This document summarizes four research projects conducted by Aruna Earla. Project 1 developed new spin trap reagents to study free radicals using EPR and NMR spectroscopy. Project 2 synthesized plasticizers covalently linked to PVC via click chemistry reactions to prevent plasticizer migration. Project 3 further explored covalently linking phthalate plasticizers to PVC with flexible linkers. Project 4 synthesized new fluorinated alkoxyamine initiators and studied their use in nitroxide-mediated polymerization of styrene in supercritical carbon dioxide. A fifth project at Roosevelt University explored using BSTFA as a greener silylating agent for carbonyl compounds.

1. RESEARCH SUMMARY
Aruna Earla
University of California Santa Cruz, Santa Cruz, CA
Project 1: Polystyrene Supported Cyclic Fluorinated Nitrones: Spin Traps for Transient Free Radicals
Free radicals such as reactive oxygen species (ROS) and reactive
nitrogen species (RNS) are critical mediators in cardiovascular
dysfunction, neurodegenerative diseases, as well as degenerative
diseases like Alzheimer’s, and Parkison’s disease. Nitrone spin traps
are employed both as reagents to detect radicals using EPR and as
pharmacological agents against stress-mediated injury. Nitrones
have significantly contributed to the understanding of important
free radical mediated processes in
chemical, and biological systems.
Trifluoromethylated cyclic nitrone 2-
TFDMPO 1 and polymer-supported
nitroneResin-2-HFDMPO 2 were
developed to study EPR and NMR spin-
trapping of free radicals. This project is a
collaboration with Dr. Eric Walter from the
Environmental Molecular Sciences
Laboratory (EMSL) at the Pacific Northwest
National Laboratory. Continuous flow NMR
and EPR capabilities have been developed
at EMSL, which allows the monitoring of chemistry on a solid phase while a gas or liquid mobile phase flows
through the sample cell. The EPR spectrum of the hydroxyl adduct of Resin-2-HFDMPO 3 gave broad peaks
compared to the EPR spectra of hydroxyl adducts of 2-TFDMPO and 2-HFDMPO (Figure 4.20). The absence of
hyperfine splitting makes the identification of the original radical difficult. The significant broadening of the peaks
is likely due to the close proximity of the spin-trap to the polymer, which results in restricted motion of the
nitroxide adduct. A longer linker between the nitrone and resin (Resin -2-PFDMPO, 4, Scheme 3) provided more
freedom of rotation, and should gave spectra with narrow peaks.
Project 2: Covalently Linked Plasticizers: Triazole Analogues of Phthalate Plasticizers Prepared by Mild Copper-
Free “Click” Reactions with Azide-Functionalized PVC
Polyvinyl chloride (PVC) is one of the most widely used and economically important
thermoplastics. Global annual demand for PVC increased steadily over the last few decades, and
is estimated to reach 53 million tons,
worth 79 billion USD in 2020. Pure PVC
is a rigid, brittle solid requiring a large
amount of plasticizer to obtain flexibility and
moldability. The most common plasticizer class currently
in use are phthalate esters, accounting for 70% of the
global plasticizer demand in 2014, with the (2-
ethylhexyl) phthalate diester DEHP 5, being the most
popular. However, the adverse developmental,
reproductive, neurological and immune
health effects of
many phthalates have led to a search for alternative
plasticizers. Other common small molecule plasticizers
include terphthalates, 1,2-cyclohexane-dicarboxylic acid
diisononyl ester (Hexamoll® DINCH®), epoxidized
vegetable oils, citrates, mellitates, adipates, benzoates, maleates, succinates, sebacates, phosphates, and some
polymeric plasticizers such as poly(ε-caprolactone), poly(butylene adipate), and poly(epichlorohydrin). Because
O
N
O
CF3
OH
Resin-2-HFDMPO-OH adduct
3
DEHP
O
O
O
O
5
NO2
+
O
Et3N
CH3CN
Dess-Martin periodinane Zn / HOAc
N
O
CF3
NO2
O
NO2
OH
CF3
NO2
O
CF3
Me3SiCF3
CsF
2-TFDMPO
1
Scheme 1
NO2
HO
NO2
THPO
Et3N
Dess-Martin Periodinane
Zn / HOAc
N
O
CF3
THPO Conc. HCl
N
O
CF3
HO
NO2
O
O
NO2
OTHPO
NO2
OHTHPO
CF3
NO2
OTHPO
CF3
CH2OHO H
n
Cl
NaH, DMF
3.0 - 4.0 mmol/g of Cl
200 - 400 mesh O
N
O
CF3
Resin-2-HFDMPO
Me3SiCF3
CsF
2
Scheme 2
DBUNO2
O+
DBU
NO2
THPO
NO2
HO
NO2
OTHPODHP
1. Me3SiCF3, CsF
3. DMP
NO2
O
CF3
THPO
N
O
CF3
HO1. Zn / HOAc
2. Conc. HCl
O
NaBH4
N O
O
O N
O
O
O
O
Et3NH2
N
O
CF3
OON
O
O
O
N
O
CF3
O
NH
O
NH2
DMF
0. 9 mmol/g of NH2
100 - 200 mesh
Resin-2-PFDMPO
4
Scheme 3
Cl N3
n o +
O
OO
O
THF
30 °C, 7 d Cl N
n o
N
N
O
O
O
O
PVC-DEHT
6
OH
O
OO
O
75%
HOOC COOH
Tolune, reflux, 1 h
Dean-Stark apparatus
NaN3
DMF, 62 °C, 2.5 h
Cl N3
Cl
m n o
15 % displacement of Cl
Scheme 4

2. these plasticizers are not covalently linked to PVC, they can migrate within the material and leach out when the
plastic comes into contact with air, liquid
or some absorbent solid materials. The most effective approach to avoid
migration of plasticizer from the PVC matrix is to covalently attach the plasticizer to the polymer. Thermal azide-
alkyne cycloaadition (Huisgen Cycloaddition) was employed to covalently attach triazole mimic of DEHP (PVC-DEHT
6, Scheme 4.
Project 3: Phthalate Plasticizers Covalently Linked to PVC via Copper-Free or Copper-Catalyzed Azide-Alkyne
Cycloadditions
The decrease in the glass transition temperature of virgin PVC by covalent modification is indicative of the
plasticization. Experimental values for the glass transition temperatures (Tg) of pure PVC, 15% displacement of
chlorine by azide (15% PVC-Azide), and 15% plasticized PVC bearing 2-ethylhexyl triazole diester (15% PVC-DEHT) 6
were 83 °C, 76 °C, and 65 °C, respectively, indicating plasticization by the phthalate mimic. However, the Tg of 15%
PVC-DEHT is way too high for most commercial applications. This only moderate reduction in Tg may be due to the
restricted rotation of the plasticizer mimic
attached directly to the PVC polymer chain. A
flexible linker between the triazole ring and the
plasticizer would provide additional degrees of
rotation. Phthalate (2-ethylhexyl) diesters are
covalently linked to PVC by two different
rotationally flexible tethers. These internal
plasticizers are attached either by using mild, copper-free
thermal Huisgen cycloaddition, or by copper-catalyzed
azide-alkyne cycloadditions. Specifically, phthalate
diesters bearing a terminal alkyne were designed with
either an ester or ether linkage, with triazole formation as
the chemoselective attachment strategy, to form PVC-
DEHP-ether 7 and PVC-DEHP-ester 8. The synthesis of
phthalate-based terminal alkynes DEHP-ether Scheme 5
and DEHP-ester Scheme 6 is illustrated.
Project 4: Synthesis of Fluorinated Alkoxyamines and
Alkoxyamine-Initiated Nitroxide-Mediated Precipitation
Polymerizations of Styrene in Supercritical Carbon Dioxide
Three fluorinated alkoxyamine initiators are synthesized and used to study the effect of adding carbon dioxide-
phillic fluorinated fragment in the nitroxide-
mediated precipitation polymerizations of styrene in
supercritical carbon dioxide. Two alkoxyamines have
fluorinated functional handles built on the nitroxide
part of the alkoxyamine (Scheme 7 and 8) whereas
the third initiator has fluorinated functional handle
on the benzyl-initiating fragment of the alkoxyamine
(Scheme 9). The partitioning of fluorinated nitroxide
derivatives in supercritical carbon dioxide impacts on
the controlled/living character and broadening of
the molecular weight distributions but does not have
O
O
O
O
O
O
Br
HO
O
O
O
O
BrpTSA
OH
NBS
cat. (PhCO2)2
NaH
Cl N3
n o
cat. CuSO4•5H2O
Ascorbic acid
Cl N
n o
N
N
O
O
O
O
O
7
PVC-DEHP-ether
O
O
O
O
O
Scheme 5
O
O
O
OBr
COOH
K2CO3, DMF
O
O
O
OO
O
Cl N3
n +
DMF
Cl N3
n o+ cat. CuSO4•5H2O
Ascorbic acid
o
Cl N
N
N
O
O
O
O
O
O
n o
8
PVC-DEHP-ester
Cl N
N
N
O
O
O
O
O
O
n o
8
PVC-DEHP-ester
O
O
O
OO
O
O
O
O
OO
O
Scheme 6
O
ClpTSA
Conc. HCl
MeOH, THF Et3N, CH2Cl2
OH
Br
O
OTHP
Br
OTHP
MgBr
O
N
OTHP
N
O
cat. Mn(salen)Cl
NaBH4, air
OTHP
N
O
OH
N
O
O
N
O
O
(CF2)7CF3
(CF2)7CF3
CH2Cl2
Mg
THF
9
F-TIPNO-Alkoxyamine
Scheme 7
HO
NO2
O
Conc. HCl
THPO
NO2
O
Zn, NH4Cl
THPO
N
O
1. PhMgBr
2. cat. CuSO4, air
THPO
N
O cat. Mn(salen)Cl
NaBH4, air
THPO
N
O
pTSA
MeOH, THF
HO
N
O
Si CH2CH2(CF2)9CF3H
CF3SO3H
Pyridine
O
N
O
Si
F3C(F2C)9
10
F-Si-TIPNO-AlkoxyamineScheme 8
O
(CF2)7CF3
O
N
Ph
Cl
O
N
Ph
(CF2)7CF3
HO
50% aq. NaOH
O
N
Ph
Cl
Salen Catalyst
NaBH4, air
O
N
1. PhMgBr
2. Cu(OAc)2, air
NO2
O
Zn, NH4Cl
11
TIPNO-F-foot-Alkoxyamine
Scheme 9

3. any significant effect on the rate of precipitation polymerization in supercritical
carbon dioxide.
Project 4: Syntheses of Pro-Fluoroscent Nitroxide for Detection of Urushiol
A method to visually detect minute amounts of urushiol, the toxic catechol from
poison oak, poison ivy, and poison sumac, was envisioned by utilizing the reaction
of a profluorescent nitroxide 13, Scheme 10 with the B-n-butylcatecholboronate
ester formed in situ from urushiol and B-n-butylboronic acid. The resulting N-
alkoxyamine should be fluorescent upon illumination with a fluorescent lamp,
allowing the location of the toxic urushiol contamination to be visualized. This
methodology constitutes the groundwork for the future development of a spray
to detect urushiol to avoid contact dermatitis, as well as to detect catecholamines
for biomedical applications. The preparation of pro-fluorescent TEMPO-based
nitroxide is described in Scheme
Roosevelt University, Schaumburg, IL
Project : Green Chemistry Approach for Silylation of Carbonyl Compounds
The goal of this research was to determine if {N, O- bis(trimethysilyl)triflouroacetamide} (BSTFA) can be used
effectively as a silylating agent on organic substrates to improve
the regioselectivity and to reduce the overall reaction times. My
participation in the research involved completing the synthesis
of the trimethyl–(cyclohex-1-enyloxy)-silane and trimethyl–(2-
R-cyclohex-1-enyloxy)-silane 14 (R=CH3, OCH3, COCH3) (Scheme
11). The reactions were monitored by gas chromatography and
were characterized by
1
HNMR.
Dr. Reddy’s Laboratories Limited, India
Project: Total Synthesis of Carboprost Methyl Ester (Prescursor of Prostaglandin)
We developed the technology for the total synthesis of Carboprost Methyl Ester (precursor of Prostagl-
andin) 15 via condensation of three key intermediates: Methyl-7-iodo-5-heptynoate 16 (Scheme 12), 4
tertbutyldimethylsilyloxycyclopent-2-enone 17 (Scheme 13), and (S)-3-tert-butyldimethylsilyloxy-3-
methyl-oct-1-yn 18 (Scheme 14).
Alembic Limited, India
Project: Impurity Profiling
My job profile included the synthesis and characterization of various impurities of antibiotics. I characterized five
impurities of clarithromycin, 3 impurities of erythromycin, 2 impurities of leflunomide, 1 impurity of azithromycin
utilizing various purification techniques
Uma Laboratories (P) Ltd.
Project: Developing technology for the synthesis of Heterocyclic drug intermediates (Custom chemical synthesis
for Chiron Corporation, USA)
Uma Laboratory handled projects of custom synthesis. Chiron Corporation was one of the customers of Uma
Laboratory. My Job profile included developing the synthetic scheme for various heterocyclic drug intermediates.
During my tenure of 2 years with Uma laboratories, I synthesized derivatives of Imidazoles, thiazoles, pyrimidines,
pyridines, oxazoles (ranging from singles step synthesis to fifteen step synthesis) from 100 mg scale to 10 kg scale. I
handled 10 projects for Uma. I am presenting one of those schemes to give an idea of the work I did in this
organization.
HO OCH3
OH
OH
15
F
mCPBA
F
F F
NH2 N
O
NaNO3, H2SO4
NaN3, DMSO
F
N
O
N
F
N
O
N
NO2 N
NH2
O
NH
N
O
N
NO2
N
O
Cl
N
O
N
NO2
N
NH2
O
NH
N
O
N
NO2
N
O
Scheme 10
13
13
O
H
R'
H
H
Base
O
H
H
R'
BSTFA
OSiR3
H
H
R'
OSiR3
R' H
O
HR'
Base
BSTFA
14
Scheme 11
HO
DHP
THPO n-BuLi
Br Cl
THPO Cl
KCN
THPO CN
Conc. HCl
HO COOMeH2SO4
MeOH
PBr3
Br COOMe
NaI
Acetone I COOMe
16
Scheme 12
O
OH O
TBDMSCl
OH
O
OTBDMS
Al/LiBrpH 4.1
OH
OTBDMS
Pancreatin
Vinyl actetate
LiOH
OTBDMS
OAc
OTBDMS
OH
PCC
OTBDMS
O 17Scheme 13
O
MgBr OH Phthalic acid Ophthalate
Brucine salt
Ophthalate OH TBDMSCl OTBDMS
18Scheme 14