Synthesis and spin trapping properties of polystyrene supported trifluoromethylated cyclic nitrones

FREE RADICAL RESEARCH

https://doi.org/10.1080/10715762.2019.1683171

ORIGINAL ARTICLE

Synthesis and spin trapping properties of polystyrene supported

trifluoromethylated cyclic nitrones

a

b

a

Aruna Earla

, Eric D. Walter

and Rebecca Braslau

a

b

Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA; Pacific Northwest National

Laboratory, Richland, WA, USA

ABSTRACT

ARTICLE HISTORY

Received 20 June 2019

Revised 8 October 2019

Accepted 10 October 2019

Published online 14 Novem-

ber 2019

Polystyrene supported fluorinated cyclic nitrone spin-traps: Resin-2-HFDMPO (2-hydroxymethyl-2-

methyl-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole-1-oxide) and Resin-2-PFDMPO (2-(3-hydroxy-

propyl)-2-methyl-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide) containing a trifluoromethyl

pyrroline-N-oxide core were developed to detect free radicals under flow conditions. A continu-

ous flow EPR technique was used to evaluate the spin trapping properties of these tethered

nitrones. While both resins trapped radicals, polymer supported nitrone Resin-2-PFDMPO with a

longer and more flexible linker showed a more information rich spectrum than Resin-2-HFDMPO.

KEYWORDS

Fluorinated; free radicals;

nitrone; polymer supported;

spin trapping

Introduction

ozone and secondary organic aerosols (SOAs) (photo-

chemical smog, air quality, and air pollution) [1]. The

reactions of gas phase HOꢀ, NO ꢀ and O with volatile

Free radicals such as reactive oxygen species (ROS) and

reactive nitrogen species (RNS) play major roles in

physiological, pathological, environmental, and atmos-

pheric processes. They are also important intermediate

species in a variety of chemical processes such as cataly-

sis, batteries, and polymerisation reactions. As such, rad-

icals can exist in all phases of matter, with their

detection restricted many times by short lifetimes. The

lifetime of a radical in liquid solution is often controlled

by the reaction rate with other constituents. One detec-

tion strategy for solution state radicals is spin trapping:

forming a secondary stable product that is amenable to

both quantitative and qualitative analysis. In most cases,

this product is detected in its radical form, usually by

electron paramagnetic resonance (EPR). In other cases,

the trapped radical can be analysed by NMR or mass

spectrometry after the radical has been quenched. One

advantage of detecting the radical form by EPR is the

ability to do in situ or operando experiments and collect

real time data during a process. This can include not

only chemically generated radicals, but also products

from photolysis/radiolysis and electrochemistry.

3

organic compounds such as terpenes [2–4], and alkanes

and aromatics [5] result in the formation of SOAs in the

atmosphere. SOA accounts for a major fraction of

the fine particulate matter in the atmosphere, affecting

the climate by scattering sunlight and serving as nuclei

for cloud droplets and ice crystals [6]. UV irradiation

promotes free radical processes on the surface of aero-

sol particles, contributing to the aging of aerosols [7],

which changes their climate influencing properties such

as hygroscopicity [8], light scattering [9], and absorp-

tion of the particles as well as their cloud forming abil-

ities [10–14]. Despite large differences in molecular

composition, concentration, and conditions among

atmospheric, environmental, and biological systems,

the underlying chemistry of ROS has many similarities.

The coupling and exchange of atmospheric and physio-

logical ROS and RNS proceed through various biosurfa-

ces such as the animal respiratory tracts, skin, and plant

leaves [15]. ROS and RNS in the atmosphere can deposit

onto surfaces, causing oxidative stress and nitrosative

stress. Epidemiological studies show a clear correlation

between air pollutants and adverse health effects,

including cardiovascular [16], respiratory, and allergic

diseases in humans [17,18].

The chemistry and ultimate fate of free radicals play

a role in many aspects of the environment: the control

of greenhouse gases (climate change), the formation of

atmospheric acids (acid rain), and the production of

CONTACT Rebecca Braslau

rbraslau@ucsc.edu

Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street,

Santa Cruz, CA, USA

ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2

A. EARLA ET AL.

Several sampling and analytical methods have been

However, this process does not provide an accurate

measurement of the HOꢀ in the atmosphere due to the

multiple manipulations. Sakakibara and coworkers [28]

reported the use of poly[N-(p-vinylbenzylidene)-tert-

butylamine oxide] (PolyPBN) 2, originally developed by

Janzen and Wang [29], and copolymers of PBN and styr-

ene (Poly(St-co-PBN)) 3 (Figure 1) in reactions with alkyl

radicals in the gas phase. The spin-trap polymers were

deposited on glass wool or on a solid foam in a reaction

tube. Alkyl radicals were generated via photolysis of the

corresponding alkyl chlorides. The resultant spin-

adducts were characterised and quantified by EPR. The

peaks of the PolyPBN adducts were considerably

broader than those of the monomeric PBN, due to the

restricted motion of the nitroxide moiety on the poly-

meric support. The broadening was decreased to some

extent in the spectrum of Poly(St-co-PBN) 3 adducts,

presumably due to a decrease in the steric congestion

around the nitroxide moiety. Other examples of the

attachment of spin traps to solid supports include deco-

rating the surface of a Au nanoparticle with a thiol-

derivatised cyclic nitrone by Liu [30], and the covalently

embedding a phosphorylated cyclic nitrone into meso-

porous silica by Besson et al. [31].

developed to identify and quantify ROS in air samples.

The most common methods include low matrix isola-

tion and electron spin resonance (MI-ESR) [19], chemical

ionisation mass spectrometry (CIMS) [20], laser-induced

fluorescence (LIF) [19,21–23], and peroxyl radical chem-

ical amplification (PERCA) [24–26]. These methods have

been applied to various outdoor and indoor air sam-

ples, such as laboratory-generated tobacco smoke and

SOA particles from ozone chemistry. However, the

accurate analytical determination of ROS is still chal-

lenging, due to the high reactivity of the radicals and

the instability of probes. Furthermore, methods used

successfully to determine high ROS concentrations

(

such as those present in tobacco smoke and other

combustion sources) may not be directly applicable to

lower levels found in the atmosphere. While spin trap-

ping of short-lived free radicals using nitrones coupled

with EPR has been widely used in biomedical research,

employment of this method for the detection of free

radicals in the atmosphere is less common. Watanabe

et al. [27] succeeded in trapping HOꢀ from the

atmosphere using the nitrone alpha-(4-pyridyl-1-oxide)-

N-tert-butylnitrone (4-POBN) 1 (Figure 1). An airborne

sampler, mounted with a filter paper impregnated with

The direct detection of the nitroxide spin-adducts by

H NMR is difficult due to the broadening of the NMR

1

4

-POBN was used to trap HOꢀ. The resulting 4-POBN-

signal by the unpaired electron as well as the instability

of most spin-adducts. Therefore, nitroxides are usually

reduced using phenyl hydrazine or ascorbic acid to

form diamagnetic hydroxylamines. However, the use of

OH adduct was isolated after washing the filter paper

with acetone. The acetone was evaporated and the resi-

due was dissolved in benzene and analysed by EPR.

1

13

H NMR or C NMR in detection of free radicals is sig-

nificantly limited by the complexity of multiple overlap-

19

ping signals. The stable isotope F, when incorporated

into the spin-trap should give resolvable spectra of the

diamagnetic hydroxylamine adducts. The concept of

NMR spin-trapping (ST-NMR) was introduced in the

1

980s, when Motten and coworkers [32] synthesised

five fluorinated analogues of PBN 4 and evaluated

1

9

detection of free radicals in organic reactions using

F

NMR spectroscopy (Figure 2). The introduction of the

19

Figure 1. Spin trap 4-POBN (Watanabe) [27] and polymeric

spin traps PolyPBN and Poly(St-co-PBN) (Sakakibara) [28].

NMR-sensitive label F into PBN enabled the selective

monitoring of chemical reactions associated with

Figure 2. Fluorinated PBN spin traps 4 (Motten) [32], trifluoromethylated FDMPO 5a (Clanton) [33] and 5-TFDMPO 5b (Tordo)

34] spin traps.

[

FREE RADICAL RESEARCH

3

Figure 3. Generalised scheme for flow spin-trapping experiments. Left side, photograph of spin trap column in front of EPR res-

onator. Right, instrument setup: (a) double syringe pump, (b) mixer, (c) EPR electromagnet, (d) EPR resonator, (e) spin trap col-

umn, (f) UV lamp connected to resonator with flexible light pipe, and (g) solvent waste.

phenyl radical after the reduction of spin-adducts with

phenylhydrazine.

gas or liquid mobile phase flows through the sample

cell. Herein is described the application of continuous

flow technique to study reactive radical species using

polymer-supported fluorinated cyclic nitrone spin-traps

as the solid phase. As shown in Figure 3, radicals were

either dissolved chemical species or created in situ via

photolysis via UV illumination at the centre of the EPR

resonator. The mobile phase carried solution state radi-

cals, which were trapped by the fluorinated nitrone col-

umn (right). The contents of the spin-trap column were

then analysed by EPR.

FDMPO 5 is the only fluorinated nitrone spin-trap com-

mercially available that can be tethered to a solid support.

FDMPO 5 is extremely expensive ($83 for 10 mg from Enzo

Life Sciences, Farmingdale, NY) and the synthesis is not

straightforward. Attempts in our lab to replicate Janzen

et al.’s synthesis [36] of 2-TFDMPO 6 failed, and the syn-

thetic steps described in the literature are enigmatic.

Therefore, a new synthetic route to prepare 2-TFDMPO 6

was developed, and then modified to develop two

hydroxyl analogues: 2-hydroxymethyl-2-methyl-5-(trifluor-

omethyl)-3,4-dihydro-2H-pyrrole 1-oxide (2-HFDMPO) 7

and 2-(3-hydroxypropyl)-2-methyl-5-(trifluoromethyl)-3,4-

dihydro-2Hpyrrole 1-oxide (2-PFDMPO) 8 (Figure 4). These

hydroxyl-substituted analogues 7 and 8 were then

attached to a polystyrene solid support to form resin 2-

HFDMPO 9 and resin 2-PFDMPO 10 with a shorter (9) and

longer (10) linker. Continuous flow EPR under conditions

generating free hydroxy radicals probed the EPR spectra of

the resulting solid supported nitroxides. The synthesis of

these trifluoromethylated nitrone derivatives and their

covalent attachment to polystyrene, and the EPR spectra

of the resulting nitroxide spin-adducts are presented.

In 2001, Clanton et al. [33] synthesised a water

soluble fluorinated analogue of DMPO (5,5-dimethyl-1-

pyrroline N-oxide), 4-hydroxy-5,5-dimethyl-2-trifluor-

methyl-pyrroline-1-oxide (FDMPO) 5a, to study EPR and

NMR spin trapping of free radicals. Not only does the

nitroxide adduct of FDMPO 5a has superior stability (up

to 24 h), but following nitroxide reduction, the original

19

radical can be identified via F NMR. This provides two

important advantages: the data can be acquired long

after the radical has been trapped, and a lower average

concentration of radicals can be detected because the

concentration of nitroxide spin-trap adduct can be built

31

up over time. Likewise, P NMR with 5-diethoxyphos-

phoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) cyclic

nitrone has been used to monitor several biologically

relevant radicals [35]. In 2014, Tordo et al. [34] prepared

5-methyl-5-trifluoromethyl-1-pyrroline

N-oxide

(5-

TFDMPO) 5b, and demonstrated trapping of radicals in

both aqueous buffer and organic solution.

We envisioned developing a trifluoromethylated cyc-

lic nitrone spin trap tethered to a polymer support for

the detection of free radicals in both the gas phase and

the liquid phase. The trifluoronated trap should both

give increased radical stability for EPR measurements,

19

and may also allow for detection via F MAS-NMR,

increasing the ability to detect gas phase radicals.

However, the tethered spin trap will also enable new

liquid phase experiments. Continuous flow NMR and

EPR capabilities have been developed at Pacific

Northwest National Laboratory (PNNL), which allows

the monitoring of chemistry on a solid phase while a

4

A. EARLA ET AL.

Figure 4. Monomeric and polymer-supported cyclic fluorinated nitrones investigated in this work.

1

19

Materials and methods

Alto, CA) using a 4 mm H FXY MAS probe. FTIR spec-

tra were recorded on a Perkin-Elmer spectrometer as a

neat film on a KBr cell. High-resolution mass spectra

Tetrahydrofuran (Fisher Scientific, Waltham, MA) was

dried over sodium and benzophenone when anhydrous

conditions were required. All other chemicals were

used as received. The following chemicals were pur-

chased from Sigma-Aldrich (St. Louis, MO): sodium

hydride (60% in mineral oil, used without removal of

the oil), triethylamine (99%), benzylamine (99%), paraf-

ormaldehyde (95%), Merrifield resin (3.0–4.0 mmol/g of

chloride), glacial acetic acid (17.4 N), and N,N-dimethyl-

formamide. The following chemicals were purchased

from Acros (Geel, Belgium): Dess–Martin periodinane

(HRMS) were recorded either on a benchtop Mariner

electrospray ionisation time-of-flight (ESITOF) mass

spectrometer or on LTQ Orbitrap. All EPR measure-

ments were performed on Bruker ELEXSYS E580 spec-

trometer equipped with an SHQe resonator. A capillary

with ID 0.8 mm and OD 1 mm was used to hold the

solution in the EPR cavity with both ends sealed by

Critoseal. The typical settings for the static spectra were

microwave frequency ¼9.86 GHz, sweep width ¼150 G,

sweep time ¼20.9 s, power ¼20 mW, field modulation

amplitude ¼0.5 G. Time resolved data were obtained by

recording EPR spectrum continually (one spectrum

every 20.9 s) during and after UV irradiation. For flow

EPR, a two syringe pump with separate control for each

syringe (KD Scientific, Holliston, MA) was used to inject

solutions into a mixer and then to a flow cell in EPR

cavity. The flow cell was created by containing the

resin beads in 1.8 mm OD ꢁ 0.75 mm ID FEP tubing

(

97%), 3,4-dihydro(2H)pyran (99%), tetrabutylammo-

nium fluoride (1 M in THF), and caesium fluoride (99%).

-Nitropropanol (98%) was purchased from Alfa Aesar

Haverhill, MA). The following reagents were purchased

2

(

from Fisher Scientific (Waltham, MA): magnesium sul-

phate (98%), sodium bicarbonate (98%), chloroform,

methanol, ethanol, magnesium turnings, zinc (99%),

sodium borohydride (98%), and concentrated hydro-

chloric acid (12 M). Trifluoromethyltrimethylsilane (99%)

was purchased from Oakwood Chemicals (West

Columbia, SC). 2-Nitropropane (98%) was purchased

from Spectrum Chemicals (New Brunswick, NJ).

Aminomethylated polystyrene was purchased at

(

1

McMaster-Carr, Elmhurst, IL) between frits. A Spectrum

00a UV source (Lesco, Cleveland, OH) was used for in

situ photolysis of EPR samples. It is equipped with an

8-W mercury vapour lamp, a shutter controlled with a

1

00–200 mesh size. Silica gel column chromatography

switch and timer, an iris, and 280–400 nm bandpass fil-

ters. The light is directed to the sample using a liquid

filled light guide connected to the light access port on

the EPR resonator.

TM

was performed on a Biotage Isolera Prime automated

flash purification system. Flash chromatography was

performed using premium grade 60, 40–75 mesh silica

gel from Sorbent Technologies (Norcross, GA).

Analytical thin layer chromatography (TLC) was carried

out on Whatman silica gel plates (0.25 mm thick). NMR

spectra were recorded at ambient temperature on a

varian 500-MHz spectrometer or in ovo 500 MHz in

Synthesis of 2-nitropropan-1-ol 11 [37]

To

1

a

stirred mixture of nitroethane (10.26 g,

36.7 mmol) and paraformaldehyde (4.105 g,

36.7 mmol) in 100 mL of acetonitrile, 0.2 mL of triethyl-

CDCl as solvent unless otherwise noted. The spectra

3

were recorded with the residual CHCl peak (d

3

1

7

.27 ppm) as internal standard for H NMR and CDCl

amine was added at room temperature. The reaction

mixture was stirred for 72 h and the solvent was evapo-

rated in vacuo. The resulting yellow oil was diluted with

100 mL of chloroform and filtered. The filtrate was

3

13

central peak of 1:1:1 “triplet” (d 77.27 ppm) for C NMR.

1

9

F SSNMR spectra were obtained at 19.9 T (850 MHz

for proton) on an Agilent VNMRS spectrometer (Palo

FREE RADICAL RESEARCH

5

concentrated in vacuo to give the title compound as a

give the title compound as a pale yellow oil (15.18 g,

red oil (5.805 g, 40.42% yield).

83.66% yield).

1

H NMR (500 MHz, CDCl ): d 4.67 (ddq, J ¼ 7.0, 3.3 Hz,

H NMR (500 MHz, CDCl , two diastereomers): d

3

1

3

H), 4.00 (dd, J¼ 12.4, 7.5 Hz, 1H), 3.92 (dd, J¼ 12.4,

.3 Hz, 1H), 2.22 (br s, 1H, OH), 1.55 (d, J¼ 7.0, 3H).

4.84–4.72 (m, 1H), 4.66 (q, J ¼ 3.0 Hz, 1H), 4.60 (q,

J ¼ 3.0 Hz, 1H), 4.17–4.09 (m, 1H), 3.95–3.83 (m, 1H),

3.82–3.77 (m, 1H), 3.76–3.70 (m, 1H), 3.69–3.64 (m, 1H),

3.56–3.49 (m, 2H), 1.83–1.56 (m, 2H), 1.56–1.45 (m, 3H).

1

3

C NMR (125 MHz, CDCl , DEPT): d 84.6 (CH), 64.2

3

(

CH ) 15.3 (CH ).

2 3

13

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

ꢂ

d 99.4 (CH), 98.0 (CH), 82.8 (4 ), 82.2 (4 ), 68.9 (CH ),

2

Synthesis of 4-nitropentan-1-ol 12 [38]

6

8.0 (CH ), 62.2 (CH ), 61.7 (CH ), 30.2 (CH), 30.1 (CH),

2 2 2

2

5.3 (CH ), 19.1 (CH ), 18.7 (CH ), 15.8 (CH ), 15.7 (CH ).

To a stirred solution of nitroethane (21.08 g, 280.8 mmol)

and acrolein (18.8 mL, 280 mmol) in 300 mL of aceto-

nitrile, 0.1 mL of DBU was added at 0 C. The reaction

2

3

ꢂ

Synthesis of 2-((4-nitropentyl)oxy)tetrahydro-2H-

mixture was stirred for 15 minutes and then 2 mL of

acetic acid was added to quench the reaction. The reac-

tion mixture was concentrated in vacuo to give 15.12 g

of an orange crude oil. Methanol (350mL) was added

pyran 13c

To a stirred solution of 4-nitropentan-1-ol 4.83 (5.326 g,

4

0.01 mmol)

and

3,4-dihydro-2H-pyran

(4.035 g,

8.01 mmol) in 100 mL of DCM, 1 mL of concentrated

ꢂ

and the reaction mixture was cooled to 0 C. Sodium

hydrochloric acid was added at room temperature. The

reaction mixture was stirred for 24 h and then washed

sequentially with 30 mL of water, 30 mL of saturated

NaHCO solution, 20 mL of brine, dried over MgSO and

borohydride (4.172 g, 110.3 mmol) was added in portions

over 20minutes. The reaction mixture was stirred for 1 h

and the solvent was evaporated in vacuo. The resulting

orange oil was dissolved in 500 mL of dichloromethane

3

4

concentrated in vacuo. The resulting crude orange oil

8.326 g) was purified by silica gel column chromatog-

(DCM), washed with 100 mL of water, dried over MgSO₄

(

and concentrated in vacuo to give the title compound as

a pale yellow oil (16.82 g, 46.99% yield).

raphy with 75:25 hexanes/ethyl acetate as eluent, to

give the title compound as a clear oil (6.065 g,

TLC: 50:50 hexanes/ethyl acetate, p-anisaldehyde,

6

7.78% yield).

R : 0.51.

f

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde

1

H NMR (500 MHz, CDCl ): d 4.65–4.58 (m, 1H),

3

stain, R : 0.64.

f

3

1

.71–3.63 (m, 2H), 2.11–2.03 (m, 1H), 1.90–1.82 (m, 1H),

.66 (br s, 1H), 1.61–1.56 (m, 2H), 1.54 (d, J¼ 7 Hz, 3H).

1

H NMR (500 MHz, CDCl two diastereomers): d 4.62

3,

(

2

dddd, J¼ 8.2, 6.8, 5.5, 1.4 Hz, 1H), 4.46 (dt, J¼ 5.5,

1

3

C NMR (125 MHz, CDCl , DEPT): d 80.3 (CH), 60.2

3

.1 Hz, 1H), 3.86–3.70 (m, 1H), 3.70–3.61 (m, 1H), 3.40

(

CH ), 30.2 (CH ), 28.1 (CH ), 19.8 (CH ).

2 2 2 3

FTIR: 3369 (O–H stretch), 1547 (N–O stretch), 1391

(

1

2

dt, J¼ 10.0, 6.0 Hz, 1H), 3.31 (dt, J¼ 10.0, 6.0 Hz, 1H),

.98 (dddd, J¼ 16.7, 14.2, 8.2, 4.1 Hz, 1H), 1.82–1.66 (m,

N-O stretch), 1278 (C–N stretch), 1064 (C–O

H), 1.65–1.56 (m, 1H), 1.56–1.50 (m, 2H), 1.45 (m, 7 H).

ꢃ1

stretch) cm

.

13

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

HRMS: calcd. for C H NO [M–H]: 132.0666:

5

11

3

d 98.9 (CH), 83.4 (CH), 83.3 (CH), 66.4 (CH ), 66.3 (CH ),

2

found 132.0666.

6

2

2.2 (CH ), 62.3 (CH ), 32.2 (CH ), 32.1 (CH ), 30.6 (CH ),

2 2 2 2 2

5.9 (CH ), 25.4 (CH ), 25.3 (CH ), 19.5 (CH ), 19.2 (CH ).

2

3

FTIR: 1548 (N–O stretch), 1391 (N-O stretch), 1278 (C–N

Synthesis of 2-(2-nitropropoxy)tetrahydro-2H-

pyran 13b [39]

ꢃ1

stretch), 1064 (C–O stretch) cm

.

HRMS: calcd. for C H NO [M–H]: 216.1214:

10

19

4

To a stirred solution of 2-nitropropan-1-ol 11 (10.08 g,

found 216.1237.

95.87 mmol)

and

3,4-dihydro-2H-pyran

(8.871 g,

1

0.55 mmol) in 100 mL of DCM, 1 mL of concentrated

Synthesis of 4-methyl-4-nitropentanal 14a [40]

hydrochloric acid was added at room temperature. The

reaction mixture was stirred for 21 h and then washed

sequentially with 30 mL of water, 30 mL of saturated

The following procedure using the 2-nitropropane is a

representative of the general procedure for the addition

of dialkylnitro anion to acrolein. To a solution of freshly

distilled acrolein (14.6 mL, 219 mmol) under ambient

pressure and 2-nitropropane (15.9 mL, 175 mmol) in

60 mL of acetonitrile, triethylamine (4.5 mL g, 50 mmol)

NaHCO solution, and 20 mL of brine, dried over MgSO₄

3

and concentrated in vacuo. The resulting crude orange

oil (17.24 g) was purified by silica gel column chroma-

tography with 50:50 hexanes/ethyl acetate as eluent, to

6

A. EARLA ET AL.

was added at room temperature. The reaction mixture

was stirred for 22 h and concentrated in vacuo. The

resulting crude yellow oil (20.03 g) was purified by silica

gel column chromatography with 85:15 hexanes/ethyl

acetate as eluent, to give the title compound as a col-

ourless oil (15.33 g, 60.19% yield).

FTIR: 1725 (C-O stretch), 1537 (N–O stretch), 1391 (N-

ꢃ1

O stretch), 1033 (C–O stretch) cm

.

Synthesis of 1,1,1-trifluoro-5-methyl-5-nitrohexan-

-ol 15a

2

To a stirred mixture of 4-methyl-4-nitropentanal 14a

3.898 g, 26.85 mmol) and caesium fluoride (1.273 g,

.8381 mmol) in 30 mL of anhydrous tetrahydrofuran,

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

(

0

R : 0.46.

f

1

H NMR (500 MHz, CDCl ): d 9.77 (s, 1H), 2.50 (t,

3

trifluoromethyltrimethylsilane (4.3 mL, 29 mmol) was

added dropwise over 10 minutes at 0 C. The reaction

mixture was stirred for 30 minutes, and then 20 mL of

J¼ 7.5 Hz, 2H), 2.34 (t, J¼ 7.5 Hz, 2H), 1.59 (s, 6H).

1

3

ꢂ

C NMR (125 MHz, CDCl , DEPT): d 199.9 (C-O), 87.3

3

ꢂ

4 ), 38.9 (CH ), 32.3 (CH ), 25.9 (CH ).

2 2 3

(

4

N hydrochloric acid was added. The layers were sepa-

FTIR: 1721 (C-O stretch), 1536 (N–O stretch), 1349 (N-

ꢃ1

rated and the aqueous layer was extracted three times

with 30 mL of DCM. The combined organic layer was

washed with 30 mL of saturated NaHCO₃solution,

O stretch), 1278 (C–N stretch) cm

.

Synthesis of 4-nitro-4-((tetrahydro-2H-pyran-2-

20 mL of brine, dried over MgSO and concentrated in

4

yl)oxy)pentanal 14b

vacuo. The resulting crude yellow oil (4.023 g) was puri-

fied by silica gel column chromatography with 85:15

hexanes/ethyl acetate as eluent, to give the title com-

pound as a colourless oil (2.633 g, 46.17% yield).

Pale yellow oil (11.39 g, 82.69% yield).

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

R : 0.36.

f

1

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

H NMR (500 MHz, CDCl , two diastereomers): d 9.77

3

R : 0.48.

f

(

3

1

s, 1H), 9.75 (s, 1H), 4.84–4.72 (m, 2H), 4.59 (dt, J¼ 10.5,

1

H NMR (500 MHz, CDCl ): d 3.44 (dd, J¼ 10.0, 2.0 Hz,

3

.4 Hz, 2H), 4.06 (d, J¼ 10.5 Hz, 1H), 3.95 (d, J¼ 10.5 Hz,

H), 3.77–3.66 (m, 3H), 3.63 (d, J¼ 10.5 Hz, 1H), 3.51 (dt,

1

H), 2.28 (m, 2H), 2.23 (m, 2H), 1.64 (s, 3H), 1.63 (s, 3H).

1

3

C NMR (125 MHz, CDCl , DEPT): d 105.4 (CF ), 87.8

3

J¼ 11.0, 4.4 Hz, 2H), 2.54 (dt, J¼ 11.1, 7.7 Hz, 3H), 2.35

ꢂ

4 ), 82.6 (CH), 37.2 (CH ), 26.3 (CH ), 26.2 (CH ),

2 3 2

(

7

3

ddt, J¼ 23.0, 15.2, 7.5 Hz, 2H), 2.17 (ddt, J¼ 23.0, 15.2,

2

5.3 (CH₃).

FTIR: 3468 (O–H stretch), 1536 (N–O stretch), 1349

.5 Hz, 2H), 1.77–1.61 (m, 2H), 1.61 (s, 4H), 1.59–1.55 (m,

H), 1.53–1.44 (m, 8 H).

(

N-O stretch), 1278 (C–N stretch), 1127 (C–F

1

3

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

ꢃ1

stretch) cm

.

ꢂ

d 199.9 (CHO), d 199.8 (CHO), 98.9 (CH), 89.7 (4 ), 71.7

HRMS: calcd. for C H F NO [M–H]: 214.0696:

7

12 3

3

(

CH ), 71.6 (CH ), 62.2 (CH ), 62.0 (CH ), 38.5 (CH ), 38.3

2 2 2 2 2

found 214.0607.

CH ), 30.2 (CH), 30.1 (CH), 28.3 (CH ), 28.1 (CH ), 25.2

2

CH ), 20.8 (CH ), 20.5 (CH ), 18.9 (CH ), 18.8 (CH ).

2

3

2

Synthesis of 1,1,1-trifluoro-5-methyl-5-nitro-6-

(tetrahydro-2H-pyran-2-yl)oxy)hexan-2-ol 15b

(

Synthesis of 4-methyl-4-nitro-7-((tetrahydro-2H-

pyran-2-yl)oxy)heptanal 14c

The following procedure using 4-nitro-4-((tetrahydro-

H-pyran-2-yl)oxy)pentanal 14b is a representative of

2

Clear oil (1.754 g, 37.16% yield).

the general procedure for the addition of trifluoro-

methyl to the aldehyde. To a stirred mixture of 4-

methyl-4-nitro-5-((tetrahydro-2H-pyran-2-yl)oxy)penta-

nal 14b (7.068 g, 28.82 mmol) and caesium fluoride

(0.6566 g, 4.323 mmol) in 50 mL of dry tetrahydrofuran,

trifluoromethyltrimethylsilane (5.1 mL, 34 mmol) was

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

R : 0.26.

f

1

H NMR (500 MHz, CDCl two diastereomers): d 9.77

3,

(s, 1H), 4.54 (m, 1H), 3.84–3.81 (m, 1H), 3.79–3.71 (m,

1

2

1

H), 3.49–3.47 (m, 1H), 3.39–3.36 (m, 1H), 2.52–2.46 (m,

H), 2.37–2.32 (m, 1H), 2.16–2.08 (m, 2H), 1.94–1.91 (m,

H), 1.80–1.78 (m, 1H), 1.73–1.24 (m, 10H).

ꢂ

added dropwise for 10 minutes at 0 C. The reaction

mixture was stirred for 1 h and tetrabutylammonium

fluoride (28 mL, 1 M in THF) was added. The reaction

mixture was stirred for 10 minutes and diluted with

100 mL of DCM. The organic layer was washed with

50 mL of water and 50 mL of brine, dried over MgSO₄

and concentrated in vacuo. The resulting crude yellow

1

3

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

d 199.2 (HC-O) 99.0 (CH), 98.9 (CH), 90.0 (4 Å), 66.7

(

CH ), 62.5 (CH ), 62.4 (CH ), 38.6 (CH ), 36.6 (CH ), 36.5

2 2 2 2 2

CH ), 31.0 (CH ), 30.6 (CH ), 25.4 (CH ), 24.4 (CH ), 22.0

2

CH ), 19.5 (CH ).

3

2

FREE RADICAL RESEARCH

7

oil (6.238 g) was purified by silica gel column chroma-

tography with 60:40 hexanes/ethyl acetate as eluent, to

give the title compound as a colourless oil (4.295 g,

FTIR: 1761 (C-O stretch), 1541 (N–O stretch), 1351 (N-

ꢃ1

O stretch), 1271 (C–N stretch), 1154 (C–F stretch) cm

.

HRMS: calcd. for C

found 212.0534.

H

10

F

NO

[M–H]: 212.0540:

7

3

4

7.27% yield).

TLC: 60:40 hexanes/ethyl acetate, p-anisaldehyde,

R : 0.62.

f

1

,1,1-Trifluoro-5-methyl-5-nitro-6-((tetrahydro-2H-

1

H NMR (500 MHz, CDCl₃_,multiple diastereomers): d

.69–4.56 (m, 1H), 4.16–3.99 (m, 1H), 3.83–3.67 (m, 2H),

pyran-2-yl)oxy)hexan-2-one 16b

4

3

2

1

.60–3.47 (m, 1H), 3.22–3.05 (m, 1H), 2.95–2.80 (m, 1H),

.57–2.38 (m, 1H), 2.38–2.18 (m, 1H), 1.82–1.45 (m, 10H),

.29 (d, J¼ 24.9 Hz, 1H).

Pale yellow oil (8.064 g, 77.96% yield).

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

R

f

: 0.40.

1

3

1

C NMR (125 MHz, CDCl , DEPT, multiple diaster-

H NMR (500 MHz, CDCl3, two diastereomers): d

3

eomers): d 127.1–120.3 (m, CF ), 98.10 (CH), 97.12 (CH),

4.69–4.56 (m, 1H), 4.16–3.99 (m, 1H), 3.83–3.67 (m, 2H),

3.60–3.47 (m, 1H), 3.22–3.05 (m, 1H), 2.95–2.80 (m, 1H),

2.57–2.38 (m, 1H), 2.38–2.18 (m, 1H), 1.82–1.45 (m, 10H).

3

ꢂ

9

(

7.8 (CH), 97.8 (CH), 89.0 (4 ), 88.8 (4 ), 88.76 (4 ), 70.8

CH ), 70.4 (CH ), 70.1 (CH ), 69.9 (CH ), 69.2–68.3 (m,

2

13

CH-CF ), 61.5 (CH ), 61.3 (CH ), 61.0 (CH ), 60.9 (CH ),

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

2

3

2

0.7 (CH ), 30.6 (CH ), 30.4 (CH ), 30.0 (CH ), 29.0 (CH ),

d 191.7–186.04 (m, CF

(CH), 98.8 (CH), 89.4 (4 ), 89.2 (4 ), 71.7 (CH

3

ꢂ

–C-O), 116.6–114.3 (m, CF

3

), 98.9

2

ꢂ

8.95 (CH ), 28.91 (CH ), 23.9 (CH ), 23.00 (CH ), 22.7

2

), 71.6 (CH

), 30.09 (CH

), 21.2 (CH ), 21.0 (CH

2

3

),

2

(

CH ), 22.6 (CH ), 19.6 (CH ), 19.5 (CH ), 18.9 (CH ), 18.6

CH ), 17.9 (CH ), 17.8 (CH ), 17.7 (CH ), 17.6 (CH ).

62.1 (CH

28.9 (CH

18.9 (CH

2

), 62.0 (CH

), 28.7 (CH

), 18.8 (CH

2

), 31.2 (CH ), 31.1 (CH

2 2

), 25.20 (CH

).

2

3

2

3

FTIR: 3393 (O–H stretch), 1544 (N–O stretch), 1352

(

1

N-O stretch), 1278 (C–N stretch), 1121 (C–F stretch),

FTIR: 1716 (C-O stretch), 1546 (N–O stretch), 1348 (N-

ꢃ1

074 (C–O stretch), 1005 (C–O stretch) cm

.

O stretch), 1241 (C–N stretch), 1183 (C–F stretch) cm

.

Synthesis of 1,1,1-trifluoro-5-methyl-5-nitro-8-

(tetrahydro-2H-pyran-2-yl)oxy)octan-2-ol 15c

1,1,1-Trifluoro-5-methyl-5-nitro-8-((tetrahydro-2H-

pyran-2-yl)oxy)octan-2-one 16c

(

Pale yellow oil (74.63% yield) was used without

purification.

Pale yellow oil (1.545 g, 74.96% yield).

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

R : 0.25.

f

1

H NMR (500 MHz, CDCl₃_,two diastereomers): d 4.51

m, 1H), 3.82–3.79 (m, 1H), 3.73–3.70 (m, 1H), 3.48–3.47 (m,

H), 3.39–3.36 (m, 1H), 2.76–2.75 (m, 2H), 2.45–2.35 (m,

Synthesis of 1,1,1-trifluoro-5-methyl-5-nitrohexan-

(

1

2

-one 16a

The following procedure using 1,1,1-trifluoro-5-methyl-

-nitro-6-((tetrahydro-2H-pyran-2-yl)oxy)hexan-2-ol 15a

1H), 2.19–2.15 (m, 2H), 2.09–2.04 (m, 2H), 1.96–1.93 (m, 1H)

1.79–1.77 (m, 1H), 1.70–1.68 (m, 1H), 1.67–1.49 (m, 6H).

5

13

is a representative of the general procedure for the

oxidation of the alpha-trifluoromethyl alcohol to the

corresponding ketone. To a stirred solution of 1,1,1-tri-

C NMR (125 MHz, CDCl , DEPT, two diastereomers):

3

d 190.0 (q, J ¼ 30 Hz, C–CF ), 115.2 (q, J ¼ 240 Hz,

CF

3

CF

ꢂ

CF ), 99.1 (CH), 99.0 (CH), 89.9 (4 ), 66.8 (CH ), 66.5

3

2

fluoro-5-methyl-5-nitrohexan-2-ol

7.49 mmol) in 50 mL of DCM, Dess–Martin periodinane

8.903 g, 20.99 mmol) was added at room temperature.

15a

(3.764 g,

(CH ), 62.8 (CH ), 62.5 (CH ), 36.5 (CH ), 31.2 (CH ), 31.1

2 2 2 2 2

(CH ), 30.5 (CH ), 25.3 (CH ), 24.3 (CH ), 24.2 (CH ), 22.1

2 2 2 2 2

(CH ), 21.9 (CH ), 19.6 (CH ).

2 2 3

1

(

The reaction mixture was stirred for 18 h, concentrated

in vacuo, diluted with 150 mL of hexanes, and filtered.

The filtrate was concentrated in vacuo to give the title

compound as a pale yellow oil (2.761 g, 74.07% yield).

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

FTIR: 1766 (C-O stretch), 1539 (N–O stretch), 1351 (N-

O stretch), 1278 (C–N stretch), 1175 (C–F stretch), 1024

ꢃ1

(C–O stretch) cm

.

HRMS: calcd. for C H F NO [M–H]: 340.1377: found

14

22 3

5

340.1364.

R : 0.40.

f

1

H NMR (500 MHz, CDCl ): d 2.79 (t, J¼ 7.5 Hz, 2H),

3

Synthesis of 2,2-dimethyl-5-(trifluoromethyl)-3,4-

dihydro-2H-pyrrole 1-oxide 6 [36]

2

.31 (t, J¼ 7.5 Hz, 2H), 1.64 (s, 6H).

13

C NMR (125 MHz, CDCl , DEPT): d 189.9 (q,

3

J ¼ 35.5 Hz, CF –C-O), 115.4 (q, J ¼ 290 Hz, CF ), 86.7

To a stirred mixture of 1,1,1-trifluoro-5-methyl-5-nitro-

hexan-2-one 16a (2.761 g, 12.95 mmol) and zinc

CF

3

CF

3

(

4 Å), 32.8 (CH ), 31.6 (CH ), 25.9 (CH ).

2

3

8

A. EARLA ET AL.

(

2.424 g, 38.87 mmol) in 70 mL of ethanol, acetic acid

Synthesis of 2-hydroxymethyl-2methyl-5-

(trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide 7

4.5 mL, 78 mmol) was added in an ice bath to keep the

ꢂ

temperature below 10 C. The reaction mixture was

allowed to warm to room temperature and stirred for

2

This procedure using 2-methyl-2-(((tetrahydro-2H-

pyran-2yl)oxy)methyl)-5-(trifluoro-methyl)-3,4-dihydro-

4 h, filtered over celite, concentrated in vacuo, and

50 mL of DCM was added. The organic layer was

2

H-pyrrole 1-oxide 17b is a representative for the

1

reductive cyclisation to form the nitrone. To a stirred

solution of 2-methyl-2(((tetrahydro-2H-pyran-2yl)oxy)-

washed sequentially with 20 mL of water, 20 mL of satu-

rated NaHCO , and 20 mL of brine. The organic layer

was concentrated in vacuo to give the title compound

as a pale yellow oil (1.082 g, 46.14% yield).

3

methyl)-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole

oxide 17b (6.811 g, 24.22 mmol) in 70 mL of methanol,

mL of concentrated hydrochloric acid was added at

1-

3

TLC: 75:25 hexanes/ethyl acetate, p-anisaldehyde,

room temperature. The reaction mixture was stirred for

1 h and then sodium bicarbonate (3.089 g, 36.77 mmol)

was added. The reaction mixture was filtered and the

filtrate was concentrated in vacuo. The resulting crude

brown oil was purified by silica gel column chromatog-

raphy using 50:50 hexanes/ethyl acetate as eluent, to

give the title compound as a white solid (1.719 g,

R : 0.25.

f

1

H NMR (500 MHz, CDCl ): d 2.82 (t, J¼ 7.0 Hz, 2H),

3

2

.16 (t, J¼ 7.0 Hz, 2H), 1.45 (s, 6H).

1

3

C NMR (125 MHz, CDCl , DEPT): d 129.3 (q,

3

J ¼ 35.1 Hz, C–CF ), 119.7 (q, J ¼ 271 Hz, CF ), 77.7

CF

3

CF

3

ꢂ

(4 ), 32.1 (CH ), 25.1 (CH ), 23.9 (CH ).

2

3

2

1

9

F NMR (470 MHz, C F ): d ꢃ 68.6 (s, CF ).

ꢂ

6

3

37.33% yield, m.p.: 70–72 C).

FTIR: 1581 (N–O stretch), 1424 (C ¼ N stretch), 1258

TLC: 50:50 hexanes/ethyl acetate, p-anisaldehyde,

ꢃ1

(C–N stretch), 1144 (C–F stretch) cm

.

R : 0.22.

f

1

HRMS: calcd. for C H F NO [M–H]: 181.0641:

7

10 3

H NMR (500 MHz, CDCl ): d 3.94 (d, J¼ 12.1 Hz, 1H),

3

found 181.0480.

3.56 (d, J¼ 12.1 Hz, 1H), 2.96–2.97 (m, 2H), 2.43 (m, 1H),

2

.04 (m, 1H), 1.44 (s, 3H).

13

C NMR (125 MHz, CDCl , DEPT): d 133.2 (q,

3

Synthesis of 2-methyl-2-(((tetrahydro-2H-pyran-

2

ꢂ

J ¼ 36.1 Hz, C-N), 119.3 (q, J ¼ 271 Hz, CF ), 81.2 (4 ),

CF

3

yl)oxy)methyl)-5-(trifluoro-methyl)-3,4-dihydro-

H-pyrrole 1-oxide 17b

6

6.1 (CH ), 26.7 (CH ), 24.9 (CH ), 20.6 (CH ).

2 2 2 3

19

F NMR (470 MHz, C F ): d –68.7 (s, CF ).

6

3

FTIR: 3392 (O–H stretch), 1610 (N–O stretch), 1417

Yellow oil (6.811 g, 94.07% yield).

(

1

C-N stretch), 1376 (N-O stretch), 1238 (C–N stretch),

TLC: 60:40 hexanes/ethyl acetate, p-anisaldehyde,

ꢃ1

135 (C–F stretch) cm

.

R : 0.33.

f

1

HRMS: calcd. for C H F NO [M–H]: 196.0590:

7 10 3 2

found 196.0580.

H NMR (500 MHz, CDCl , two diastereomers): d

3

4

3

2

1

.98–4.78 (m, 2H), 4.11–3.98 (m, 2H), 3.82–3.66 (m, 4H),

.58–3.46 (m, 2H), 3.17–3.05 (m, 1H), 2.92–2.79 (m, 2H),

.53–2.36 (m, 2H), 2.35–2.16 (m, 2H), 1.79–1.42 (m,

8 H), 1.27–1.12 (m, 1H).

Synthesis of 2-(3-hydroxypropyl)-2-methyl-5-

trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide 8

(

1

3

C NMR (125MHz, CDCl , DEPT, two diastereomers):

3

Pale yellow oil (0.3733 g, 36.76% yield).

d 131.4–129.7 (m, C–CF ), 121.7–116.6 (m, CF ), 98.5 (CH),

3

TLC: ethyl acetate, UV, p-anisaldehyde, R : 0.37.

ꢂ ꢂ

6.1 (CH), 79.1 (4 ), 78.7 (4 ), 73.1 (CH ), 72.0 (CH ), 70.3

2 2

f

9

1

H NMR (500 MHz, CDCl ): d 3.59 (td, J¼ 6.3, 2.6 Hz,

3

(

CH ), 68.9 (CH ), 61.6 (CH ), 61.3 (CH ), 29.2 (CH ),

2 2 2 2 2

2

(

2

H), 2.85–2.70 (m, 2H), 2.81 (s, 4H), 2.60 (br s, 1H), 2.25

2

9.0 (CH ), 26.9 (CH ), 26.5 (CH ), 24.1 (CH ), 23.9 (CH ),

2 2 2 2 2

m, 1H), 2.04 (m, 1H), 1.88–1.74 (m, 2H), 1.70–1.59 (m,

0.2 (CH ), 19.9 (CH ), 18.5 (CH ), 18.3 (CH ).

3

2

H), 1.58 (m, 1H), 1.41 (s, 3H).

FTIR: 1589 (N–O stretch), 1421 (C ¼ N stretch), 1378

13

C NMR (125 MHz, CDCl , DEPT): d 131.9 (q,

3

(

N-O stretch), 1245 (C–N stretch), 1135 (C–F

ꢂ

J ¼ 36 Hz, C–CF ), 119.5 (q, J ¼ 270 Hz, CF ), 80.6 (4 ),

CF

3

CF

3

ꢃ1

stretch) cm

.

6

2

2.5 (CH ), 34.0 (CH ), 28.8 (CH ), 26.3 (CH ), 24.6 (CH ),

2

3

4.5 (CH ).

2

19

F NMR (470 MHz, C F ): d –68.4 (s, CF ).

6

3

Synthesis of 2-(3-(((tetrahydro-2H-pyran-

FTIR: 3401 (O–H stretch), 1590 (N–O stretch), 1352

2

yl)oxy)methyl))-5-(trifluoromethyl)-3,4-dihydro-

H-pyrrole-1-oxide 17c

(

1

N-O stretch), 1278 (C–N stretch), 1146 (C–F stretch),

ꢃ1

058 (C–O stretch) cm

.

Red oil (75.56% yield) was used in next step without

purification.

HRMS: calcd. for C H F NO [M–H]: 224.0903:

9 14 3 2

found 224.0900.

FREE RADICAL RESEARCH

9

Synthesis of 2-((benzyloxy)methyl)-2-methyl-5-

trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-

oxide 18

Synthesis of 2-(3-((((2,5-dioxopyrrolidin-1-

yl)oxy)carbonyl)oxy)propyl)-2-methyl-5-

(trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-

oxide 21

(

To a stirred solution of 2-hydroxymethyl-2-methyl-5-(tri-

fluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide 7 (0.511 g,

To a stirred solution of 2-(3-hydroxypropyl)-2-methyl-

5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide

0

.2587 mmol) in 3 mL of dimethylformamide, sodium

0

hydride (0.0093 g, 0.39 mmol) was added at room tem-

perature. The reaction mixture was stirred for 1 h and

then quenched with 1 mL of saturated ammonium

chloride solution. The reaction mixture was diluted with

(2-PFDMPO) (0.6085 g, 2.702 mmol) and N,N -disuccini-

midyl carbonate (0.6922 g, 2.702 mmol) in 15 mL of

acetonitrile, triethylamine (0.38 mL, 2.7 mmol) was

added at room temperature. The reaction mixture was

stirred for 24 h and then concentrated in vacuo. The

resulting red oil (1.235 g) was purified by silica gel col-

umn chromatography with 50:50 hexanes/ethyl acetate

as eluent, to give the title compound as a pale yellow

oil (0.6341 g, 64.10% yield).

5

mL of DCM. The organic layer was separated and

washed one time with 3 mL of brine, dried over MgSO₄,

filtered and concentrated in vacuo. The resulting crude

brown oil was purified by silica gel column chromatog-

raphy using 50:50 hexanes/ethyl acetate as eluent, to

give the title compound as a yellow oil (0.0236 g,

TLC: ethyl acetate, UV, p-anisaldehyde, R

: 0.73.

H NMR (500 MHz, CDCl ): d 4.34 (m, 1H), 4.29 (m,

3

f

1

37.6% yield).

TLC: 50:50 hexanes/ethyl acetate, p-anisaldehyde,

1H), 2.81 (s, 4H), 2.22 (m, 1H), 2.08 (m, 1H), 1.95–1.86

(m, 1H), 1.86–1.74 (m, 2H), 1.70–1.59 (m, 1H), 1.44

(s, 3H).

R : 0.64.

f

1

H NMR (500 MHz, CDCl ): d 7.37–7.34 (m, 2H),

3

13

7

.32–7.20 (m, 3H), 4.60 (d, J¼ 12.0 Hz, 1H), 4.46 (d,

C NMR (125 MHz, CDCl

(C-O), 130.0 (q,

CF¼ 270 Hz, CF ), 79.7 (4 ), 70.7 (CH

(CH ), 25.4 (CH ), 24.4 (CH ), 24.2 (CH

3

, DEPT): d 168.6 (C-O), 151.4

35 Hz, C–CF ), 119.5 (q,

), 33.9 (CH ), 28.9

), 22.8 (CH ).

J¼ 12.0 Hz, 1H), 3.87 (d, J¼ 10.1 Hz, 1H), 3.36 (d,

J¼ 10.1 Hz, 1H), 2.95–2.81 (m, 1H), 2.73 (m, 1H), 2.57 (m,

J

¼

CF

3

ꢂ

J

3

2

1

H), 2.01 (m, 1H), 1.38 (s, 3H).

2

3

2

1

3

ꢂ

C NMR (125 MHz, CDCl , DEPT): d 137.9 (4 ), 131.8

FTIR: 1788 (C-O stretch), 1740 (C-O stretch), 1587

3

(

q, J ¼ 36.1 Hz, C-N), 128.6 (2 CH), 127.9 (CH), 127.6 (2

(N–O stretch), 1352 (N-O stretch), 1144 (C–F stretch),

CF

ꢃ1

ꢂ

CH), 119.5 (q, J ¼ 275 Hz, CF ), 80.3 (4 ), 73.6 (CH ),

1095 (C–O stretch) cm

.

CF

3

2

7

3.4 (CH ), 27.6 (CH ), 25.1 (CH ), 21.4 (CH ).

HRMS: calcd. for C14

found 365.0934.

H F N O [M–H]: 365.0965:

17 3 2 6

2

3

FTIR: 1610 (N–O stretch), 1417 (C-N stretch), 1376 (N-

ꢃ1

O stretch), 1238 (C–N stretch), 1135 (C–F stretch) cm

.

HRMS: calcd. for C H F NO [M þ H]: 288.1167:

14

16 3

2

Synthesis of 2-(3-((benzylcarbamoyl)oxy)propyl)-2-

methyl-5-(trifluoromethyl)-3,4-dihydro-2H-pyrrole

found 288.1198.

1-oxide 22

To a stirred solution of nitrone (0.0512 g, 0.1398 mmol)

in 5 mL of acetonitrile, benzyl amine (0.0149 g,

Synthesis of Merrifield resin supported nitrone

resin-2HFDMPO) 9

0

.1398 mmol) was added at room temperature and

(

stirred for 10 minutes. The reaction mixture was con-

centrated in vacuo. The resulting yellow oil (0.0632 g)

was purified by silica gel column chromatography with

To a stirred solution of 2-hydroxymethyl-2methyl-5-(tri-

fluoromethyl)-3,4-dihydro-2H-pyrrole 1-oxide

0.3879 g, 1.969 mmol) in 4 mL of DMF, sodium hydride

0.1889 g, 10.23 mmol) was added at room temperature

7

(

5

0:50, ethyl acetate/hexanes as eluent to give the title

compound as a colourless oil (0.0313 g, 62.47% yield).

and stirred for 30 minutes. Merrifield resin (0.7501 g)

was added and the reaction mixture was stirred

at 50 C for 1 h. The reaction was cooled to room tem-

perature and then filtered. The resulting cake

was washed three times with 10 mL of dimethylforma-

mide, one time 20 mL of water, 20 mL of methanol,

TLC: 50:50 ethyl acetate/hexanes, UV, p-anisalde-

hyde, R : 0.73.

f

ꢂ

1

H NMR (500 MHz, CDCl ): d 7.33 (t, J¼ 7.4 Hz, 2H),

3

7.30–7.24 (m, 3H), 5.09 (br s, 1H, NH), 4.35 (d, J¼ 5.8 Hz,

2H), 4.10 (m, 2H), 2.88–2.67 (m, 4H), 2.27–2.15 (m, 2H),

1.92–1.58 (m, 2H), 1.44 (s, 3H).

13

20 mL of chloroform, and 20 mL of hexanes. The result-

C NMR (125 MHz, CDCl , DEPT): d 156.5 (C-O), 138.5

3

ꢂ

ing cake was dried in vacuo to yield 0.8121 g of a brown

solid.

(4 ), 128.7 (CH), 127.5 (CH), 130.0 (q, J ¼ 35 Hz, C–CF ),

CF

3

ꢂ

119.5 (q, J ¼ 270 Hz, CF ), 80.1 (4 ), 64.4 (CH ), 45.1

CF

3

2

1

0

A. EARLA ET AL.

(

2

CH ), 34.4 (CH ), 29.0 (CH ), 24.5 (CH ), 24.3 (CH ),

3.5 (CH₂).

nitro product 13c in 68% yield (Scheme 1). The nitroal-

kanes 13a, 13b, and 13c were subjected to the Michael

addition to acrolein using triethylamine as base to give

nitroaldehydes 14a, 14b, and 14c in 46, 83, and 37%

yields, respectively (Scheme 2). Trifluoromethylation of

the nitroaldehydes using the Ruppert–Prakash reagent

2

3

2

FTIR: 1788 (C-O stretch), 1587 (N–O stretch), 1352 (N-

ꢃ1

O stretch), 1144 (C–F stretch), 1095 (C–O stretch) cm

.

HRMS: calcd. for C H F N O [M þ H]: 359.1538:

17 19 3 2 3

found 359.1567.

(

TMS-CF ) and catalytic caesium fluoride followed by

3

desilylation using concentrated hydrochloric acid for 14a

and tetrabutylammonium fluoride for 14b and 14c gave

the corresponding trifluoromethylated alcohols 15a,

Synthesis of polystyrene supported 2-PFDMPO

resin-2-PFDMPO) 10

(

To a stirred solution of aminomethylated polystyrene

0.4063 g, 0.3657 mmol) in 5 mL of dimethylformamide,

15b, and 15c in 74, 47, and 75% yields, respectively.

(

Dess–Martin periodinane oxidation of trifluoromethy-

lated alcohols produced trifluoromethyl ketones, which

underwent reductive cyclisation in the presence of zinc

and acetic acid, via the hydroxylamine generated in situ,

to yield nitrones 6, 17b, and 17c in 46, 94, and 75%

yields, respectively (Scheme 2). Final deprotection of the

THP group of 17b and 17c using hydrochloric acid in

methanol produced 2-HFDMPO 7 and 2-PFDMPO 8

(Scheme 3).

nitrone (0.1339 g, 0.3657 mmol) was added at room

temperature, stirred for 3 h, and then filtered. The

resulting cake was washed three times with 10 mL of

methanol, one time with 10 mL of hexanes, and dried

to give 0.6013 g of Resin-2-PFDMPO as a pale yel-

low solid.

Results and discussion

Benzyl chloride was selected as a model compound

to test the viability of nucleophilic substitution of the

benzylic chloride in Merrifield resin by the alcohol of 2-

HFDMPO 7 (Scheme 4). The reaction of benzyl chloride

with 2-HFDMPO in DMF using sodium hydride at 50 C

afforded the desired ether 18 in 38% yield. To append

Commercially available 2-nitropropane 13a was used as

the starting material for our alternate synthesis of 2-

TFDMPO 6. For the synthesis of 2-HFDMPO 7, the starting

material, THP protected 2-nitropropanol 13b, was syn-

thesised using nitroethane and paraformaldehyde in

acetonitrile with triethylamine as a base, followed by the

protection of alcohol group in 11 using 3,4-dihydropyran

in the presence of a catalytic amount of hydrochloric acid

ꢂ

2

-HFDMPO to the Merrifield resin, a mixture of resin, 2-

HFDMPO, and sodium hydride was stirred in anhydrous

ꢂ

dimethylformamide at 50 C for 1 h. The progress of the

(Scheme 1). The starting material for 2-PFDMPO 8 was

obtained by Michael addition of the anion of nitroethane

to acrolein using catalytic 1,8-diazabicycloundec-7-ene

reaction was monitored by TLC to observe the dis-

appearance of 2-HFDMPO (Scheme 4).

(

DBU) as base in acetonitrile, to give the corresponding

The presence of the nitrone spin-trap on the resin was

confirmed by EPR of the HOꢀ trapped adduct. Hydroxyl

radical was generated by photolysis of 3% hydrogen per-

oxide solution in water using a UV lamp; addition to the

nitroaldehyde, which was reduced using sodium borohy-

dride in methanol to yield alcohol 12 in 47% yield. The

alcohol was protected using 3,4-dihydropyran to give the

Scheme 1. Synthesis of THP-protected alcohol starting materials for 2-HFDMPO 7 and 2-PFDMPO 8.

FREE RADICAL RESEARCH

11

Scheme 2. Preparation of trifluoromethylated nitrones.

Scheme 3. Deprotection of hydroxyl groups to prepare 2-HFDMPO 7 and 2-PFDMPO 8.

Scheme 4. Model reaction of benzyl chloride with 2-HFDMPO 7 and preparation of spin trap 7 tethered to Merrifield resin:

Resin-2-HFDMPO 9.

Merrifield resin supported 2-HFDMPO gave the EPR

active nitroxide. The spin-trap nitrone resin was rejuven-

ated by reducing it with ascorbic acid for the next experi-

ment (Scheme 5). When reduction was attempted using

ascorbic acid in water, the EPR spectrum would reappear

once the solvent was changed back to water alone.

However, when the ascorbic acid was introduced in an

aprotic solvent, the trap remained in the reduced state.

The EPR spectrum of the hydroxyl adduct of Resin-2-

HFDMPO 9 gave broad peaks compared to the EPR spec-

tra of hydroxyl adducts of 2-TFDMPO 6 and 2-HFDMPO 7

Significant peak broadening is likely due to the short

tether between the nitrone spin-trap and the polymer,

which results in restricted motion of the nitroxide adduct.

A longer linker between the nitrone and resin should

provide more rotational freedom, resulting in spectra

with narrow peaks, providing more information about

the initial radical species. Triethylene glycol was investi-

gated as a potential linker. However, 2-HFDMPO failed to

undergo S 2 reaction with the chloro- or iodo-triethylene

N

glycol derivatives 19, probably due to the steric hin-

drance of the neopentyl alcohol nucleophile (n ¼ 1)

(Scheme 6). Therefore, a nitrone with a tether to a pri-

mary alcohol, 2-PFDMPO 8, was developed. The alkoxide

(Figure 5(a)). The absence of hyperfine splitting makes

the identification of the original HOꢀ radical unclear.

1

2

A. EARLA ET AL.

Scheme 5. Rejuvenation of Resin-2-HFDMPO 9.

Scheme 6. Attempted S 2 reactions of chloro- and iodo-triethylene glycol derivatives, a bromo-tetraethylene glycol derivative,

N

and a benzylic chloride derivative with 2-HFDMPO 7 and 2-PFDMPO 8.

anion of 2-PFDMPO was generated in dry tetrahydro-

furan using sodium hydride at room temperature, with

the intention to use it as a nucleophile with the bromo-

derivative of THP-protected tetraethylene glycol.

Attempted nucleophilic substitution reactions of 2-

HFDMPO and 2-PFDMPO were not successful, and even

benzylic chloride 20 failed to react with the sodium alk-

acetonitrile using triethylamine as a base to afford the

desired activated alcohol acyl succinate of 2-PFDMPO

21 in 64% yield (Scheme 7). As a model reaction, the

activated acyl succinate of 2-PFDMPO 21 was treated

with benzylamine in acetonitrile at room temperature

to give the isolated carbamate 22 in 62% yield (Scheme

7). To append 2-PFDMPO onto an aminomethylated

polystyrene resin, a mixture of resin and acyl succinate

nitrone 21 was stirred in dimethylformamide for 3 h.

The progress of the reaction was monitored by TLC to

observe the disappearance of the activated nitrone 21.

The presence of the nitrone on the resin was confirmed

oxides of 2-HFDMPO and 2-PFDMPO.

3

S 2 substitution by alcohols at an sp carbon bear-

N

ing a leaving group is much more sterically demanding

2

than nucleophilic acylation at a flat sp carbon. Thus, an

acylation approach was pursued, in which the hydroxyl

group of 2-PFDMPO was acylated by addition to

19

by F MAS-NMR and by EPR of the HOꢀ adduct via

0

19

N,N -disuccinimidyl carbonate (DSC), followed by subse-

photolysis of hydrogen peroxide (Figure 5). The

F

quent coupling with a primary amine to form a carba-

mate. Nitrone 2-PFDMPO was activated with DSC in

chemical shift was d –64.91 ppm, similar to that

reported for FDMPO at ꢃ66.0 ppm [33]. The EPR

FREE RADICAL RESEARCH

13

Scheme 7. Activation of 2-PFDMPO 8, model reaction with benzyl chloride and synthesis of Resin-2-PFDMPO 10.

Figure 5. (a) EPR spectra of nitroxides 2-TFDMPO-OH, 2-HFDMPO-OH, and Resin-2-HFDMPO-OH, all three in water, EPR spectra of

1

9

Resin-2-PFDMPO-OH in water and in dichloromethane. (b) F MAS-NMR of 10, asterisks indicate spinning side bands. Top,

2.5 kHz spinning speed; bottom, 10 kHz spinning speed.

1

spectrum of the HOꢀ adduct of 10 in DCM was fit using

EasySpin [41] using starting parameters typical for a

nitroxide in the slow motion regime. Conversion of the

anisotropic results to the isotropic values typically

reported for spin traps yields a ¼ 2.46 G and a ¼ 13.54,

the longer, more flexible linker compared to Resin-2-

HFDMPO-OH (Figure 5). Although the spectrum of the

spin-adduct Resin-2-PFDMPO-OH is not as narrow as that

of the adduct of the free small molecule 2-HFDMPO, it is

narrow enough to distinguish between different radical

adducts in solvents such as DCM. Future plans are to

investigate the addition of other radical species.

F

N

comparable to values reported for FDMPO-HOꢀ in

water of a ¼ 2.75 G and a ¼ 13.90 [33].

F

N

For spin-trapping experiments using Resin-2-PFDMPO

1

0 as the solid phase, the radical HOꢀ was generated by

Flow experiments

the photolysis of HOOH. The EPR spectrum of the adduct

was compared to the EPR spectrum of 2-HFDMPO-OH. As

expected, the broadening of peaks was reduced in the

EPR spectrum of the adduct Resin-2-PFDMPO-OH with

With the nitrones successfully attached to resin beads,

continuous flow experiments were performed. In order

to test whether a radical in the mobile phase could be

1

4

A. EARLA ET AL.

Figure 6. Flow experiments with Resin-2-HFDMPO-OH. Left, the column is prepared for the experiment by reducing the radical

form of the spin trap with 200 mM ascorbic acid in 80:20 DCM/DMF. A 3% aqueous hydrogen peroxide solution is pumped

through the spin trap column. After equilibration, the EPR resonator is then illuminated with a UV lamp creating hydroxyl radi-

cals. Right, the column is again reduced with ascorbic acid, this time in DMSO, to remove the trapped radicals from the previous

experiment. The mobile phase is then switched to KO dissolved in DMSO with 18-crown-6 ether to aid solubility. The sharp

2

doublet at ꢄ1000 s is from solution state ascorbic acid radicals.

0

detected, a miniature column was created in 1/16

PTFE tubing containing 3–4 mg of Resin-2-HFDMPO 9

Figure 6). This column was centred in the EPR reson-

spectrum. This may be the best experimental strategy:

monitor build-up of signal in the systems solvent, then

switch to methylene chloride to increase spec-

tral resolution.

(

ator and attached to a syringe pump with the flow set

at 100 mL/min; EPR spectra were continually acquired

during the course of the experiment. A background rad-

ical signal from the resin was first removed by passing

a solution of ascorbic acid in DCM/DMF over the col-

umn the column was then washed with water for sev-

eral column volumes. At this point, the mobile phase

was switched to a 3% H O solution and the column

allow to equilibrate. The resonator was illuminated with

a UV lamp for a series of 20-second flashes, upon each

flash, the EPR spectrum increased in magnitude as

increasing amounts of Resin-2-HFDMPO-OH was

formed. An experiment was then run to ascertain

whether the resin could also trap superoxide (Figure 6).

First, the resin was rejuvenated by removing the radical

from the previous experiment to reform the nitrone. In

this instance, ascorbic acid dissolved in DMSO was the

reductant. Then, a superoxide solution, created by dis-

Conclusions

A practical and reliable synthesis of 2-TFDMPO 6

was developed, and two new amphiphilic nitrones,

2-(hydroxymethyl)-2-methyl-5-(trifluoromethyl)-3,4-

dihydro-2H-pyrrole 1-oxide (2-HFDMPO) 7, and 2-(3-

hydroxypropyl)-2-methyl-5-(trifluoromethyl)-3,4-dihydro-

2H-pyrrole 1-oxide (2-PFDMPO) 8 were prepared. These

fluorinated spin-traps will be useful in biological studies

of free radicals in aqueous environments as well as in

subcellular lipophilic environments. Additionally, two

polymer-supported, fluorinated spin-traps 9 and 10

were successfully synthesised and then utilised to detect

free radicals in solution. There are several advantages to

these supported traps, with the main one demonstrated

here: these spin trap resins can be packed in columns.

This allows for several unique experiments, such as the

ability to monitor external reaction vessels. By support-

ing the nitrone on a polymer, this prevents the trap

from becoming a reactant in the system, particularly

important with electrochemical systems due to the mul-

tiple redox states of nitrones. Likewise, a tethered trap is

restricted to detecting radicals that can diffuse to it. This

could provide a means of distinguishing the site of rad-

ical production: for a mixed phase system, if the radical

species is trapped by a traditional small molecule spin

trap but not a tethered trap, this would mean that the

site of reaction is not the solution but a surface or

2

solving KO in DMSO and 18-crown-6 ether (18-C-6)

2

was flowed over the column. The spectrum of Resin-2-

HFDMPO-OOH was then detected. However, in both

cases, because of the low mobility of the radical, there

was poor spectral resolution.

Similar experiments were performed with Resin-2-

PFDMPO 10 (Figure 7), where hydroxyl radicals were

again formed from H O using photolysis. In this case,

2

after the hydroxyl radicals were trapped, the mobile

phase was switched to methylene chloride. The com-

bination of resin swelling and reduced viscosity both

contributed to mobility and therefore a much narrower

FREE RADICAL RESEARCH

15

Figure 7. Flow experiments with Resin-2-PFDMPO-OH. Left, time resolved EPR spectra. Right, EPR spectra at indicated time

points. (1) A 3% aqueous hydrogen peroxide solution is pumped through the spin trap column at a rate of 200 mL/min using a

syringe pump. (2) The EPR resonator is illuminated with a UV lamp creating hydroxyl radicals in the flowing hydrogen peroxide

solution. Radicals are trapped by the column, but the EPR spectrum is broad because of low mobility. (3) The mobile phase is

changed from water to dichloromethane. The EPR spectrum narrows and increases in amplitude because of the increased mobil-

ity, allowing for analysis of the spectrum. (4) The column is prepared for the next experiment by reducing the radical form of

the spin trap with 200 mM ascorbic acid in 80:20 DCM/DMF.

confined space. There is also the potential to greatly

increase the detection limit in large volume systems: if a

large volume of solution is passed over the column, the

radicals will be captured and concentrated in the much

smaller active volume of the EPR resonator. The same

could be accomplished by adding the loose resin to a

reaction vessel, stirring, and then filtering it out. The

spin trap columns could also be used to perform

stopped flow experiments: with the set-up shown in

Figure 3, two reactants could be mixed and a reaction

time determined by the flow rate and distance between

the mixer and the column. Another advantage of having

spin traps tethered to a solid phase support is the ability

to rejuvenate the trap and reuse the resin (at least with

oxygen-based radicals, covalent attachment of carbon-

based radicals is likely to be permanent). Besides the

attachment to solid phase resin as shown here, the

hydroxyl functional groups on 2-HFDMPO 7 and 2-

PFDMPO 8 can provide a functional handle to enable

the tethering of spin-traps to other macromolecules

such as peptides and cyclodextrins, enabling site-spe-

cific detection of free radicals in the cell.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

We gratefully acknowledge funding from NSF DMR-1404550,

in addition to NSF CHE 1427922 for MS instrumentation, and

NMR equipment grants NSF CHE 0342912 and NIH

S10-RR19918.

ORCID

Aruna Earla

Eric D. Walter

Rebecca Braslau

http://orcid.org/0000-0003-4805-0712

http://orcid.org/0000-0003-3644-5514

http://orcid.org/0000-0002-7331-7653

References

[1] Fuzzi S, Baltensperger U, Carslaw K, et al. Particulate

matter, air quality and climate: lessons learned and

future needs. Atmos Chem Phys. 2015;15(14):

8

217–8299.

[

2] Tang X, Price D, Praske E, et al. NO3 radical, OH rad-

ical and O3-initiated secondary aerosol formation

from aliphatic amines. Atmos Environ. 2013;72:

1

05–112.

Acknowledgements

[

3] Carlton AG, Wiedinmyer C, Kroll JH. A review of sec-

ondary organic aerosol (SOA) formation from iso-

prene. Atmos Chem Phys. 2009;9(14):4987–5005.

A portion of this research was performed using EMSL

(grid.436923.9), a DOE Office of Science User Facility spon-

sored by the Office of Biological and Environmental

Research.

[4] Iinuma Y, B o€ ge O, Miao Y, et al. Laboratory

studies on secondary organic aerosol formation from

1

6

A. EARLA ET AL.

terpenes. Faraday Discuss. 2005;130:279–294, discus-

sion 363.

[20] Hornbrook RS, Crawford JH, Edwards GD, et al.

Measurements of tropospheric HO and RO by oxy-

2

[

5] Donahue NM, Robinson AL, Pandis SN. Atmospheric

organic particulate matter: from smoke to secondary

organic aerosol. Atmos Environ. 2009;43(1):94–106.

6] Ervens B, Turpin BJ, Weber RJ. Secondary organic

aerosol formation in cloud droplets and aqueous par-

ticles (aqSOA): a review of laboratory, field and model

studies. Atmos Chem Phys. 2011;11(21):11069–11102.

7] Slade JH, Thalman R, Wang J, et al. Chemical aging of

single and multicomponent biomass burning aerosol

surrogate particles by OH: implications for cloud con-

densation nucleus activity. Atmos Chem Phys. 2015;

gen dilution modulation and chemical ionization mass

spectrometry. Atmos Meas Techn. 2011;4(4):735–756.

[21] Heard DE. Atmospheric field measurements of the

hydroxyl radical using laser-induced fluorescence spec-

troscopy. Annu Rev Phys Chem. 2006;57(1):191–216.

[22] Stevens PS, Mather JH, Brune WH. Measuring OH and

HO in the troposphere by laser-induced fluorescence

2

[

at low-pressure.

J

Geophys Res. 1994;99(D2):

3543–3557.

[23] Brune WH, Stevens PS, Mather JH. Measuring OH and

HO in the troposphere by laser-induced fluorescence

2

15(17):10183–10201.

at low-pressure. J Atmos Sci. 1995;52(19):3328–3336.

[

8] Hung HM, Lu WJ, Chen WN, et al. Enhancement of

the hygroscopicity parameter kappa of rural aerosols

in northern Taiwan by anthropogenic emissions.

Atmos Environ. 2014;84:78–87.

9] Moise T, Flores JM, Rudich Y. Optical properties of sec-

ondary organic aerosols and their changes by chem-

ical processes. Chem Rev. 2015;115(10):4400–4439.

[24] Green TJ, Reeves CE, Brough N, et al. Airborne meas-

urements of peroxy radicals using the PERCA tech-

nique. J Environ Monitor. 2003;5(1):75–83.

[25] Heard DE, Pilling MJ. Measurement of OH and HO in

2

the troposphere. Chem Rev. 2003;103(12):5163–5198.

[26] Feilberg KL, Sellevag SR, Nielsen CJ, et al. þ OHꢃ >

CO

2

þ H: the relative reaction rate of five CO isotopo-

[

10] Chou C, Kanji ZA, Stetzer O, et al. Effect of photo-

chemical ageing on the ice nucleation properties of

diesel and wood burning particles. Atmos Chem Phys.

logues. Phys Chem Chem Phys. 2002;4(19):4687–4693.

[27] Watanabe T, Yoshida M, Fujiwara S, et al. Spin trap-

ping of hydroxyl radical in the troposphere for deter-

mination by electron spin resonance and gas

chromatography/mass spectrometry. Anal Chem.

1982;54(14):2470–2474.

2013;13(2):761–772.

11] Corbin JC, Lohmann U, Sierau B, et al. Black carbon

surface oxidation and organic composition of beech-

wood soot aerosols. Atmos Chem Phys. 2015;15(20):

[28] Kuno N, Sakakibara K, Hirota M, et al. A new polymer-

incorporated spin-trapping reagent aimed at environ-

mental use. Reactions with organic free radicals. React

Funct Polym. 2000;43(1–2):43–51.

[29] Janzen EG, Wang YY. Spin trapping with immobilized

spin traps. Poly(p[.alpha.-(N-tert-butylnitronyl)]styrene).

J Phys Chem. 1979;83(7):894–896.

[30] Du L, Huang SP, Zhuang QF, et al. Highly sensitive

free radical detection by nitrone-functionalized gold

nanoparticles. Nanoscale. 2014;6(3):1646–1652.

[31] Besson E, Gastaldi S, Bloch E, et al. Embedding cyclic

nitrone in mesoporous silica particles for EPR spin

trapping of superoxide and other radicals. Analyst.

2019;144(14):4194–4203.

11885–11907.

12] Brooks SD, Suter K, Olivarez L. Effects of chemical

aging on the ice nucleation activity of soot and poly-

cyclic aromatic hydrocarbon aerosols. J Phys Chem A.

2014;118(43):10036–10047.

13] Hiranuma N, Brooks SD, Moffet RC, et al. Chemical

characterization of individual particles and residuals of

cloud droplets and ice crystals collected on board

research aircraft in the ISDAC 2008 study. J Geophys

Res Atmos. 2013;118(12):6564–6579.

14] Kanji ZA, Welti A, Chou C, et al. Laboratory studies of

immersion and deposition mode ice nucleation of

ozone aged mineral dust particles. Atmos Chem Phys.

[

2

013;13(17):9097–9118.

[32] Selinsky BS, Levy LA, Motten AG, et al. Development of

fluorinated, NMR-active spin traps for studies of free

radical chemistry. J Magn Reson. 1989;81(1):57–67.

[33] Khramtsov VV, Reznikov VA, Berliner LJ, et al. NMR

spin trapping: detection of free radical reactions with

a new fluorinated DMPO analog. Free Radic Biol Med.

2001;30(10):1099–1107.

[34] Karoui H, Nsanzumuhire C, Le Moigne F, et al.

Synthesis and spin-trapping properties of a trifluoro-

methyl analogue of DMPO: 5-methyl-5-trifluoro-

methyl-1-pyrroline N-oxide (5-TFDMPO). Chem Eur J.

2014;20(14):4064–4071.

15] P o€ schl U, Shiraiwa M. Multiphase chemistry at the

atmosphere–biosphere interface influencing climate

and public health in the Anthropocene. Chem Rev.

2015;115(10):4440–4475.

[

16] Shanley RP, Hayes RB, Cromar KR, et al. Particulate air

pollution and clinical cardiovascular disease risk fac-

tors. Epidemiology. 2016;27(2):291–298.

17] (a) Shi XF, Liu HB, Song Y. Pollutional haze as a poten-

tial cause of lung cancer. J Thorac Dis. 2015;7(10):

E412–E417. (b) Kurt OK, Zhang JJ, Pinkerton KE.

Pulmonary health effects of air pollution. Curr Opin

Pulm Med. 2016;22(2):138–143.

[35] Khramtsov V, Berliner LJ, Clanton TL. NMR spin trap-

ping: detection of free radical reactions using a phos-

phorus-containing nitrone spin trap. Magn Reson

Med. 1999;42(2):228–234.

[18] Goldizen FC, Sly PD, Knibbs LD. Respiratory effects of

air pollution on children. Pediatr Pulmonol. 2016;51(1):

94–108.

[

19] Clemitshaw KC. A review of instrumentation and

measurement techniques for ground-based and air-

borne field studies of gas-phase tropospheric chemis-

try. Crit Rev Environ Sci Technol. 2004;34(1):1–108.

[36] Janzen EG, Zhang YK, Arimura M. Synthesis and spin-

trapping chemistry of 5,5-dimethyl-2-(trifluoromethyl)-

1-pyrroline N-oxide.

5434–5440.

J

Org Chem. 1995;60(17):

FREE RADICAL RESEARCH

17

[

37] Zhang F, Wei M, Dong J, et al.

A

recyclable

[39] Stolze K, Rohr-Udilova N, Patel A, et al. Synthesis and

characterization of 5-hydroxymethyl-5-methyl-pyrro-

line N-oxide and its derivatives. Bioorg Med Chem.

2011;19(2):985–993.

[40] Cl ꢀe ment JL, Ferr ꢀe N, Siri D, et al. Assignment of the

EPR spectrum of 5,5-dimethyl-1-pyrroline N-oxide

(DMPO) superoxide spin adduct. J Org Chem. 2005;

70(4):1198–1203.

organocascade reaction system: stereoselective pre-

cipitation of optically active cis-d-lactols with quater-

nary

hemiacetalization reaction. Adv Synth Catal. 2010;

52(17):2875–2880.

stereocenters

during

the

Michael-

3

38] Motokura K, Tanaka S, Tada M, et al. Bifunctional het-

erogeneous catalysis of silica–alumina-supported ter-

tiary amines with controlled acid–base interactions for

efficient 1,4-addition reactions. Chem Eur J. 2009;

[41] Stoll S, Schweiger A. EasySpin, a comprehensive soft-

ware package for spectral simulation and analysis in

EPR. J Magn Reson. 2006;178(1):42–55.

15(41):10871–10879.

Article Doi

Synthesis and spin trapping properties of polystyrene supported trifluoromethylated cyclic nitrones

DOI: 10.1080/10715762.2019.1683171

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Article abstract of DOI:10.1080/10715762.2019.1683171

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