Development of N-Cyclopropylanilines to Probe the Oxidative

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Development of N-cyclopropylanilines to probe the oxidative properties of triplet-state photosensitizers Nicholas C. Pflug, Markus Schmitt, and Kristopher McNeill Environ. Sci. Technol., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019 Downloaded from http://pubs.acs.org on April 3, 2019

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Environmental Science & Technology

Development of N-cyclopropylanilines to probe the oxidative properties of triplet-state photosensitizers Nicholas C. Pflug, Markus Schmitt, and Kristopher McNeill*

Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, 8092 Zurich Switzerland

*Corresponding Author: Kristopher McNeill Phone: +41-(0)44-6324755; Fax: +41-(0)44-6321438; Email: [email protected];

Submitted to Environmental Science & Technology March 26, 2019

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ABSTRACT 3sensitizer*

oxidation R1 R2

H N

back electron transfer antioxidant quenching

2

R1 R2

H N

ring opening

R1 R2

+ sens

antioxidant

H N

CH2

O2 Oxidized Products

3

Anilines have been shown to be especially susceptible to single-electron oxidation by

4

excited triplet-state photosensitizers (3sens*), and thus, are good potential candidates to probe

5

the oxidative properties of triplet-state chromophoric dissolved organic matter (3CDOM*).

6

However, steady-state experiments tend to underestimate their rate of oxidation by 3CDOM*

7

due to radical cation quenching (i.e., aniline+  aniline) by antioxidant moieties present in

8

DOM. We envisioned the potential utility of N-cyclopropylaniline (CPA) to overcome this

9

limitation, as it is known to undergo spontaneous, irreversible cyclopropyl ring-opening after

10

an initial single-electron oxidation. To test this, first a set of CPA analogs was synthesized

11

and then paired with a model sensitizer and antioxidant, or various DOM isolates, to examine

12

their reactivity and susceptibility to antioxidant quenching during steady-state photolysis

13

experiments. Next, time-resolved measurements of CPA and CPA analog oxidation were

14

obtained by laser flash photolysis through direct observation of 3sens* and radical cations of

15

CPA and CPA analogs. Finally, CPA photolysis products were isolated by semi-preparative

16

high-performance liquid chromatography and identified by nuclear magnetic resonance

17

spectroscopy. Outcomes of this work, including oxidation bimolecular rate constants of CPA

18

and CPA analogs (~9 x 108 to 4 x 109 M-1s-1), radical cation lifetimes of CPA and its analogs

19

(140-580 ns), and identified ring-opened products, support the usefulness of

20

cyclopropylanilines as single-electron transfer probes in photosensitized aqueous solutions.

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21 22

INTRODUCTION In most natural aquatic systems, chromophoric dissolved organic matter

23

(chromophoric DOM or CDOM) is the dominate light absorber.1-5 Upon absorption of light

24

of sufficient energy, ground-state CDOM is initially promoted to its excited singlet-state and

25

then a small portion (i.e., ~5-10%) undergoes intersystem crossing to the excited triplet-state

26

(3CDOM*).6 3CDOM* is a highly reactive species that plays a central role in sunlit natural

27

waters through the generation of other reactive intermediates (e.g., singlet oxygen, 1O2) via

28

energy transfer, and also through the degradation of environmental contaminates via direct

29

oxidation.6-7

30

There are numerous examples in the literature of small molecule, pollutant oxidation

31

by 3CDOM*,8-11 of which, those pollutants containing aniline or phenol moieties are well

32

represented.7 It has been shown that 3CDOM* is capable of oxidizing electron-rich phenols to

33

phenoxy radicals and there is evidence that supports both two-step (i.e., electron transfer

34

followed by proton transfer) and single-step (i.e., proton-coupled electron transfer) oxidation

35

mechanisms.7 By contrast, despite their structural similarity to phenols, both electron-rich

36

and -poor classes of anilines have been shown to be especially susceptible to oxidation by

37

3CDOM*,

38

an electron donor to an acceptor) mechanism.7, 12 The lower aqueous oxidation potentials of

39

anilines relative to phenols, allows them to be more easily oxidized by SET reactions.12

40

Because of this, anilines and compounds with aniline moieties, are good potential candidates

41

to probe the single-electron oxidative properties of 3CDOM*.

mainly through a single-electron transfer (SET, i.e., transfer of one electron from

42

In order to quantify and study triplet states of organic matter, it is desirable to have

43

probe molecules that react with these triplet states in a selective and well understood way.

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Anilines are good candidate SET probes, because of their inherent susceptibility to oxidation

45

by triplet sensitizers (3sens*) and 3CDOM*. However, their reaction kinetics are complicated

46

by the fact that one-electron oxidized products (i.e., aniline•+) have been shown to be

47

vulnerable to back electron transfer (BET) from reduced sensitizers and also radical cation

48

quenching (i.e., aniline+  aniline) by antioxidant moieties present in DOM.13-15 Thus,

49

steady-state experiments can give a net rate constant of aniline oxidation that is significantly

50

lower than the rate constant for SET oxidation by 3sens* or 3CDOM*. The net rate constant

51

of oxidation of anilines by 3CDOM* is therefore a combination of the base rate constant of

52

oxidation, which is directly related to the concentration of 3CDOM*, and repair by both BET

53

and by a pool of antioxidant moieties, the latter of which depends both on the amount and the

54

potency of the antioxidants. There are some secondary processes that are known to

55

outcompete BET, after initial SET from a donor to an acceptor, including fast chemical

56

reaction, isomerization, or fragmentation.16 An ideal aniline-based probe for 3CDOM* would

57

not be susceptible to repair by BET or antioxidants present in the DOM mixture.

58

N-cyclopropylanilines have been used as SET probes in both enzymatic17 and

59

chemical systems,18 in addition to their use as scaffolds in organic synthesis.19-23 Their utility

60

as SET probes or synthetic scaffolds arises from an irreversible ring-opening of the

61

cyclopropyl group upon an initial oxidation to their nitrogen radical cations.20 The

62

irreversibility of this process is due to gains in free energy (i.e., strain energy, ~28 kcal/mol)24

63

associated with cyclopropane ring-opening to yield an iminium distonic radical cation. The

64

resulting distonic radical cation is then able to undergo downstream chemical reactions. We

65

envisioned a similar plausible scenario upon SET oxidation of N-cyclopropylaniline (CPA) by

66

3sens*

or 3CDOM*. We hypothesize that CPA would undergo near diffusion-controlled


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67

oxidation to form CPA radical cation (CPA+) in the presence of 3sens* or 3CDOM* and a

68

subsequent spontaneous, irreversible cyclopropyl ring-opening would outcompete the rate of

69

BET or antioxidant quenching (AQ). The irreversible nature of cyclopropyl ring-opening

70

would act as a short-circuit in BET or AQ processes and thus prevent CPA+ from returning to

71

its neutral state (i.e., CPA).

72

To test this hypothesis, first a suite of CPA analogs was synthesized and then paired

73

with an appropriate model sensitizer and antioxidant, or various DOM isolates, to examine

74

their reactivity and susceptibility to BET and AQ during steady-state photolysis experiments.

75

Next, time-resolved measurements of CPA oxidation were obtained by laser flash photolysis

76

(LFP) through direct observation of 3sens* and CPA+ lifetimes. Finally, CPA photolysis

77

products were isolated by semi-preparative high-performance liquid chromatography (HPLC)

78

and identified by nuclear magnetic resonance spectroscopy (NMR).

79

MATERIALS AND METHODS

80

Reagents. Synthetic procedures used cyclopropylamine (Sigma; 98%, cryodistilled

81

before use), bromobenzene (Sigma; ≥ 99.5%), 2-bromoanisole (Sigma; 97%), 1-bromo-3-

82

chlorobenzene (Sigma; ≥ 99%), palladium (II) acetate [Pd(OAc)2, Apollo Scientific; ≥

83

99.95%], BrettPhos (Sigma; 96%), potassium tert-butoxide (t-BuOK, Sigma; ≥ 98%), aniline

84

(Sigma; ≥ 99.5%), acetic anhydride (Sigma; ≥ 99%), anhydrous sodium acetate (Fluka; ≥

85

99.5%), ethyl acetate (Fisher Scientific; 99.97%), concentrated hydrochloric acid (Merck;

86

37%), toluene (Acros; 99.8%, extra dry, over molecular sieves, degassed via three freeze-

87

pump-thaw cycles before use), and chloroform-d (CDCl3, Armar; 99.8 atom%D, 0.03 v/v%

88

TMS).



89

Photolysis experiments used N-cyclopropylaniline (Acrotein; 97%), N-

90

isopropylaniline (N-IPA, Sigma; PESTANAL analytical standard), 2-acetonaphthone (2AN,

91

Sigma; ≥ 99%), 3-methoxyacetophenone (3MAP, Aldrich; 97%), phenol (PhOH, Sigma; ≥

92

99%), TEMPO (Sigma; 98%), 2,4-dimethylphenol (DMP, Sigma; 97%), 4-methoxyphenol (4-

93

MP, Aldrich; 99%), 2,4,6-trimethylphenol (TMP, Sigma; 99%), furfuryl alcohol (FFA,

94

Merck; ≥ 98%), anhydrous potassium phosphate monobasic (Sigma; ≥ 99%), nanopore water

95

(resistivity >18 M cm), acetonitrile (Fisher Scientific; ≥ 99.9%), isopropanol (IPA, Chemie

96

Brunschwig; HPLC grade). Suwannee River Fulvic Acid (SRFA, Standard II, 2S101F),

97

Suwannee River Natural Organic Matter (SRNOM, 2R101N), and Nordic Reservoir Natural

98

Organic Matter (NRNOM, 1R108N) samples were purchased from the International Humic

99

Substances Society. HPLC analysis used mixtures of nanopore water (resistivity >18 M

100

cm) and acetonitrile (Fisher Scientific; ≥ 99.9%) as the mobile phase.

101

Synthetic Procedures. CPA probes (i.e., CPA, 3-Cl-CPA, and 2-MeO-CPA) were

102

synthesized according to previously described Buchwald-Hartwig amination procedures.23, 25-

103

26

104

loaded with Pd(OAc)2 (0.9 mg, 0.004 mmol) and BrettPhos (6.4 mg, 0.012 mmol), degassed

105

under vacuum, sealed with a Teflon stopper, and then transferred to a glovebox. The tube was

106

then loaded with bromobenzene (60.0 mg, 0.38 mmol; for CPA), 1-bromo-3-chlorobenzene

107

(73.1 mg, 0.38 mmol; for 3-Cl-CPA), or 2-bromoanisole (71.5 mg, 0.38 mmol; for 2-MeO-

108

CPA), cyclopropylamine (26.2 mg, 0.459 mmol), t-BuOK (64.3 mg, 0.573 mmol), and

109

toluene (2 mL), sealed, removed from the glovebox, and heated (80 oC, while stirring) for ~

110

18 h. After completion, the reaction mixture was cooled to room temperature, diluted with

111

ethyl acetate, filtered over a short pad of silica gel, and concentrated in vacuo. Purification by

Briefly, a Schlenk tube (10 mL), equipped with a Teflon-coated magnetic stir bar, was


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112

reverse-phase semi-preparative HPLC (100% acetonitrile mobile phase) afforded the CPA

113

probes (~85% CPA, 89% 2-MeO-CPA, and 92% 3-Cl-CPA isolated yields).

114

Steady-State Photolysis Experiments. Photochemical experiments were conducted

115

using a commercially available Rayonet merry-go-round photoreactor (The Southern New

116

England Ultraviolet Company, Branford, CT, USA) equipped with 1-6 x 365 nm UVA bulbs

117

[3.5 x 10-9 mEcm-2s-1nm-1 average spectral irradiance, see Figure S1 in the Supporting

118

Information (SI) for spectrum]. Samples were irradiated in 15 x 85 mm borosilicate culture

119

tubes (100% transmittance at  > 340nm). Tubes were loaded with 6 mL of 5 mM potassium

120

phosphate buffer (pH 7), an initial aqueous probe (e.g., CPA or N-IPA) concentration of 10

121

μM (~ 1-2 mg/L), and initial aqueous 2AN concentration of 5 M (~ 1 mg/L) or DOM

122

concentration of 1-20 mgC/L (total organic carbon measurements were performed using a

123

Shimadzu TOC-L analyzer). Antioxidant quenching experiments used an initial aqueous

124

phenol concentration of 2.5-25 M (~0.25-2.5 mg/L) and radical chain scavenging

125

experiments used an initial aqueous inhibitor (e.g., 4-MP) concentration of 2.5-50 M (~0.3-6

126

mg/L) or 1-20 v/v% of isopropanol. In some experiments, 50 M FFA (~5 mg/L) was used

127

as an internal probe for monitoring 1O2 steady-state concentrations. All working solutions of

128

CPA analogs, N-IPA, and 2AN were made from freshly prepared 2.5 mM acetonitrile stock

129

solutions (CPA>3-Cl-CPA and relative rate of cyclopropyl

217

ring-opening: 3-Cl-CPA>CPA>2-MeO-CPA (Figure 1A).

218

UV-vis spectra of the CPA analogs showed similar absorptive features, however, a

219

noticeable bathochromic shift (~10-20 nm) was observed for 3-Cl-CPA (Figure 1B).

220

Notably, the secondary, lowest intensity absorption band presumably arising from n*

221

transitions of 3-Cl-CPA was found to overlap more than the other analogs with UVB 9 ACS Paragon Plus Environment


222

wavelengths (i.e., 290-320 nm) of light. Thus, UVA bulbs with an irradiance range of ~350-

223

400 nm (peak ~365 nm; see Figure S1) were used in photolysis experiments in an attempt to

224

avoid potential direct photolysis of the CPA probes. Indeed, phototransformation of probes in

225

the absence of 2AN and CDOM was found to be negligible over equivalent timescales of

226

sensitized experiments (Figure S2 and Figures S5-S7).

227

Duel experimental approach to test CPA susceptibility to AQ. To test the utility of

228

CPAs as steady-state SET probes, a dual experimental approach was employed (Figure 2),

229

similar to that first described by Wenk and Canonica.13 First, a model system (i.e., System 1)

230

was used with 32AN* operating as the photochemical oxidant and phenol fulfilling the role of

231

antioxidant to test the susceptibility of CPA to AQ after an initial SET. 2AN was chosen as

232

the model photosensitizer because it absorbs light in the UVA region and has an excited-state

233

single-electron reduction potential [Eo* (32AN*2AN) ~1.34 VNHE in water]13 above the

234

oxidation potential of all three CPA probes and thus, SET is predicted to be

235

thermodynamically favorable. Phenol was selected as the model antioxidant because it does

236

not absorb light in the UVA region and 32AN* quenching by phenol has previously been

237

found to be negligible, while aniline radical cation quenching by phenol (i.e., AQ) was found

238

to readily occur.13 Second, a system (i.e., System 2) with DOM operating as both the oxidant

239

and antioxidant was used to further examine the effectiveness of CPAs as SET probes. The

240

utility of System 2 lies in the structurally heterogeneous nature of DOM itself, particularly its

241

quinone and phenol moieties, which gives it the capacity to both accept or donate electrons,

242

respectively. It is predicted that an antioxidant inhibitory effect, previously described by

243

Wenk and Canonica for anilines,13 will not be observable in either CPA system if the rate of

244

cyclopropyl ring-opening outcompetes AQ (Figure 2).


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245 246 247 248 249 250 251 252 253 254

Figure 2. A duel experimental approach to test CPA susceptibility to AQ with either (1) a system using 2AN as the oxidant and phenol as the antioxidant or (2) a system using DOM as both the oxidant and antioxidant. Also shown are expected trends in reactivity, with no inhibition effect13 observable in either system if the rate of ring-opening (RO) outcompetes AQ. Figure S14 in the Supporting Information gives a more complete proposed mechanism for the conversion to the observed products.

255

approach outlined for System 1 were conducted in parallel for CPA and N-IPA (positive AQ

256

control). N-IPA was chosen due to its close structural similarity to CPA, but with an N-

257

isopropyl group substituted for the N-cyclopropyl group, which should render it susceptible to

258

AQ back to the starting N-IPA compound. As shown in Figure 3A, with the concentration of

259

2AN held constant, increasing concentrations of phenol had no observable effect on the rate

260

of CPA photodecay, suggesting that the rate of cyclopropyl ring-opening does indeed

261

outcompete AQ. By contrast, an inhibitory effect of ~20% was observed on the rate of N-IPA

To test our hypothesis, first, steady-state photochemical experiments following the

262 11 ACS Paragon Plus Environment


1.0

10.0

B

0.020 0.015

H N

0.010

kobs (10-3 s-1)

0.9

0.8 H N

0.7

2

R

N-IPA 0.6 0

5

10

15

20

25

30

=

H N

R

=

6 95 0.

OCH3

4.0

H N

2.0

0.000

0.0 0

4.0

5

10

15

3.0

20

25

0 1.2

D 2

R

=

0.6

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0.0

0.0 0

5

10

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5

20

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10

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25

E

0.9

4 99 0. H N

[PhOH] M

263

2

6.0

2 81 0.

0.005

2.0 CPA

C

8.0

0. 99 8

A

Normalized kobs (k2AN,PhOH/k2AN)

System 2

0.025

R2 =

System 1

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H N

Cl

0

5

10

15

20

25

[SRFA] mgC/L

264 265 266 267 268 269

Figure 3. Relative reaction rate constants for the photooxidation of 10 M CPA or N-IPA with 5 M 2AN at pH 7 as a function of phenol concentration (A) and light-screening corrected reaction rate constants for the photooxidation of 10 M N-IPA (B) and CPA analogs (C-E) at pH 7 as a function of SRFA concentration. Lines connecting data points in (B) and (C) are shown to accentuate their deviation from a linear correlation.

270

decay, apparent from the gradual decrease in rate constant with increasing phenol

271

concentrations.

272

With this proof of concept in hand, steady-state photolysis experiments following the

273

approach outlined for System 2 were conducted in parallel for N-IPA and all three CPA

274

analogs, using SRFA as a representative DOM model. In these experiments, the following

275

trend in rates of reactivity was observed: 2-MeO-CPA>CPA>3-Cl-CPA>>N-IPA (Figures

276

3B-3E), which is consistent with the reactivity trend predicted by Eo (CPACPA+) values of

277

the CPA probes (Figure 1A). The ~2-orders of magnitude lower kobs found for N-IPA relative

278

to CPA, assuming a similar single-electron Eo value for both compounds, suggests an AQ

279

effect on the former. Indeed, increasing concentrations of SRFA showed an antioxidant

280

inhibitory effect on the rate of N-IPA decay, apparent from the steady, albeit nonlinear


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281

increase in rate constant (Figure 3B). This behavior can be explained by the antagonistic

282

photosensitizing and inhibitory effects of SRFA.

283

A slight inhibitory effect with increasing concentrations of SRFA was observed for 2-

284

MeO-CPA (Figure 3C). After initial oxidation, we suspect that 2-MeO-CPA’s methoxy

285

substituent provides sufficient resonance stabilization to the resulting nitrogen radical cation

286

to slow cyclopropyl ring-opening and thus, allows AQ to become a more competitive process.

287

Alternatively, 2-MeO-CPA may be susceptible to a radical chain reaction as discussed in

288

further detail below. By contrast, no antioxidant inhibitory effect was observed for CPA

289

(Figure 3D) nor 3-Cl-CPA (Figure 3E), evident from the steady, linear increase in rate

290

constant. These observed AQ susceptibility trends are consistent with expected relative rates

291

of CPA probe ring-opening (i.e., 3-Cl-CPA>CPA>2-MeO-CPA; Figure 1A).32 Finally,

292

photolysis experiments were conducted for CPA using other sources of DOM (i.e., NRNOM

293

and SRNOM) and analogous to the results found for SRFA, no antioxidant inhibitory effect

294

was observed in these systems (Figure S8).

295

Direct observation of 3sens* and CPA+ lifetimes via LFP. With steady-state

296

photochemical experiments showing the potential utility of CPA and 3-Cl-CPA as SET

297

probes, the two compounds were used in LFP experiments to directly measure their effect on

298

3sens*

299

in Figure 4A, LFP-based control experiments with 2AN showed an absorption signal for

300

3AN*

301

presence of CPA (e.g., 2 mM), the lifetime of the 3AN* signal was notably shortened ( ~180

302

ns) and a new transient signal appeared (Figure 4B). This new transient species, which we

303

attributed to CPA+, was observed to have a transient absorbance maximum at ~495 nm and a

lifetime and to detect any transients (e.g., CPA+) formed during oxidation. As shown

with a transient absorbance maximum at ~440 nm and lifetime of ~450 ns. In the



3O*

A

H N

B

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C

 = 580 ns ± 18 ns H N

2 mM

3O*

H N

D Cl

OCH3

304

E

A (490-520 nm)

Time (s)

1 mM

F

 = 140 ± 20 ns H N

Cl

Time (s)

Wavelength (nm)

305 306 307 308 309 310

Figure 4. 3D LFP spectra of 400 M 2AN (A), 400 M 2AN + 2 mM CPA (B), 400 M 3MAP (D), and 400 M 3MAP + 3mM 3-Cl-CPA (E) at pH 7 under O2 purged conditions. The colors indicate transient absorption (A) intensity. Also shown is the kinetic trace of CPA+ (C) and 3-Cl-CPA+ (F) transients averaged over A 490-520 nm. CPA+ and 3-ClCPA+ transient lifetimes were calculated from exponential decay fits.

311

lifetime of ~580 ns and has similar properties to previously published LFP data for the radical

312

cation of N-methyl-N-cyclopropylaniline (max ~480 nm,  ~580 ns).33 In addition, the

313

intensity of the transient signal was observed to increase with increasing concentrations of

314

CPA (Figure 4C), providing additional support for CPA+ as the species observed. By

315

contrast, the lifetime of the transient signal showed no dependence on the energy of the laser

316

pulse (Figure S9). This suggests that CPA+ lifetime is dictated by the rate of cyclopropyl

317

ring-opening rather than consumption in bimolecular reactions, as previous studies have

318

shown that the rate of bimolecular reactions increases with increases in laser pulse energy.34

319

Experiments were also conducted with N-IPA, which showed a much longer lived (i.e.,  >50

320

s) transient signal than CPA+ (Figure S10), presumably due to N-IPA+. The transient

321

signal for N-IPA+ (max ~445 nm) was observed in a comparable region of the visible 14 ACS Paragon Plus Environment

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322

spectrum as the reported absorbance maximum for N-ethyl-N-isopropylaniline radical cation

323

(max ~460 nm).33 The longer lifetime of N-IPA+ relative to CPA+ is consistent with the

324

stronger AQ effects observed for the former as it has more time to encounter antioxidants

325

present in the system.

326

LFP experiments conducted in the presence of 3-Cl-CPA (e.g., 1 mM) showed a

327

similar shortening of the lifetime of the 3AN* signal ( ~235 ns), however, no other transient

328

signals were observed. In an attempt to facilitate 3-Cl-CPA oxidation, 3MAP was selected as

329

a sensitizer because of its slightly higher Eo* value [(33MAP*3MAP) ~1.64 VNHE in

330

water/ethanol mixture].29 As shown in Figure 4D, LFP-based control experiments with

331

3MAP showed an absorption signal for 33MAP* with a maximum at ~410 nm and lifetime of

332

~200 ns. In the presence of 3-Cl-CPA (e.g., 3 mM), the lifetime of the 33MAP* signal was

333

shortened ( ~50 ns) and a new transient signal grew in over time (Figure 4E). Notably, the

334

new transient species, which we attributed to 3-Cl-CPA+, appears in a similar region of the

335

visible spectrum (max ~500 nm) as CPA+, but has a considerably shorter lifetime ( ~140 ns;

336

Figure 4F). The CPA probe radical cation lifetimes observed by LFP are consistent with the

337

expected relative rates of ring-opening (i.e., 3-Cl-CPA>CPA; Figure 1A).

338

Comparison of steady-state and LFP kinetics. Bimolecular reaction rate constants,

339

or kCPA,2AN values, for CPA and 3-Cl-CPA were estimated by calculating [1O2]ss and [32AN*]ss

340

values derived from FFA depletion kinetics (see Text S1 discussion in the SI) during 2AN

341

sensitized steady-state experiments (Figure 5A). Whereas, bimolecular quenching rate

342

constants, or kq values, were estimated by direct observation of 32AN* lifetime (plotted as 1/)

343

as a function of CPA probe concentration during LFP experiments (i.e., Stern-Volmer plots;

344

Figure 5B). Estimated rate constants for 3-Cl-CPA were found to be near the diffusion15 ACS Paragon Plus Environment


0

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LN Ct/Co

FFA (CPA) FFA (3-Cl-CPA) CPA 3-Cl-CPA

-0.4 -0.6 -0.8 -1

7.6 x 1010 M-1s-1

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s -1

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4-MP 20% IPA TMP DMP TEMPO No Scavenger

4 2.0 x 109 M-1s-1

3 2 1

B 250

500

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[CPA] M

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70 60 50 40 30 20 10

2.0 x 109 M-1s-1

0 0

Time (s)

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6000

C

M -1s -1

7 6.

10

-4

-1 s-1 010 M

-3.5

10

-3

2.7

7.6 x 1

-2.5

2000

kCPA,2AN (109 M-1s-1)

0

2.3 x

LN [CPA]t/[CPA]o

1000

-0.5

-2

3-Cl-CPA

5

0 0

-1.5

CPA

6

0

-1.4

-1

Page 18 of 29

10

20

30

40

[4-MP] M

50

60

346 347 348 349 350 351 352 353 354 355

Figure 5. Steady-state depletion kinetics of 10 M CPA and 3-Cl-CPA pH 7 solutions spiked with 50 M FFA and irradiated in the presence of 5 M 2AN (A), LFP Stern-Volmer plot of inverse 32AN* lifetime as a function of CPA analog concentration at pH 7 (B), steady-state depletion kinetics of 10 M CPA pH 7 solutions spiked with 50 M FFA and 25 M of various radical scavengers (or 20% IPA) and irradiated in the presence of 5 M 2AN (C), and bimolecular CPA, 2AN rate constants obtained from steady-state experiments using the same conditions as in (C), as a function of 4-MP concentration (D). All bimolecular rate constants listed for steady-state experiments (i.e., A, C, and D) were derived from FFA depletion kinetics.

356

controlled limit and in close agreement for steady-state and LFP methods (4.5 vs. 4.3 x 109 M-

357

1s-1,

358

of kCPA,2AN values for CPA when compared to kq values derived from LFP experiments (76 vs.

359

2.0 x 109 M-1s-1, respectively). We speculate that a radical chain reaction is responsible for

360

the notable discrepancy in estimated rate constants between the two methods, as CPA LFP

361

experiments required solutions to be purged with O2 (i.e., an electron acceptor) and with 1%

362

isopropanol (i.e., a radical scavenger) added to promote sufficiently stable conditions for data

respectively). However, steady-state experiments resulted in an apparent overestimation


Page 19 of 29


363

collection. Thus, a suite of known radical scavengers were screened in steady-state

364

experiments (Figure 5C).

365

Using the kq value derived from CPA LFP experiments as a point of reference,

366

TEMPO and DMP were found to yield relatively poor-to-moderate scavenging ability (23 vs.

367

6.7 x 109 M-1s-1 kCPA,2AN values, respectively), while 4-MP, IPA, and TMP were notably more

368

effective (2.4-2.7 x 109 M-1s-1 kCPA,2AN values). Next, the radical scavenging ability of 4-MP

369

was examined. As shown in Figure 5D, with increasing concentrations of 4-MP, kCPA,2AN

370

values for CPA tended to an asymptotic value (2.0 x 109 M-1s-1) which agreed with the kq

371

value measured during LFP experiments, suggesting the complete disruption of radical chain

372

oxidation. Notably, increasing concentrations of 4-MP  10 M had little-to-no observable

373

effect on the rate of CPA photodecay, suggesting that the rate of CPA cyclopropyl ring-

374

opening outcompetes AQ by 4-MP. We speculate that the slightly higher oxidation potential

375

of 3-Cl-CPA makes it less susceptible than CPA to the radical chain process. By contrast, we

376

speculate that the lower oxidation potential of 2-MeO-CPA makes it more susceptible than

377

CPA to the radical chain reaction, and thus, is a potential explanation for the observed

378

behavior in SRFA photosensitized experiments (Figure 3C).

379

Both CPA and 3-Cl-CPA were found to undergo single-electron oxidation near the

380

diffusion-controlled limit (~2-4 x 109 M-1s-1 kCPA,2AN values), and thus, are expected to be as

381

effective as the commonly employed 3CDOM* probe, TMP (~7 x 108 M-1s-1 kTMP,2AN value).29

382

As a direct comparison, SRFA photosensitized experiments were run in parallel for TMP,

383

CPA (with 4-MP added), and 3-Cl-CPA. Measuring kobs for the compounds (Figure S11),

384

with kTMP,SRFA known (5.4 x 108 M-1s-1),35 allowed for the estimation of kCPA,SRFA (1.2 x 109

385

and 8.7 x 108 M-1s-1) for CPA and 3-Cl-CPA, respectively. In these experiments, CPA was



Page 20 of 29

386

found to be less susceptible (kCPA,SRFA ~3.2 x 109 M-1s-1 with no added 4-MP) to the radical

387

chain reaction observed in 2AN systems, likely due to radical scavenging moieties inherently

388

present in SRFA.

389

We do not expect other reactive intermediates potentially generated in photosensitized

390

solutions (e.g., 1O2 or OH) to play a major role in CPA degradation. For example,

391

experiments conducted in D2O did not show an increase in the rate of CPA decay, which

392

indicates that reaction with 1O2 is not a major pathway.36 In addition, OH could potentially

393

react with CPA, although, reported OH quantum yield values for DOM are less than 0.01%

394

and thus this reaction is likely not important.14

395 396

Photoproduct identification. Initial HPLC assessment of CPA and 2AN dark control mixtures (Figure 6A) showed no reactivity over equivalent timescales of photochemical CPA O

2AN

H N

A H N

Absorbance

2AN

H N

1

~25%

O

2 3 0

2

4

6

8

10

0

2

C

CPA

4

6 H N

1

0

398 399 400 401 402

2

2

SRFA

4

6

8

10

0

2

10

D

~70%

O

SRFA

8

OH

H N

397

B

OH

~45%

O

~30% O

4

6

8

10

Retention Time (min) Figure 6. HPLC chromatogram of 10 M CPA and 5 M 2AN (A) or 5 mg C/L SRFA (C) pH 7 dark control solutions and 10 M CPA and 5 M 2AN (B) or 5 mg C/L SRFA (D) pH 7 photolysis mixtures. Peaks labelled 1-3 in B (and 1-2 in D) correspond to products generated during irradiation. HPLC calibration curves of isolated photoproducts were used to calculate % conversion of CPA. 18 ACS Paragon Plus Environment

Page 21 of 29


403

experiments. Irradiation of the mixtures showed three, more polar products (relative to CPA,

404

with earlier retention times of ~2.0, 2.7, and 3.4 min on a reverse phase C18 column) grow in

405

over time by HPLC analysis (Figure 6B). Next, a CPA-2AN mixture was scaled large

406

enough to generate a sufficient amount of products for characterization (1 L and 375 M

407

initial CPA concentration), irradiated until CPA was below our limit of analytical detection,

408

concentrated, and the products isolated via semi-preparative HPLC. The spectroscopic

409

analyses that led to the identification of each product are discussed in greater detail below.

410

1H

NMR analysis of photolysis fraction 1 (i.e., product 1, retention time ~2.0 min)

411

showed loss of the three cyclopropyl proton signals and emergence of a methylene triplet at

412

 2.63 and a downfield methylene triplet at  3.99, consistent with oxidation (Figure S12).

413

The 1H NMR data for product 1 agree with that of 3-hydroxy-N-phenylpropanamide, a

414

previously identified ring-opened product of CPA air oxidation.37 Isolated product 1 was

415

used for HPLC calibration and was found to account for ~45% of the converted CPA mass in

416

2AN sensitized systems.

417

1H

NMR analysis of photolysis fraction 2 (i.e., product 2, retention time ~2.7 min)

418

showed loss of the three cyclopropyl proton signals and emergence of a three-proton singlet at

419

 2.17 (Figure S13). The 1H NMR data for product 2 agree with that of acetanilide, another

420

previously identified ring-opened product of CPA air oxidation.37 Product 2 was found to

421

account for ~25% of the converted CPA mass in 2AN sensitized systems.

422

Previous studies have suggested that after an initial SET oxidation of CPA, the

423

resulting CPA+ undergoes cyclopropyl ring-opening to yield a distonic radical cation, which

424

is then capable of reacting with molecular O2 to form an endoperoxide intermediate.20, 37 The

425

intermediate is proposed to undergo subsequent endoperoxide ring-opening and fragmentation 19 ACS Paragon Plus Environment


426

to yield 3-hydroxy-N-phenylpropanamide and acetanilide products.37 We suspect a similar

427

mechanism of oxidative transformation in the 2AN photosensitized systems (see Figure S14

428

for proposed mechanism and associated discussion).

429

During the course of concentrating the CPA-2AN photolysis mixture, product 3

430

(retention time ~3.4 min) was found to degrade, and thus, was not isolated. Because of its

431

instability, we suspect that this product likely corresponds to the above mentioned

432

endoperoxide intermediate (i.e., N-phenyl-1,2-dioxolan-3-amine, Figure S14).

433

Initial HPLC assessment of CPA and SRFA dark control mixtures (Figure 6C) also

434

showed no reactivity over equivalent timescales of photochemical experiments. Irradiation of

435

the mixtures showed two, more polar products (relative to CPA, with retention times of ~2.0

436

and 2.7 min) grow in over time by HPLC analysis (Figure 6D). In this case, the two products

437

were not isolated, however, retention time data suggest the formation of 3-hydroxy-N-

438

phenylpropanamide (i.e., product 1, ~70%) and acetanilide (i.e., product 2, ~30%) in SRFA

439

photosensitized experiments. Although not explicitly explored, we speculate that analogous

440

ring-opened products are also formed for 3-Cl-CPA in 2AN and SRFA sensitized

441

experiments, because of the similar product distributions observed by HPLC analysis.

442

Environmental implications. As previously mentioned, anilines have been shown to

443

be especially susceptible to single-electron oxidation by 3sens*, and thus, are good potential

444

candidates to probe the oxidative properties of 3CDOM*. However, steady-state experiments

445

tend to underestimate their rate of oxidation by 3CDOM* due to radical cation quenching (i.e.,

446

aniline+  aniline) by antioxidant moieties present in DOM. Two of the three synthesized

447

CPA analogs that we have studied in this report (i.e., CPA and 3-Cl-CPA) are able to

448

overcome this limitation of AQ through a spontaneous, irreversible cyclopropyl ring-opening


Page 22 of 29

Page 23 of 29


449

event, supported by direct observation of CPA+ via LFP and identification of ring-opened,

450

oxidized products. The effectiveness of CPA and 3-Cl-CPA in this process is likely governed

451

by their relatively short CPA+ lifetimes (i.e., 140-580 ns) compared to anilines without a N-

452

cyclopropyl group (e.g, >50 s for N-IPA+). In addition, their fast single-electron oxidation

453

rate constants near the diffusion-controlled limit (~2-4 x 109 M-1s-1 kCPA,2AN values), make

454

them more than competitive from a kinetic point of view with the commonly employed

455

3CDOM*

456

Cl-CPA, and TMP in SRFA photosensitized experiments allowed for the estimation of

457

kCPA,SRFA (1.2 x 109 and 8.7 x 108 M-1s-1) for CPA and 3-Cl-CPA, respectively, which were

458

found to have a higher rate constant than TMP (5.4 x 108 M-1s-1 kTMP,SRFA). Although CPA

459

was susceptible to a radical chain reaction in photosensitized systems and therefore required

460

the addition of a radical scavenger, 3-Cl-CPA was not observed to be affected by this process.

461

probe, TMP (~7 x 108 M-1s-1 kTMP,2AN value). Indeed, direct comparison of CPA, 3-

Outcomes of this work, including CPA bimolecular rate constants, CPA+ lifetimes,

462

and identified ring-opened products, support the usefulness of N-cyclopropylanilines as

463

steady-state SET probes in photosensitized aqueous solutions. These outcomes also likely

464

benefit other areas of study where N-cyclopropylanilines have been used as SET probes in

465

biological and chemical systems, in addition to their use as scaffolds in organic synthesis.

466

Finally, this work has laid the foundation for future studies, including the use of CPA analogs

467

for a more thorough investigation of the oxidative properties of 3CDOM*

468 469 470

SUPPORTING INFORMATION List of abbreviations, Rayonet UVA spectrum, steady-state kinetic plots, equations and associated discussion for determination of steady-state bimolecular reaction rate



471

constants, laser pulse energy plot, N-IPA LFP spectrum, NMR spectra, and proposed

472

mechanism (PDF).

473

ACKNOWLEDGMENTS

474

This work was financially supported by ETH Zurich and a grant from the Swiss

475

National Science Foundation (Grant number 200021_156198). We would like to thank

476

Rachele Ossola for providing spectral irradiance measurments.


Page 24 of 29

Page 25 of 29


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Development of N-Cyclopropylanilines to Probe the Oxidative

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