Structural Effects on the pH-Dependent Redox Properties of Organic

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Structural Effects on the pH-Dependent Redox Properties of Organic Nitroxyls: Pourbaix Diagrams for TEMPO, ABNO and Three TEMPO Analogs James B. Gerken, Yutong Q Pang, Markus B. Lauber, and Shannon S. Stahl J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02547 • Publication Date (Web): 28 Nov 2017 Downloaded from http://pubs.acs.org on December 1, 2017

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Structural Effects on the pH-Dependent Redox Properties of Organic Nitroxyls: Pourbaix Diagrams for TEMPO, ABNO and Three TEMPO Analogs James B. Gerken, Yutong Q. Pang, Markus B. Lauber, Shannon S. Stahl* Department of Chemistry, University of Wisconsin – Madison, 1101 University Avenue, Madison, WI 53706-1322, USA. [email protected]

TOC Graphic O

O

O

O

O

N

N

N

N

N

O NHAc

NH 2 O

1.5

O

1.5

O

N

N

OH N

1

0.5

EH (V)

1 EH (V)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

TEMPO H

0

OH

OH

H

0

OH

N

ABNO

0.5

OH

N

N

N

-0.5

-0.5 0

2

4

6

pH

8

10

12

0

14

2

4

6

pH

8

10

12

14

Abstract Electrochemical studies of the reduction and oxidation reactions of five different organic nitroxyls have been performed across a wide pH range (0 – 13). The resulting Pourbaix diagrams illustrate structural effects on their various redox potentials and on the pKa values of the corresponding hydroxylamine and hydroxylammonium ions. Evidence is also given for the reversible formation of a hydroxylamine N-oxide when nitroxyls are oxidized in alkaline media. Structural effects on the thermodynamics of this reaction are assessed.

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Introduction Organic nitroxyls such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) are widely used as catalysts and mediators in chemical and electrochemical redox reactions. The three most common redox states involved in these reactions are illustrated in Scheme 1. One electron oxidation of the nitroxyls affords oxoammonium ions, which are key intermediates in catalytic alcohol oxidation reactions (Scheme 2). Such reactions represent some of the most widely used applications of organic nitroxyls.1-11 The reaction of an alcohol with an oxoammonium species results in its two-electron reduction to a hydroxylamine species, and many different secondary oxidants have been used to reoxidize the hydroxylamine to the oxoammonium and enable catalytic turnover.

Scheme 1. Common redox states for TEMPO OH N

O - e-, - H +

N

+ e-, + H +

Hydroxylamine

O - e-

N

+ e-

Nitroxyl

Oxoammonium

Scheme 2. Oxoammonium-catalyzed oxidation of alcohols O N OH [O] NaOCl Br 2 PhI(OAc) 2 cat. NO x, O2 electrode

R1

[O]H 2

R2

O

H + + [O] OH

R1

R2

N

Despite the central role played by different oxidation and protonation states of these compounds in alcohol oxidation and other applications,2,4,5, 12 - 15 there is relatively little

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fundamental data in the literature defining the proton-coupled redox behavior of nitroxyls other than TEMPO. 16 - 19 Oxidation of nitroxyls to their oxoammonium species is often the only reported redox property of newly synthesized nitroxyls.

20

This oxidation is usually

electrochemically reversible and displays rapid kinetics. 21 , 22 In contrast, the proton-coupled reduction of a nitroxyl to its hydroxylamine is typically irreversible on the CV time-scale and displays a pH-dependent peak potential.18 Bridged polycyclic nitroxyls such as ABNO (9-azabicyclo[3.3.1]nonane-N-oxyl) and AZADO (2-azaadamantane-N-oxyl) have achieved recent prominence as catalysts for aerobic and electrochemical oxidations.9,13,23,24,25 These nitroxyls have much less steric encumbrance around the N-O moiety and a different C-N-C bond angle, but can have oxoammonium/nitroxyl reduction potentials close to analogous monocyclic nitroxyls. Herein, we use cyclic voltammetry (CV) to analyze the pH-dependent redox properties of a series of different organic nitroxyls: five six-membered ring derivatives that resemble TEMPO together with ABNO as a prototypical bicyclic nitroxyl (Chart 1). The resulting Pourbaix diagrams show how the proton-coupled redox properties of organic nitroxyls vary as a function of the different electronic and steric features of these molecules.

Chart 1. Nitroxyls investigated in this study. O

O

O

O

O

N

N

N

N

N

O HN TEMPO

O ACT

NH 2 TEMMO

AMT

ABNO

3



Results TEMPO Cyclic voltammograms of TEMPO in buffered aqueous solutions of TEMPO at pH 4.7, 5.5 and 10 (Figure 1) reveal a reversible electrochemical oxidation of TEMPO (eq 1) that is insensitive to the pH and buffer identity. In contrast, the proton-coupled reduction of TEMPO to its hydroxylamine (eq 2c) or hydroxylammonium ion (the latter arising from transfer of a second proton to the nitrogen of the hydroxylamine; eq 2c'), is slow on the CV time-scale and displays a pH-dependent peak potential in the cathodic scan. (Note: Subscript designations "a" and "c" are used to denote anodic and cathodic reactions, respectively). CV features associated with oxidation of the hydroxylamine or hydroxylammonium ion, either to TEMPO or directly to the oxoammonium ion, are evident in the anodic scan. The anodic peak corresponding to TEMPO oxidation is diminished on the second scan, and the hydroxylammonium oxidation peak that appears on the second scan can be observed at a potential that is higher than that observed for the oxidation of TEMPO. Observation of the oxidation of TEMPOH2+ to TEMPO+ at potentials higher than the TEMPO/TEMPO+ potential (Figure 1, pH 4.7 and 5.5) indicates that the comproportionation of hydroxylammonium and oxoammonium is slow under these conditions for TEMPO (eq 3; see further discussion below).26 Reduced peak separation is observed for the proton-coupled redox process when using an oxidized carbon (OC) electrode rather than a glassy carbon (GC) electrode (Figure 2), reflecting the ability of surface functional groups to catalyze the proton-coupled electron transfer step. 27 The reduced peak separation at an OC electrode reduces the possible error introduced by taking the midpoint potential as the reduction potential. O N

-e-

O N

(1)

4


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O N

OH

e-, H+

H

2

(2c,c')

O N

-2 e-, -2 H+

O N

OH N

2c'

OH N

H

H+ pKa ~ 7

N

2c

(2a')

H

2 H+

O N

OH N

+

(3)

7

O N

OH N -e-,

-H+

2a

6

5

pH 10 OH

O N

N e-,

H+

2c

1a

4

j (mA/cm2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3

pH 5.5

O N

O N -e-

2

H

OH N

O N

-2 e-, -2 H+ 1a

1

2a’

1

2a'

mA/cm2

0

pH 4.7

-1

H

OH

2c’

O N

N e-,

-0.5

0

2

1c

H+

0.5 E (V vs. NHE)

1

1.5

Figure 1. Cyclic voltammograms of TEMPO (10 mM) at pH 4.7 in 0.1 M acetate buffer (black trace), pH 5.5 in 0.1 M phthalate buffer (red trace), and pH 10 in 0.1 M carbonate buffer (blue

5



trace) at 25 mV/s. Peaks 1a and 1c correspond to the single electron oxidation of TEMPO and the subsequent reduction of TEMPO+. Peaks 2c and 2a correspond to the reduction of TEMPO to TEMPOH and its oxidation to TEMPO. Peaks 2c' and 2a' correspond to the reduction of TEMPO to TEMPOH2+ and its oxidation to TEMPO+. Peak numbers match the anodic and cathodic directions of equations shown above.

2.5 2 1.5

j (mA/cm2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1 OC background 0.5 0 TEMPO at GC

-0.5 -1

TEMPO at OC

-1.5 -2 -0.4

-0.2

0

0.2

0.4

0.6

0.8

1

E (V vs. NHE)

Figure 2. Comparison of cyclic voltammograms of TEMPO at pH 9.9 when using glassy carbon (GC) and oxidized carbon electrodes (OC). Also shown is the background due to the oxidized carbon electrode. The glassy carbon electrode may be compared with the CV data in Figure 1, in which the scan window is wide enough to observe TEMPO reduction.

By varying the identity of the buffering electrolyte, it is possible to maintain well-buffered conditions across a wide pH range while performing CV experiments. Peak potentials for quasireversible processes are not thermodynamically meaningful because they are convoluted with kinetic factors; 28 however, the presence of both of the relevant oxidation and reduction peaks allows for the estimation of a more thermodynamically significant midpoint potential. The nitroxyl reduction was studied at both glassy carbon and oxidized carbon electrodes, and the observed midpoint potential did not vary significantly. This independence of midpoint potential on electrode surface suggests that a thermodynamic property is being measured with minimal distortion due to electrochemical kinetics. Accumulation of CV data from pH 0 – 13 provides the

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basis for construction of a Pourbaix diagram that shows all of the oxidation and protonation states that TEMPO can achieve (Figure 3a).

a)

1.5

1

b)

1.5 O

O N

OH

O N

OH N

pKa 11.6

?

N

O

HN

1

0.91 V - 59 mV/pH

HN O

0.95 V - 59 mV/pH

O

0.858 V

0.5

EH (V)

EH (V)

0.745 V

O N

1.08 V - 118 mV/pH

1.55 V - 59 mV/pH O

0.5

N

1.05 V - 118 mV/pH

O

N H

0.67 V - 59 mV/pH H

0.65 V - 59 mV/pH

OH

H

N

0

OH N

0

OH OH

pKa 7.34

NH

N

N

pKa 6.40

O

-0.5

-0.5

NH O

0

2

4

6

8

10

12

14

0

2

4

6

pH

8

10

12

d) O N

O N

1.5

pKa 10.8 O

pKa 5.7

O

OH

O N

N

OH NH3

N

O

NH2

NH2 O

0.900 V 1.54 V - 59 mV/pH

O N

0.5

1.00 V - 118 mV/pH

O

?

0.926 V

1 EH (V)

0.95 V - 59 mV/pH

1

14

pH

c) 1.5

EH (V)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.26 V - 59 mV/pH O

0.74 V N pKa 8.9

NH3

0.5

O 0.95 V - 118 mV/pH

N NH2

H H

0

OH

0.68 V - 59 mV/pH

0.61 V - 59 mV/pH

0.54 V - 59 mV/pH

OH

OH

O

1.14 V - 118 mV/pH

N

0

N

OH

NH3

N

N

OH N

pKa 5.25

-0.5

O

-0.5

pKa 5.6

NH3 pKa 10.1

0

2

4

6

8

10

12

14

0

2

pH

4

6

8

10

NH2

12

14

pH

Figure 3. Pourbaix diagrams of four structurally related nitroxyls a) TEMPO, b) ACT, c) TEMMO, and d) AMT in buffered aqueous solutions. The hydroxylammonium pKa values shown were determined by NMR (cf. Figures S2, S3, S4, S6), the AMT pKa was determined by UV-visible spectroscopy (cf. Figure S7), and other values are determined from CV measurements. Fitted lines have been constrained to have slopes corresponding to 0, 1, or 2 H+/e-, and to intersect at points. Black circles and lines correspond to oxoammonium reduction, red stars and lines correspond to nitroxyl reduction. Solid blue lines are pKa values measured spectroscopically. Dashed blue lines are pKa values inferred from voltammetric data. Dashed red lines are redox potentials inferred from spectroscopic data.

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Several conclusions may be drawn from the Pourbaix diagram in Figure 3a. The oxoammonium reduction potential is pH insensitive, as would be expected from a process that does not produce or consume protons. Further, this potential is insensitive to the identity of the buffering electrolyte, indicating that there is no strong ion pairing between the oxoammonium species and the electrolytes. The nitroxyl reduction potential is pH-dependent and has a break in slope, corresponding to the hydroxylammonium pKa. The pKa of TEMPOH2+ was independently determined by NMR (Figures S1, S2), and the measured value of 7.34 is similar to the one obtained voltammetrically (6.9). Previously reported values for this pKa range from 6.3 to 7.96.16,18

Other Cyclic Nitroxyls A similar approach was used to characterize the pH-dependent redox properties of three substituted analogs of TEMPO. The data lead to similar Pourbaix diagrams, albeit with notable differences (Figure 3b-d). 4-Acetamido-TEMPO (ACT) and 3,3,5,5-tetramethylmorpholine-Noxyl (TEMMO) exhibit an increase in the oxoammonium reduction potential relative to TEMPO (858 and 900 mV, respectively, relative to 745 mV), as expected from the electron-withdrawing effects of the heteroatom substituents. The pKas of the hydroxylammonium ions decrease along the series of TEMPO, ACT and TEMMO: pKa = 7.34, 6.40, and 5.25, respectively. The 1 H+/1 enitroxyl/hydroxyamine reduction potentials increase in this series, albeit with a smaller magnitude (DE° ≤ 30 mV for the largest gap in the series) than observed for the oxoammonium/nitroxyl potentials (largest DE° = 155 mV). In contrast, the 2 H+/1 e- and 2 H+/2 e- reduction potentials of these nitroxyl or oxoammonium species to the corresponding

8


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hydroxylammoniums exhibit an inverted trend. This inversion arises from the divergent trends of the substituent effects on electron and proton transfer, as discussed further below. 4-Amino-TEMPO (AMT) features a primary amine substituent that is protonated at many of the pH values studied here. This protonation event introduces an additional pKa at each oxidation state, and the protonation state of the amine dramatically influences the nitroxyl redox properties.29 The AMT Pourbaix diagram reflects the influence of these processes, as observed via a combination of voltammetric and spectroscopic data. The pH dependence of the potentials for AMT reduction and oxidation reflects the protonation state of the distal amine moiety. At low pH, the protonated amine has a stronger inductive effect than the other substituents studied here, and it remains protonated at all potentials. This communication between functional groups is bidirectional, with the ammonium pKa decreasing in response to oxidation of the hydroxylamine through the nitroxyl to the oxoammonium. At high pH, AMT displays an irreversible oxidation, possibly arising from oxidation of the amino group, that limits the range over which data may be collected. Attempts were made to extend the series to 4-oxo-TEMPO, a very electron-poor nitroxyl. These efforts were unsuccessful, however, due to a facile decomposition of the corresponding oxoammonium species, originating from the acidic protons adjacent to the carbonyl group (see Supporting Information).30 O N 4-oxo-TEMPO O

At pH values greater than 10.8 and 11.6 respectively, TEMMO and ACT exhibit a scan-rate dependent loss of reversibility for the oxidation to the oxoammonium.31 The midpoint potential shifts to a lower potential and the CV appears more reversible at low scan rates. Both of these

9



features are consistent with a reversible equilibrium following the oxidation. Kinetic parameters for this coupled equilibrium were estimated by numerical modeling (Figure 4).32 The available data suggest that the process responsible for this effect is the formation of a hydroxylamine Noxide by attack of hydroxide on the oxoammonium (eq 4). This hydroxide adduct is similar to often-proposed intermediates in oxidations of alcohols by oxoammonium ions. 33 A similar species has been invoked in the oxidation of TEMPO at pH 12,34 but our data do not support its existence until pH 14 (Figure S13). Under these alkaline conditions, the species in question could undergo deprotonation to an anion;35 however, pH trends in the voltammetric data for ACT and TEMMO are best fit as a 1 e-/H+ process. A correlation does appear to exist across these three nitroxyls between the oxoammonium reduction potential and the equilibrium constant for hydroxylamine N-oxide formation (Figure 3).

0.7

400 mV/s

0.6 0.5

j (mA/cm2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

0.4 0.3

50

0.2 10

0.1 0 -0.1 -0.2 0.2

0.3

0.4

0.5

0.6 0.7 0.8 E (V vs. NHE)

0.9

1

1.1

Figure 4. Voltammograms of TEMMO in pH 13 aqueous 0.1 M NaOH at scan rates of 10, 50, and 400 mV/s. As the scan rate increases, the oxidation becomes less reversible. Experimental data are in red; the fitted model is in black. Fitting parameters are: E° = 900 mV, DO = DR = 3 x 10-6 cm2/s, kf[OH-] = 4000 s-1, kb = 20 s-1.(DO and DR are the diffusion constants of the oxidized and reduced species) For further data and similar studies on ACT, ABNO, and TEMPO, see the Supporting Information.

O

O N O

-e-

N O

O kf[OH-]

OH N

kb

(4)

O

10


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ABNO: A Bicyclic Nitroxyl Cyclic voltammetry studies of ABNO reveal a reversible, pH-independent oxidation to the oxoammonium, as expected (Figure 5). A pH-dependent reduction of ABNO is also evident, yet the reoxidation of ABNOH appears to be pinned to the foot of the ABNO oxidation wave. This unusual behavior may be rationalized by more facile comproportionation of ABNO+/ABNOH relative to the comproportionation of TEMPO+/TEMPOH (cf. eq 3 and further discussion below). In this scenario, ABNOH oxidation to ABNO is catalyzed by the small amount of oxoammonium generated at the foot of the ABNO/ABNO+ wave. The position of the ABNOH oxidation peak is dependent on the initial concentration of ABNO (Figure 5b). This concentration dependence is also explained by a comproportionation mechanism since a catalytically competent concentration of oxoammonium will be reached at lower potential for a higher initial concentration of ABNO. This distinctive reactivity of ABNO relative to the TEMPO analogs described above makes it difficult to construct a complete Pourbaix diagram for ABNO with a glassy carbon electrode. However, use of an OC electrode catalyzes the reduction of ABNO and oxidation of ABNOH to give pH-dependent peaks at medium and high pH. At low pH, facile disproportionation produces a direct 2 H+/2 e– equilibrium between the oxoammonium and hydroxylammonium that is pH-dependent (Figure 6). The disproportionation reaction may proceed via protonolysis of an ABNO dimer, which has been observed previously (eq 6).36 A NMR pH titration was used to establish the pKa of ABNOH2+ as 6.90 (Figure S5).

11



a)

0.5

N

N

N

0.3

e-, H+

2

j (mA/cm )

O

-e-

O

OH

0.4

0.2 0.1 pH 9.04

0 -0.1

pH 7

-0.2 -0.3 -0.4

b)

-0.2

0

0.2 0.4 0.6 E (V vs. NHE)

0.8

1

1.2

0.3 pH 5.29, 3 mM ABNO

0.25 j (mA/cm2)

0.2 0.15

0.6 mM ABNO

0.1 0.05 0

0.12 mM ABNO

-0.05 -0.1 -0.15 -0.2

0

0.2

0.4 0.6 0.8 E (V vs. NHE)

1

1.2

1.4

Figure 5. a) CV of 3 mM ABNO at pH 7 in 0.1 M phosphate buffer (red trace) and pH 9.04 in 0.1 M borate buffer (blue trace) at 25 mV/s at a glassy carbon electrode. Reversible peaks correspond to the single electron oxidation of ABNO and the subsequent reduction of ABNO+. The irreversible peak at low potential corresponds to the reduction of ABNO to ABNOH. The shoulder near 0.6 V corresponds to a comproportionation-mediated oxidation of ABNOH to ABNO. b) CV of 3, 0.6, and 0.12 mM ABNO at pH 5.29 in 0.1 M phthalate buffer. Arrows indicate the ABNOH oxidation peak potentials (701, 729, and 768 mV respectively); other peaks do not vary with ABNO concentration. 0.3 0.2

j (mA/cm2)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

0.1 0

pH 9.04

-0.1 pH 2.94

-0.2 -0.3 -0.4 -0.4

-0.2

0

0.2 0.4 0.6 E (V vs. NHE)

0.8

1

1.2

1.4

Figure 6. CV of 3 mM ABNO at pH 2.94 in 0.1 M citrate buffer (red trace) and pH 9.04 in 0.1 M borate buffer (blue trace) at 10 mV/s at a glassy carbon electrode. At low pH, the oxoammonium/nitroxyl equilibrium is replaced by a pH-dependent 1 e- / 2 H+ oxoammonium/hydroxylammonium equilibrium. 12


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O

N

O

N

HO

O

N

O

NH+

N

2 H+

2

+

(6)

The unhindered oxoammonium moiety of ABNO+ also displays a kinetically facile interaction with hydroxide to form a hydroxylamine N-oxide (eq 7, Figures S11, S12).25 This interaction is stronger than the one exhibited by TEMMO (see above), even though the oxoammonium reduction potential of ABNO is ca. 160 mV lower than that of TEMMO. Taking all the available voltammetric and spectroscopic data together, a Pourbaix diagram for ABNO can be constructed (Figure 7). Due to the higher ABNO/ABNOH reduction potential, the region of nitroxyl stability is significantly reduced for ABNO relative to the monocyclic nitroxyls. O

O

O

N -e-

N

OH N

kf[OH-]

(7)

kb

1.5

O

O

N

1

pKa 9.4

OH N

0.97 V - 59 mV/pH 0.742 V

EH (V)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.30 V - 59 mV/pH

O

0.5

N

1.20 V - 118 mV/pH

0.80 V - 59 mV/pH

OH

0

+HN

OH N pKa 6.90

-0.5

0

2

4

6

8

10

12

14

pH

Figure 7. Pourbaix diagram of ABNO in buffered aqueous solutions. The hydroxylammonium pKa value shown was determined by NMR (cf. Figure S5), other values are from CV measurements. Fitted lines have been constrained to have slopes corresponding to 0, 1, or 2 H+/e-, and to intersect at points. Black circles and lines correspond to nitroxyl oxidation to oxoammonium, red squares correspond to nitroxyl oxidation to hydroxylamine N-oxide, red stars correspond to hydroxylamine or hydroxylammonium oxidation. Solid blue line is the pKa value measured spectroscopically. Dashed blue line is pKa value inferred from voltammetric data. 13



Discussion The CV measurements and NMR pH titrations described above characterize the pHdependent redox properties of a series of different organic nitroxyls, and the similarities and difference are evident in the five Pourbaix diagrams in Figures 3 and 7. The substituent effects on reduction potential and pKa combine to create some counterintuitive trends in the thermodynamics of proton-coupled redox processes. Perhaps most notably, modifying the TEMPO structure to produce a more oxidizing oxoammonium ion slightly decreases the nitroxyl-hydroxylammonium reduction potentials and has little net effect on the nitroxylhydroxylamine reduction potentials. These results are rationalized by the opposing substituent effects on the electron-transfer and protonation components of the PCET reduction of the nitroxyls. These effects combine to produce little net change in O–H bond strength of the corresponding hydroxylamines (Table 1).37

Table 1. Hydroxylamine O-H BDFE values. Compound R2NO/R2NOH E° (V) R2NO-H BDFE (kcal/mol) TEMPO 0.65 72.6a, 69.6b, 71.0c ACT 0.67 73.1 TEMMO 0.68 73.3 + + AMT 0.61 (RNH3 ) / 0.54 (RNH2) 71.7 (RNH3 ) / 70.1a, 66.0d (RNH2) ABNO 0.80 76.0a, 76.2b a b c d This work. BDE in benzene, Ref. 38. BDFE in water, Ref. 37. BDFE in hexane, Ref. 37.

A nitrogen atom within a strained bicyclic structure, as in ABNO would be expected produce a less acidic hydroxylammonium species relative to TEMPO. In contrast, however, the pKa of ABNOH2+ is lower than that of TEMPOH2+, presumably due to decreased substitution adjacent to the nitrogen atom in ABNOH, leading to less inductive stabilization of the cation. An even

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larger shift in conjugate acid strength has also been observed between 1,2,2,6,6pentamethylpiperidine and 9-methyl-9-azabicyclo[3.3.1]nonane. 39 The stronger O–H bond in ABNO compared to TEMPO may be an effect of pyramidalization at nitrogen producing a more oxygen-centered radical by destabilizing the planar delocalized radical tautomer. Electrochemical evidence has been obtained for the reversible formation of an adduct between hydroxide and the oxoammonium cation. We assign a covalent hydroxylamine N-oxide structure to this adduct, based on analogy to previous studies of its anion.40 Hydroxide binding is stronger for more oxidizing or less hindered oxoammonium ions. The dramatic steric effect on relative hydroxide binding between TEMPO and ABNO may help explain the increased catalytic activity of ABNO in oxidations of sterically hindered alcohols, assuming that alcohol binding to ABNO+ is similarly favored.9,28,41 Hydroxide binding to ABNO+ can also compete with alkoxide binding, and this effect has been used to explain inhibition of electrocatalytic alcohol oxidation in the pH range where we now have robust voltammetric evidence for hydroxide binding.25 As shown in Figure 1, it is possible to observe the oxidation of TEMPOH2+ to TEMPO+ at potentials higher than the TEMPO/TEMPO+ potential, and this feature is attributed to slow comproportionation of hydroxylammonium and oxoammonium (cf. eq 3) under the reaction conditions. These results may be contrasted with the behavior of ABNO-derived species. The disproportionation of ABNO in acid is thermodynamically similar but kinetically more facile compared to TEMPO, which may be important to aerobic oxidations that take place under acidic conditions.9,26 In such a milieu, the hydroxylamine produced by alcohol oxidation may comproportionate with oxoammonium to produce nitroxyls that can undergo facile oxidation by co-catalysts through single electron transfer reactions.26

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The chemistry of 4-amino-TEMPO is more complex owing to the protonation-deprotonation equilibrium of its amino-substituent. This group exhibits a pKa that is dependent on the oxidation state of the N–O moiety, varying from 10.08 for the hydroxylamine through 8.87 for the nitroxyl to 5.9 for the oxoammonium (cf. Figures 3d, S6, and S7). The interaction between the two nitrogens leads to PCET reactivity at intermediate pH, where oxidation of the nitroxyl is coupled with deprotonation of the ammonium. This unusual pH-dependent redox chemistry undoubtedly contributes to its effectiveness in the electrochemical oxidation of alcohols under mildly acidic conditions.29

Conclusions Herein, we have established Pourbaix diagrams for five different organic nitroxyls by characterizing their pH-dependent redox properties. The results illustrate the importance of understanding the different protonation and oxidation states accessible by nitroxyls, viz. hydroxylamine, hydroxylammonium, oxoammonium, and hydroxylamine N-oxide. Substituent effects on reduction potential or pKa can be straightforward when only electrons or protons are being transferred, but can become counterintuitive when substituents produce opposing effects on the electron and proton transfers relevant to a PCET process. Of particular note is the negligible influence of substituent effects on the O–H bond strength of the different TEMPO–H analogs, in spite of considerable differences in the oxoammonium/nitroxyl reduction potential for the same series of compounds. Increased ring strain and decreased steric hindrance in bicyclic nitroxyls, such as ABNO, accounts for changes in their thermodynamics, and these changes could explain some of the differences in catalytic activity that have been observed between cyclic and bicyclic nitroxyls. In light of these observations, design or selection of an optimal

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nitroxyl catalyst will depend on whether the catalyst cycles between oxoammonium/nitroxyl or nitroxyl/hydroxylamine manifolds. In the former case, substituent inductive effects can be expected to tune the redox potential, as has been widely documented in the literature.9,11,25,28 In the latter case, little variation is seen in the O–H bond strength of the various TEMPOH analogs. The ring strain present in ABNOH, however, contributes to a stronger O–H bond strength and offers an opportunity to tune the PCET reactivity of nitroxyl/hydroxylamine catalysts.

Experimental Materials and Methods. Cyclic voltammetry (CV) measurements were performed at a glassy carbon electrode that was polished with alumina before each experiment. An Ag/AgCl reference electrode and Pt wire counter-electrode were also used. The working electrode was a 3 mm diameter glassy carbon disc, polished with alumina. To form the oxidized carbon surface, the polished glassy carbon electrode was electrolyzed for 10 s at 3.24 V vs. Ag/AgCl in 0.1 M H2SO4.27a It was then rinsed with water and used immediately. Capacitance measurements indicated that this treatment led to a doubling of the electrochemically active surface area.42 Periodically, the reference electrode was calibrated by CV of a solution containing ferroin.43 All measured potentials are reported relative to NHE.44 Prior to CV, the solution was purged with nitrogen and experiments were performed with the cell headspace under a nitrogen purge. Nitroxyls aside from TEMMO were purchased and used without further purification. GC/MS was used to confirm the purity of the nitroxyls, all were over 95 % pure (Figures S15 - S19). NMR pH titrations were performed in D2O acidified with 1 M D2SO4. 20 mM each of the nitroxyl and benzyl alcohol were added and allowed to react. Any remaining nitroxyl was quenched with NaHSO3. Aliquots of the solution were adjusted to various pH values with 17



solutions of NaOD and D2SO4 and their pH was measured with a glass electrode pH meter. Reported pH values are corrected for the glass electrode isotope effect.45 NMR spectra were acquired at a proton frequency of 500 MHz with frequency lock to the D2O solvent. Chemical shifts were referenced to the methylene signal from unreacted benzyl alcohol. Chemical shift vs. pH data were least-squares fitted to give pKa values using standard techniques.46 EPR spectra were obtained at 9.3 GHz using a field-sweep CW instrument. Spectra were simulated and fitted using the W95EPR program.47 3,3,5,5 tetramethylmorpholine was synthesized via a literature protocol.48 Synthesis of 3,3,5,5-Tetramethylmorpholine N-oxyl (TEMMO). To a solution of 3,3,5,5Tetramethylmorpholine (600 mg, 4.19 mmol) in acetonitrile (40 ml), Na2WO4·2H2O (137 mg, 0.41 mmol) and urea hydrogen peroxide (1.15 g, 12.6 mmol) were added and the reaction mixture was stirred at room temperature for six hours. Water was added to the reaction mixture and the aqueous solution was extracted with chloroform. The organic layer was dried over potassium carbonate and concentrated. The residue was purified by flash column chromatography (hexane/ethyl acetate 1/1). 3,3,5,5-Tetramethylmorpholine N-oxyl was obtained as a yellow oil with an odor similar to that of TEMPO in 90 % yield (538 mg, 3.77 mmol). The EPR spectral data (X-band, toluene solution, 212 K) were: giso = 2.0061, ANiso = 43.54 MHz, and linear A-strain of -0.00002 (Figure S14). Purity was confirmed by GC-MS (Figure S17) m/z (% relative intensity, ion): 158 (1.75, M+), 128 (3.57, M+ - NO), 72 (10.80, C3H6NO+), 71 (13.41, C4H7O+), 41 (69.55, C3H5+), 56 (C4H8+). HRMS (ESI-TOF, acetonitrile) m/z: M+ Calcd for C8H16NO2+ 158.1181; Found 158.1177. ASSOCIATED CONTENT Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR and UV-visible pH titration data, additional cyclic voltammetry data, EPR data, GC/MS data, CV modeling methods. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We thank Dr. Bradford L. Ryland for assistance with EPR data collection. This work was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences. NMR spectroscopy facilities were partially supported by the NSF (CHE-9208463) and NIH (S10 RR08389).

References 1. Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2004, 346, 1051 - 1071. 2. Vogler, T.; Studer, A. Synthesis 2008, 1979 - 1993. 3. Bobbitt, J. M.; Brückner, C.; Merbouh, N. Org. Reactions 2009, 74, 103 - 424. 4. Wertz, S.; Studer, A. Green Chem. 2013, 15, 3116 - 3134. 5. Cao, Q.; Dornan, L. M.; Rogan, L.; Hughes, N. L.; Muldoon, M. J. Chem. Commun. 2014, 50, 4524 - 4543. 6. Ryland, B. L.; Stahl, S. S. Angew. Chem. Int. Ed. 2014, 53, 8824 - 8838. 7. Sheldon, R. A. Catal. Today 2015, 247, 4 - 13. 8. Miles, K. C.; Stahl, S. S. Aldrichim. Acta 2015, 48, 8 - 10.

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9. Lauber, M. B.; Stahl, S. S. ACS Catal. 2013, 3, 2612 - 2616. 10. Rafiee, M.; Karimi, B.; Alizadeh, S. ChemElectroChem 2014, 1, 455 - 462. 11. Synthesis of TEMPO analogues is often motivated by a desire to improve catalytic performance in or gain insight into this reaction. For recent examples, see: a) Bobbitt, J. M.; Eddy, N. A.; Cady, C. X.; Jin, J.; Gascon, J. A.; Gelpí-Dominguez, S.; Zakrzewski, J.; Morton, M. D. J. Org. Chem. 2017, 82, 9279 - 9290; b) Lambert, K. M.; Stempel, Z. D.; Kiendzior, S. M.; Bartelson, A. L.; Bailey, W. F. J. Org Chem. 2017, 82, 11440 - 11446. 12. Piera, J.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2008, 47, 3506 - 3523. 13. Kim, J.; Stahl, S. S. ACS Catal. 2013, 3, 1652 - 1656. 14. Nguyen, L. Q.; Knowles, R. R. ACS Catal. 2016, 6, 2894 - 2903. 15. Bartelson, A. L.; Lambert, K. M. Bobbitt, J. M.; Bailey, W. F. ChemCatChem 2016, 8, 3421 - 3430. 16. Sosnovsky, G; Bell, P. Life Sci. 1998, 62, 639 - 648. 17. Israeli, A.; Patt, M.; Oron, M.; Samuni, A.; Kohen, R.; Goldstein, S. Free Radical Biol. Med. 2005, 38, 317 - 324. 18. Kato, Y.; Shimizu, Y.; Yijing, L.; Unoura, K.; Utsumi, H.; Ogata, T. Electrochim. Acta 1995, 40, 2799 - 2802. 19. Even in the case of TEMPO itself, there is considerable uncertainty. For example, the reported hydroxylammonium pKa values in Refs. 16 and 18 differ by > 1 pH. For a review of the thermodynamic literature on TEMPO, see pages 237 - 241 of the supporting information for: Armstrong, D. A.; Huie, R. E.; Koppenol, W. H.; Lymar, S. V.; Mernyi, G.; Neta, P.; Ruscic, B.; Stanbury, D. M.; Steenken, S.; Wardman, P. Pure Appl. Chem. 2015, 87, 1139 1150.

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20. Reduction potentials from radical to anion of diverse nitroxyls have been reported, but these experiments were performed in non-buffered CH3CN solution, complicating analysis of the data. See: Blinco, J. P.; Hodgson, J. L.; Morrow, B. J.; Walker, J. R.; Will, G. D.; Coote, M. L.; Bottle, S. E. J. Org. Chem. 2008, 73, 6763 - 6771. 21. Grampp, G. Rasmussen, K. Phys. Chem. Chem. Phys. 2002, 4, 5546 - 5549. 22. Wu, L. M.; Guo, X.; Wang, J.; Guo, Q. X.; Liu, Z. L.; Liu, Y. C. Sci China, Ser. B 1999, 42, 138 - 144. 23. Shibuya, M.; Tomizawa, M.; Sasano, Y.; Iwabuchi, Y. J. Org. Chem. 2009, 74, 4619 - 4622. 24. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412 8413. 25. Rafiee, M.; Miles, K. C.; Stahl, S. S. J. Am. Chem. Soc. 2015, 137, 14751 - 14757. 26. This reaction has also been studied electrochemically and spectroscopically in CH3CN, see: Gerken, J. B.; Stahl, S. S. ACS Cent. Sci. 2015, 1, 234 - 243. 27. a) Fukushima, T; Drisdell, W. Yano, J.; Surendrenath, Y. J. Am. Chem. Soc. 2015, 137, 10926 - 10929; b) Engstrom, R. C. Anal. Chem. 1982, 54, 2310 - 2314. 28. Peak potentials can be correlated with catalytic activity, presumably because they reflect a combination of thermodynamic and kinetic effects; see: Hickey, D. P.; Schiedler, D. A.; Matanovic, I.; Doan, P. V.; Atanassov, P.; Minteer, S. D.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 16179 - 16186. 29. Hickey, D. P.; McCammant, M. S.; Giroud, F.; Sigman, M. S.; Minteer, S. D. J. Am. Chem. Soc. 2014, 136, 15917 - 15920. 30. Nilsen, A.; Braslau, R. J. Polym. Sci. A 2006, 44, 697 - 717. 31. Previous studies (Ref. 25) confirm that ACT does not form an adduct below pH 11.

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32. See the Supporting Information for details. 33. Both experimental and computational studies support such an intermediate: a) Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A. Tet. Lett. 1986, 27, 1119 - 1122; b) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007, 72, 4504 - 4509. 34. Fish, J. R.; Swarts, S. G.; Sevilla, M. D.; Malinski, T. J. Phys. Chem. 1988, 92, 3745 - 3751. 35. Sen', V. D.; Golubev, V. A.; Kosheleva, T. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1979, 1847 - 1850. 36. Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc. 1973, 95, 6390 - 6394. 37. BDFEs calculated using the value of CG (57.6 kcal/mol) given in: Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010, 110, 6961 - 7001. 38. Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc. 1973, 95, 8610 - 8614. 39. a) Hall Jr., H. K. J. Am. Chem. Soc. 1957, 79, 5444 - 5447; b) Krabbenhoft, H. O.; Wiseman, J. R.; Quinn, C. B. J. Am. Chem. Soc. 1974, 96, 258 - 259. 40. Golubev, V. A.; Sen', V. D.; Rozantsev, É. G. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1979, 1927 - 1931. 41. For a review where various nitroxyls used as alcohol oxidation catalysts are compared, see Ref. 6. 42. Marsan, B.; Fradette, N.; Beaudoin, G. J. Electrochem. Soc. 1992, 139, 1889 - 1896. 43. The ferroin potential is pH-dependent, corrections were taken from: Dwyer, F. P.; McKenzie H. A. J. Proc. R. Soc. NSW 1947, 81, 93-96. 44. Bates, R. G.; et al. Pure & Appl. Chem. 1976, 45, 131-134. 45. Covington, A. K.; Paabo, M.; Robinson, R. A.; Bates, R. G. Anal. Chem. 1968, 40, 700 - 706. 46. Gift. A. D.; Stewart, S. M.; Bokashanga, P. K. J. Chem. Educ. 2012, 89, 1458 - 1460.

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47. Neese, F. QCPE Bull. 1995, 15, 5. 48. Lai, J. T. Synthesis. 1984, 122-123.

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Structural Effects on the pH-Dependent Redox Properties of Organic

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