithographic performance. For block copolymers, we will 

expand our polymerization condition screens, varying temperature, catalyst/ligand 

ratios, and solvent systems, and explore alternative characterization tools (MALDI-

ToF MS, high-resolution GPC techniques) alongside new separation strategies 

(reversed-phase HPLC, preparative GPC) to overcome purification bottlenecks. 

Together, these future efforts will provide the mechanistic insights and scalable 

processes required to deploy sequence-defined peptoid materials in next-generation, 

high-resolution lithography.