Profiling the oxidative activation of DMSO-F6 by pulse radiolysis and translational potential for radical C-H trifluoromethylation

Article abstract of DOI:10.1039/c9ob02119a

The oxidative activation of the perfluorinated analogue of dimethyl sulfoxide, DMSO-F₆, by hydroxyl radicals efficiently produces trifluoromethyl radicals based on pulse radiolysis, laboratory scale experiments, and comparison of rates of reaction for analogous radical systems. In comparison to commercially available precursors, DMSO-F₆ proved to be more stable, easier to handle and overall more convenient than leading F₃C-reagents and may therefore be an ideal surrogate to study F₃C radicals for time-resolved kinetics studies. In addition, we present an improved protocol for the preparation of this largely unexplored reagent.

Full text of DOI:10.1039/c9ob02119a

Organic &
Biomolecular Chemistry
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PAPER
Profiling the oxidative activation of DMSO-F6
by pulse radiolysis and translational potential
for radical C–H trifluoromethylation†
Cite this: Org. Biomol. Chem., 2019,
7, 9734
1
Nico Santschi, * Benson J. Jelier,
Samuel Stähelin and Thomas Nauser
*
6
The oxidative activation of the perfluorinated analogue of dimethyl sulfoxide, DMSO-F , by hydroxyl radicals
efficiently produces trifluoromethyl radicals based on pulse radiolysis, laboratory scale experiments, and
Received 30th September 2019,
Accepted 17th October 2019
comparison of rates of reaction for analogous radical systems. In comparison to commercially available pre-
cursors, DMSO-F
6
proved to be more stable, easier to handle and overall more convenient than leading
C radicals for time-resolved kinetics
DOI: 10.1039/c9ob02119a
F
3
C-reagents and may therefore be an ideal surrogate to study F
3
rsc.li/obc
studies. In addition, we present an improved protocol for the preparation of this largely unexplored reagent.
methyl analogue has garnered significant attention, especially
in the past decade. Thus, the sagacious introduction of a single
Introduction
•
The generation of C-centered radical species R under laboratory trifluoromethyl group into a organic scaffold typically increases
5,6
conditions requires suitable precursors, P(R), and a matched set the lipophilicity of a drug candidate (π = 0.88) and together
of activating conditions, A, since most of the members of this with this moiety’s chemical inertness, has spurred the design of
•
class of molecules cannot be stored in bottles (Scheme 1). For a host of matched precursor/activator pairs to provide F
3
C rad-
•
7
example, methyl radicals (H C ) may be accessed most con- icals (Scheme 1). Two general paradigms exist for the unfetter-
3
veniently by the oxidative activation of readily available labora- ing of the reactive intermediate: (1) reductive activation (RA) of a
3
tory solvents, e.g. dimethyl sulfoxide (DMSO). For example, the CF -reagent is often employed with photochemical strategies
•
hydroxyl radical (HO ) readily generated under traditional and exploits readily available bulk chemicals such as trifluoroa-
8
Haber–Weiss or Fenton conditions with a suitable Fe(II) additive cetic acid derivatives and sulfonyl chlorides whereas (2) oxi-
and hydrogen peroxide liberates the methyl radical from the dative activation (OA) depends on sulfoxide or sulfinate deriva-
parent radical precursor. Even though this process is not tives, e.g. Langlois’ reagent, which are also inexpensive and
efficient in terms of yield, its striking operational simplicity readily available. The latter strategy is widely adaptable and by
allowed studying the important methylation of nucleic acid tuning of the sulfinate’s substituents, can readily provide access
1
bases under conditions inspired by Nature. Remarkably, the to other alkyl radicals, as most recently demonstrated by Baran
9
introduction of a single methyl group into a molecular scaffold and co-workers. Activation of the sulfoxide motif is most often
can drastically alter a compound’s biological profile, typically achieved using tBuOOH as stoichiometric reactant and apart
2
10
noted as the magic methyl effect. As a consequence, synthetic from an isolated example by Antonchick and co-workers, we
organic chemists have dedicated considerable efforts towards are not aware of a hydroxyl radical being used as a promoter in
expanding and optimizing the arsenal of radical methylation Fenton-like chemistry. Furthermore, the direct application of
strategies available. For example, Baran and co-workers reported the largely unknown, fully fluorinated analogue of the common
•
the use of methyl group surrogate radicals (PhSO
2
CH
2
) accessed laboratory solvent, dimethyl sulfoxide, DMSO-F
6
(1), as radical
C , i.e. in analogy to DMSO serving as precursor
fully modified the Fenton chemistry approach to achieve intro- to H C , is conspicuously absent from the literature. Specifically,
3
•
by oxidative activation, and Antonchick and co-workers success- precursor to F
3
•
3
4
duction of the CD
Similar to the methyl radical, the installation of the trifluoro- water, the HO radical constitutes one of the primary products
and DMSO-F could potentially provide a convenient entry point
3
motif on synthetically relevant scales.
in the context of radiolysis experiments, which are carried out in
•
11
6
•
into studying the kinetics of F
Moreover, DMSO-F would not necessitate specialized
handling or additives as required for previously employed
3
C radicals.
Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and
Applied Biosciences, Vladimir-Prelog-Weg 1/2, 8093 Zürich, Switzerland.
E-mail: nicosantschi@gmail.com, nauser@inorg.chem.ethz.ch
6
1
2
3
gaseous CF I or Togni’s reagents, nor would we expect any
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02119a
undesired cross-reactivity with commonly employed metal
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6
Scheme 2 Improved synthesis of DMSO-F .
reported procedure (A) (requiring heating substantially above
the boiling point of the product, and a substantial but delayed
exotherm) required significant improvements to negate an
unsafe and questionable protocol, to remove ambiguity, and
6
update key spectroscopic details of DMSO-F . Spectroscopic
1
3
examination only available by extended C NMR experiments
revealed that product A was only about 70% estimated purity
1
9
(
measured against an internal standard by F NMR with a
pulse delay value, d , of 10 s) using the reported procedure as
1
3
the by-products including TMS-F and Me SiOMe form an inse-
parable ternary azeotropic mixture. We were not able to purify
the mixture properly by any number of fractional distillations
or liquid–liquid extraction. Therefore, an alternative synthesis
strategy (B) was developed which led to the desired product
with a purity of >95% based on GC-MS analysis (Scheme 2).
Thus, a 350 mL oven-dried Ace Glass pressure vessel was
charged with CsF (0.978 g, 6.44 mmol, 0.05 equiv.) and a large
−
2
pTFE stirbar and subsequently dried at 200 °C at 1 × 10
mbar for 12 h and then backfilled with dry argon. The reaction
vessel was cooled to RT and then to −20 °C in an EtOH bath
by means of externally controlled circulator. 1,3,2-
Dioxathiolane 2-oxide (14.09 g, 130 mmol, 1.0 equiv.) and
3
TMSCF (38.20 g, 269 mmol, 2.1 equiv.) were added under an
argon atmosphere. The flask was sealed and the contents were
stirred at −20 °C for 1 h, warmed to RT and stirred for an
additional 22 h behind a blast shield. To prevent loss of the
volatile DMSO-F during post-reaction workup, the light-yellow
6
Scheme 1 General mechanistic paradigm for radical production (I),
crude reaction mixture was cooled to 0 °C, and the contents
transferred to a distillation apparatus containing a 25 cm recti-
fying column. The product was fractionally distilled twice, col-
lecting the fraction with a b.p. of approx. 34 °C at 760 mmHg
•
specific case for H
3
C generation (II), common precursors to the trifluor-
•
3
omethyl radical F C and subject of the present study (IV).
6
to afford hexafluorodimethylsulfoxide (DMSO-F ) as a colour-
salts. Furthermore, the abovementioned commercial zinc sulfi- less, volatile liquid (16.63 g, 69% yield) still containing trace
1
nate radical precursors are of limited use due to the formation trimethylsilyl impurities (ca. <5% by GC-MS). H NMR =
II
13
13
of a precipitate with K [Fe (CN) ], one of the standard indi- product contains no protons. C NMR (101 MHz, CDCl
3
) δ
4
6
•
1
cators for HO radicals. Herein, we explored the chemical kine- 123.59 ppm (qm, JCF = 338 Hz). Residual TMSF is observed at
2
19
1
tics of DMSO-F
these values with parameters available for DMSO in the litera- CDCl
ture, and perform preliminary activation test of DMSO-F
with (previously reported at 64.5 ppm (ref. 14)). IR (ATR-diamond,
Fenton’s reagent as a foundational study for an alternative cm ): 942, 955, 1100, 1119, 1182, 1244. GC-MS (EI, 70 eV) and
6
with primary radiolysis products, juxtapose −0.1 ppm (d,
J
CF = 15.3 Hz). F{ H} NMR (282.38 MHz,
) −67.45 ppm (s, 6F)
3
, 298 K, int. ref. to 2.5% w/w CFCl
3
6
−
1
radical trifluoromethylation reagent.
IR were also previously reported by Shreeve and are consistent
1
4
with our observations (see ESI† for complete analysis).
Most experiments with DMSO-F were carried out with
6
product derived from Method A. If the contaminants were less
Materials and methods
Synthesis of DMSO-F6
reactive than DMSO-F , then kinetics results are expected to be
6
essentially unaffected. Alternatively, if the trimethylsilyl fluor-
The synthesis of perfluorodimethylsulfoxide, DMSO-F
based on a sole literature report from 1972.
6
, is ide contaminants were significantly more reactive than
1
4,15
However, the DMSO-F
, then the derived reaction rates will be too high.
6
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+
•
Controls (section 3) with product from Method B (see below) 2.65, G(H ) = 2.65 and G(H ) = 0.55 with G-values given in
yielded comparable kinetics results as observed with product species per 100 eV deposited dose. If the sample solution is
A. In keeping with expectations, rates derived with product A saturated with N O prior to radiolysis (at 298.15 K: χ = 4.367 ×
2 1
−
4
16
−
are smaller than rates derived with product B.
2
10 , [N O]sat = 24.2 mM), then the solvated electrons eaq
•
can also be converted to HO according to eqn (2), thereby dou-
bling the yield of this oxidizing species.
Vapor pressure of DMSO-F
6
The unbuffered sample solutions were thoroughly degassed
and then saturated with a specific gas or gas mixture before
N2O þ eaq þ Hþ ! HO þ N2
•
ꢀ
•
ð2Þ
addition of DMSO-F . To this end, 50 µL of the reagent
6
•−
Note, that if other fast reactions with eaq do occur, they
may compete with reaction (2). In particular and in analogy
with other halogenated substances and carbonyl-derivatives,
DMSO-F is also expected to react quickly with eaq . As a
6
consequence, for our kinetics analyses we aim for a ratio
(
1
product A or B) were added to the closed vessel containing
0 mL of sample solution (ρ = 1.42 g cm (see ESI†)), thereby
−
3
minimizing losses by evaporation. The solution was then
taken up with a Sample-Lock Syringe (Hamilton) and intro-
duced into the irradiation cell by a syringe pump through
•
−
PEEK tubing. DMSO-F is highly volatile. We assumed that we
6
observe the vapor pressure over a binary mixture of liquids, i.e.
DMSO-F in water. In this case, the amount of DMSO-F in
6 6
solution is dependent on its vapor pressure and the volume of
the gas-phase. The assumption was validated and the vapor
pressure derived as follows:
(
A) The concentration of DMSO-F remaining in the solu-
6
tion is proportional to its scavenging power. This was derived
by appropriate competition experiments (section 3) with solu-
tions prepared in a Schlenk tube with known volume. Three
experiments were carried out with an identical solution. For
each experiment, 10 ml solution were put in the same Schlenk
tube and saturated with N O. Then, 0 µL, 50 µL or 100 µL
2
DMSO-F
DMSO-F
6
were added. Therefore, 0 mM DMSO-F
6
, x mM
6
, and (x + 38) mM DMSO-F , respectively, are present
6
in the solutions. The (38 – x) mM DMSO-F end up in the gas-
6
phase. With the known volume of the Schlenk tube we esti-
mated a vapor pressure of approx. 250 mbar at 22 °C.
(
B) A 10 ml solution of 3 mM Ferrocyanide (K [Fe(CN) ]),
4 6
saturated with N
syringe (Hamilton) with 50 µl DMSO-F
2
O, was spiked in a gas-tight sample-lock
. This corresponds to a
concentration of 38 mM, and the derived rate constants k and
6
4
k
7
agree with the rate constants derived above (see section 3).
C) 10 ml water at 24 °C was saturated in a Schlenk tube
with N O to a total gas-pressure of 930 mbar. Then sub-
(
2
6
sequently two portions of 50 µl DMSO-F each were added.
The total pressures in the Schlenk-tube measured after the
additions were 1230 mbar and 1234 mbar, again in agreement
with our assumption of a liquid–vapor equilibrium.
Methods
Radicals were generated by pulse-irradiation of unbuffered
aqueous solutions with ionizing radiation (2 MeV-electrons)
and the products of this pulsed radiolysis are known
1
1
(eqn (1)).
Fig. 1 (A) Temporal evolution of dose-normalized absorbance at
hν
H2O ꢀ! HO þ H þ e þ H2 þ H2O2 þ Hþ
•
•
•ꢀ
605 nm after irradiation (10 Gy) of an argon saturated solution of methyl
ð1Þ
2+
viologen MV (135 µM) and tBuOH (10%, 1.1 mM) in absence (black) and
•
+
•+
presence (maroon) of DMSO-F
6
(14.5 mM). (B) The ratio [MV ]/[MV
]
]/
0
The applied radiation deposits energy mass-proportionally
2+
varies non-linearly with the ratio [DMSO-F
6
]/[MV ]. At [DMSO-F
MV ] = 35.2, half the solvated electrons eaq are intercepted by
6
and therefore, in dilute solution, all energy is transferred to
the solvent. The product distribution and the yield of water
radiolysis are known and depend on the applied dose.
2+
−
[
•+
•+
6 0
DMSO-F . In light grey, predicted ratios [MV ]/[MV ] for DMSO based
on kinetic data available in the literature. Error bars represent two stan-
Specifically, the yields (“G-values”) are G(eaq ) = 2.65, G(HO ) = dard deviations.
−
•
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O + eaq•−) × [N
0, which correspond to >90% of the eaq being scavenged by
O.
In certain experiments tBuOH was used as a HO –scavenger
to avoid interferences by this oxidizing species (eqn (3)).
O]sat)/(k(DMSO-F
+ eaq•−) × [DMSO-F
]) ≥ Reaction of DMSO-F
The rate constant k
cyanoferrate(4-) (“ferrocyanide”) and hexachloroiridate(3-)
Fig. 2, maroon and green, respectively). Each data point is an
with HO
•
(
1
N
k(N
2
2
6
6
6
•
−
7
was determined by competition with hexa-
2
•
(
average of >4 single determinations:
•
•
ðCH3Þ COH þ HO ! ðCH3Þ CðOHÞCH2 þ H2O
ð3Þ
•
•
3
2
DMSO-F6 þ HO ! ½ðCF3Þ SðOHÞOꢁ
ð7Þ
ð8Þ
ð9Þ
2
•
The rate constant of the reaction of a CF
3
-precursor with a
II
4ꢀ
•
III
3ꢀ
þ HOꢀ
Fe ðCNÞ
þ HO ! Fe ðCNÞ
6
6
radical was always determined by competition with an indi-
cator reaction. As example see reaction (4) and competitor in
reaction (5). The product yield is given by eqn (6a) and results
are shown in Fig. 1B. The data were not linearized for analysis,
because such treatment would amplify the influence of
measurement errors. Instead, a least squares fit according to
eqn (6b) was performed by variation of the parameter r. Thus,
errors were dominated by the uncertainties in the rate con-
stants used as references.
Ir Cl6 þ HO ! Ir Cl6 þ HOꢀ
III
3ꢀ
•
IV
2ꢀ
DMSO-F (14.5 mM) was added to aqueous, unbuffered and
N O saturated solutions of Fe (CN)
pulse irradiation with doses of 10–20 Gy yields were compared
to respective measurements with 0.11 mM Fe (CN)
absence of DMSO-F . The reaction was followed spectroscopi-
cally at 420 nm (ε420(Fe (CN)
and the final absorption (“yield”) was determined as a tem-
poral average over 4–8 µs after the pulse. Alternatively,
14.5 mM DMSO-F was added to aqueous, unbuffered, N
saturated solutions of 97, 291 and 873 µM Ir Cl
were pulse-irradiated, the kinetics was followed at 435 nm and
plotted with reference to a solution of 97 µM Ir Cl
absence of reagent. Both, reaction (8) and (9), are diffusion
6
II
4−
(0.11–1 mM). After
2
6
II
4−
in the
6
6
III
3−
3
−1
−1
6
) = (0.9 − 1.1) × 10 M cm )
2
1
Results
6
2
O
III
3−
•
−
6
. Solutions
Reaction of DMSO-F with e
6
aq
The rate constant k4 was determined by competition with
methyl viologen (MV ), reaction (5), observing the intensely
blue colored methyl viologen radical (MV ) at 605 nm (ε605
III
3−
6
in the
2+
•
+
=
10
−1 22
controlled with k = (0.92 − 1.1) × 10
M
,
and k9
/k = 6.4
. The uncer-
tainty in k7 originates from the large uncertainty in k9 (see
=
8
4
−1
−1 17
1
.31 × 10 M cm ).
10
−1 23
(
0.47–1.3) × 10
M
.
Given k
8
/k
7
= 4.8 and k
9
7
9
−1 −1
•
DMSO-F6 þ eaq ꢀ ! products
(Table 1), we derive k = (0.73–2.5) × 10 M
s
7
ð4Þ
MV2 þ eaq•ꢀ ! MV•þ
þ
ð5Þ Table 1) and, therefore, the upper limit of the given range has
the higher probability of being correct.
2
+
Addition of DMSO-F to a solution of MV suppresses the
formation of MV (Fig. 1) and competition predicts
6
At longer timescales we observe in both cases additional
processes, which we cannot explain quantitatively (see ESI†).
The processes are clearly dose-dependent, suggestive for invol-
•
+
MV•þꢁ ¼ ½MV•þꢁ0 ꢂ ðk5½MV2þꢁÞ=ðk5½MV2þꢁ þ k4½DMSO-F6ꢁÞ
½
ð6aÞ
MV þꢁ=½MV•þꢁ0 ¼ ðr½MV2þꢁÞ=ðr½MV2þꢁ þ ½DMSO-F6ꢁÞ ð6bÞ
•
½
r ¼ k5=k4
ð6cÞ
•+
with [MV ]
0
the yield in absence of DMSO-F . The product con-
6
centration was measured as temporal average over 4–6 µs after
the pulse. When 14.5 mM DMSO-F was introduced to an argon
6
2+
saturated solution containing 135 µM MV and 10% tBuOH,
the absorbance at 605 nm was lowered by 74% from 23.8 to
.3 mAbs Gy− (Fig. 1A). Variation of [MV ] (0.135, 0.24, 0.35,
1
2+
6
1
3
1
.05 mM) at constant [DMSO-F
5.2 with a least squares fit of eqn (6b). With k
6 5 4
] leads to Fig. 1B and to k /k =
5
= (5.4 – 9.0) ×
1
0
−1 −1 18
9
−1 −1
0
M
s
,
we derive k = (1.5 – 2.6) × 10 M
s
.
4
Based on the rate constant k
the solubility of N O in water at 298.15 K, [N
we calculate that 84–91% of the solvated electrons are sca-
2
= (8.0 – 9.6) × 10 M s−1 and
9
−1
2
2
O]sat = 24.2 mM,
1
9a,20
venged by N
2
O in presence of 14.5 mM DMSO-F
6
,
in close
•
agreement to our aim. In consequence, G(HO ) = 4.87–5.07
and G(reaction (4)) = 0.23–0.43. Note, however, that this does
not affect our competition experiments because the branching
ratio for electrons through reactions (2) and (4) was always con-
Fig. 2 Relative yield of reference oxidation reaction for different
•
[Precursor]/[Reference] ratios. Precursors to F
3
C employed as competi-
tors: DMSO-F (magenta, green), Langlois’ reagent (black) and trifluor-
6
oacetate (light and dim grey). Error bars represent two standard
deviations.
stant if DMSO-F was used.
6
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•
II
Table 1 Compilation of literature reference rates, k(Ref. + HO ), and solution of 1.1 mM K
Fe (CN)
6
was used. Results are shown in
4
•
thereof derived rate constants for oxidative activation of F
3
C precursors,
Fig. 2 (black) and for the obtained value of r = 2 we arrive at
•
k(P + HO )
9
−1 −1
k
10 = (4.6–5.5) × 10 M
s
(Table 1).
•
•
•
Also with Langlois’ reagent we observed reactions at later
Precursor Reference k(Ref. + HO )/ k(Ref. + HO )/ k(P + HO )/
1
0
−1 −1
•
−1 −1
times, however, the reproducibility of those measurements was
unsatisfactory. We suspect a non-negligible influence of impu-
rities on our measurements at times >20 µs after pulse. While
the corresponding Zn-salt is also commercially available and is
typically provided in much better quality, its use is prohibited
(P)
(Ref.)
10
M
s
k(P + HO )
M
s
II
4−
9
DMSO-F
6
Fe (CN)
6
0.92–1.1
4.8
(1.9–2.5) × 10
(
ref. 22)
0.47–1.3
ref. 23)
0.92–1.1
ref. 22)
0.92–1.1
ref. 22)
1.4 (ref. 24)
III
3−
9
Ir Cl
6
6.4
(0.73–2.0) × 10
(
−
II
4−
4−
9
F
F
3
CSO
2
Fe (CN)
6
2.0
(4.6–5.5) × 10
2
+
by the formation of Zn
(vide infra).
precipitates with ferrocyanide
(
−
II
5
13
3
CCO
2
Fe (CN)
6
15 140
7460
(6.1–7.3) × 10
(
SCN−
1.8 × 10
6
−
•
Reaction of CF
3
CO
2
with HO
The rate constant of this reaction was measured versus ferro-
cyanide and thiocyanate:
vement of recombination reactions, i.e. reactions of/with pro-
ꢀ
•
•
ꢀ
ducts. Reaction (7) will be followed most probably by a frag-
CF CO þ HO ! F C þ CO þ HO
ð11Þ
ð12Þ
ð13Þ
3
2
3
2
−
•
mentation and we assume that CF S(O)O and F C are
3
3
ꢀ
•
•
ꢀ
SCN þ HO ! SCN þ HO
formed (see below, reaction (14)). The sulfinate is a reducing
•
agent and F
3
C is a moderately potent oxidant. It is not surpris-
ꢀ
•
•ꢀ
SCN þ SCN ! ðSCNÞ
2
ing that such species would further react in a mixture with the
partially oxidized competitors and, therefore, induce concen-
tration change of oxidized indicator.
8
The ratio k /k11 = 15 140 was determined in unbuffered,
N O saturated aqueous solutions containing either 0.11 mM
2
II
−
II
K Fe (CN) /0.5 M CF CO
or 0.05 mM K Fe (CN) /1 M
4 6
4
6
3
2
−
Controls with product B
CF
3
CO
2
(Fig. 2, light grey). As reference, a solution of
II
0
.11 mM K Fe (CN) was chosen.
4 6
Competition according to section 1 was reproduced and r =
9
−1 −1
Thiocyanate is often used as dosimeter in pulse radiolysis,
reaction (13) is an equilibrium reaction, and (SCN)
known molar absorptivity of ε475((SCN)2 ) = 7580 M cm
1
7.9 was derived, i.e. k
4
= (3 − 5) × 10 M
s . For the deter-
•
−
2
has a
mination of the vapor pressure and the concentration of
•
−
−1
−1 26
.
DMSO-F in a given Schlenk-tube, we measured the yield of
6
−
III
3−
Unbuffered, N
2
O saturated solutions of 510 mM CF
3
CO
2
and
Fe (CN)
6
(see above). Experiments were carried out with 0,
0 µl and 100 µl DMSO-F . With N O saturated solution of
we derived k using the branching of sol-
0.05–5 mM KSCN were pulse-irradiated and k12/k11 = 7460
5
3
6
2
II
4−
determined. It is noteworthy that (pseudo-)halogenide radicals
tend to form complexes with anions, e.g. reaction (13), and for
chlorine atoms even the diffusion-controlled reaction with
mM Fe (CN)
6
4
vated electrons via reactions (2) and (4). We observe a two
stage reaction, a fast initial reaction followed by a slower
2
7
•
4
−1
hydroxide is described. Possibly, SCN will react with the 0.5
M carboxylate present and such an equilibrium would
compete with equilibrium (13) resulting, in turn, in an overes-
process of pseudo-first order with kobs = 2 × 10 s . Under the
III
3−
•
assumption that the total yield G(Fe (CN)
6
)
tot = G(OH ) and
•
•−
25
9
that G(OH ) + G(eaq ) = 5.8 we estimate k = (3.4 − 4.1) × 10
4
−
1
−1
timation of k11
.
M
s
. This assumption implies also, that the initial, fast
absorption increase is due to reaction (8) and the slower is a
2
,2′-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid
III
3−
consequence of reaction (7). Therefore, G(Fe (CN)
6
)
initial
/
+
2−
(
ABTS ) as indicator for the reaction mechanism
III
3−
k [Fe (CN) ]/(k [Fe (CN)64−]
II
4−
II
G(Fe (CN) )tot
=
6
8
6
8
2
−
One-electron oxidation of ABTS produces a strongly colored
radical, ABTS , with ε
venient reagent to test for a moderately or strongly one-elec-
tron oxidizing species in a solution. We suspect [(CF ) S(HO)
O] (reaction (7)) to be of low reactivity and wished to gain
kinetics information on reaction (14). Reaction (16) is very fast,
k
1
7
[DMSO-F
6
]). We derive a rate constant of k
7
= (0.83 − 1.0) ×
•
−
4
−1
−1 28
0 M s−1. If 10 ml of a N
9
−1
= 3.6 × 10 M cm
14
.
It is a con-
4
2
O saturated solution of 3 mM
II
4−
Fe (CN)
5
was directly spiked in the sample-lock syringe with
6
9
−1 −1
3
2
0 µl DMSO-F
= (0.63 − 2.0) × 10 M s−1
.
6
, we derive k
4
= (1.7 − 4.7) × 10 M
s
and
•
9
−1
k
7
9
−1 −1
−
•
k16 = (1.2–1.9) × 10
similar magnitude, large enough to possibly monitor reactions
14) and/or (15).
M
s , and we suspect k17 to be of
3 2
Reaction of CF SO (Langlois’ reagent) with HO
The reaction rate was measured in competition with reaction (8):
(
ꢀ
•
•ꢀ
CF3SO2 þ HO ! ½CF3SO2OHꢁ
ð10Þ
•
ꢀ
•
þ
½
ðCF3Þ SðOHÞOꢁ ! CF3SO2 þ F3C þ H
ð14Þ
ð15Þ
ð16Þ
ð17Þ
2
Unbuffered, N O saturated, aqueous solutions of 10.4 mM
2
•
•
II
F3C þ O2 ! F3COO
CF SO Na and varying concentration of K Fe (CN) were
3
2
4
6
pulse-irradiated with doses of 10–20 Gy. Two independent
ABTS þ Cl3COO ! ABTS þ Cl3COOH þ HOꢀ
2ꢀ
•
•ꢀ
II
experimental series were measured, (1) [K
4
Fe (CN)
6
] =
II
ABTS þ F3COO ! ABTS þ F3COOH þ HOꢀ
2ꢀ
•
•ꢀ
0
.4–6.3 mM and (2) [K Fe (CN) ] = 0.63–3 mM. As reference a
4
6
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ABTS2 þ HO ! ABTS þ HOꢀ
ꢀ
•
•ꢀ
ð18Þ
ð19Þ
H =eaq þ O2 ! O2•ꢀ=HO2
•
•ꢀ
•
Solutions were saturated with a gas mixture of N O : O ≈
2
2
5
: 1. This will change the yields of the different radicals com-
pared to experiments with N O saturation, as we have an
2
additional reaction (19). If gas-saturation were perfectly repro-
ducible, no variation of starting conditions after the pulse is
expected. We measured DMSO-F
6
(14.5 mM) in presence of
2
−
ABTS (59, 98, 137 µM) and, as a reference in absence of
2
−
DMSO-F
6
, we used 98 µM ABTS (Fig. 3, black). For this latter
1
0
−1 −1
case, we determined k18 = 1.3 × 10
M
s , in agreement
2
8
with the reported value. The initial absorption of the kinetics
traces, directly after the pulse, increases with increasing
2
−
[
ABTS ], consistent with the aforementioned rate constant
•
−
k . Also, we observe that the yield of [ABTS ] in reaction (18)
1
8
Fig. 3 Normalized temporal evolution of absorbance at 404 nm for
2
−
is only about 57%, in full agreement with the work of ABTS solutions saturated in N O : O2 = 5 : 1 after irradiation with 10 Gy.
2
2
8
(14.5 mM) to the ABTS2− solution (98 µM) leads to a
Willson.
The gas was mixed manually for every stock solution. We
Addition of DMSOF
change in overall kinetics from pseudo-first order (black) to consecutive
reactions (salmon). Rate of oxidation depends on the initial ABTS con-
centration and increases in the order 59 µM (maroon), 98 µM (salmon)
and 137 µM (purple). Inset: magnified area as encompassed by black
6
2−
•
−
observed slightly increased yields of ABTS with each new
2
−
solution. The effect was not dependent on the ABTS concen-
tration, as the different concentrations were measured in rectangle to highlight initial offset and sigmoidal curve shape. Colored
random order. The total signal increase over the whole day was line segments are model fits.
approximately 15% (see ESI†). We judged that we were observ-
ing an artifact and, therefore, normalized the curves for the
same end-absorption.‡ Normalization does not influence the Table 2 Compilation of model parameters for modeling the system
derived rate constants. Kinetics traces can be seen in Fig. 3. comprising of eqn (14), (15) and (17)
The kinetics change dramatically in the presence of DMSO-F6,
2
a
5
−1
k
17 /10 M s−1
b
9
−1
Offset/10−3 Gy
[
ABTS −]/µM
k
calc /10 s
and there are three important qualitative observations: (i) the
st
c
b
b
reactions are distinctly slower, (ii) instead of a 1 order growth 59
2.7 ± 0.7
2.7 ± 0.2
3.6 ± 0.4
1.5 ± 0.3
1.2 ± 0.0
1.2 ± 0.1
2.4
5.6
4.0
c
b
b
b
b
9
1
8
we observe a lag-phase followed by an absorption increase to
the level observed before and (iii) the rate of increase is depen-
c
37
2
−
d
b
b
b
b
b
b
dent on [ABTS ]. The lag-phase (ii) is typical for multi-step 68
0.6 ± 0.02
0.9 ± 0.08
1.1 ± 0.02
2.9 ± 0.1
2.3 ± 0.2
2.6 ± 0.1
2.7
4.5
10
d
d
1
2
25
50
reactions, in support of our assumptions. We infer to observe
consecutive reactions of reaction (7), presumably reactions
•
−
a
b
(
14), (15) and (17). It even seems, that the total yield of ABTS
First order intermediate step. Standard deviations based on fitting
c
2
−
N ≥ 5 kinetics traces. Experiments performed with product A.
is independent whether ABTS
is oxidized directly via
d
Experiments performed with product B.
reaction (18) or indirectly via a reaction cascade starting at
reaction (7).
Based on these qualitative observations we set out to model
the kinetics traces. Again, we suspect a reaction cascade invol-
ving reactions (7), (14), (15) and (17). For our simulation of the
shape of the curve, reaction (7) is irrelevant for the kinetics
of gas saturation would govern the results. The oxygen concen-
tration, [O ], in the samples were not analytically quantified
2
6
between samples of DMSO-F and therefore different oxygen
concentrations could additionally provide a rationale for
slightly different values observed between experimental series
because it has a half-live of only t
1
= ln(2)/(k
7
× [DMSO-F
). We know that reaction (17) is
relevant, because the rate of absorption build up in Fig. 3
6
]) < 80
2
9
−1 −1
ns (for k
7
> 0.6 × 10 M
s
(
(
Table 2). It is foreseeable that measured values for reactions
14) and (17) will also be subject to the analytical quality of
2
−
(
color) is clearly dependent on [ABTS ].
DMSO-F used.
6
Because we want to limit the number of parameters in our
model, we tried to model reactions (14) and (15) together
The corresponding least-square fitted curves can be seen in
Fig. 3, the corresponding parameters are shown in Table 2.
using one single first order rate constant kcalc. With [O ] ≫
2
•
[F
3
C ], this would imply that either kcalc = k14 ≫ k15[O
2
] or Fenton reaction in presence of DMSO-F and product analysis
6
kcalc = k [O ] ≫ k . In the case that k
= k [O ], the process
15
2
14
calc
15
2
We characterized the radical species generated by oxidative
activation by its reaction with caffeine. This xanthine is an
ideal substrate: it is water soluble, features only one reactive
‡
In the controls, this effect was not observed anymore.
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3
1
is well documented. The reaction of the solvated electron
9
−1 −1
with DMSO-F , k = (2 − 5) × 10 M
s , is three orders of
6
4
magnitude larger than with ordinary DMSO (calculated curve
depicted in light grey in Fig. 1B). Conversely and as inferred,
•
9
−1
the oxidation of DMSO-F with HO , k = (0.6 − 2.5) × 10 M
s
6
7
−
1
32
, is an order of magnitude slower than that of DMSO.
•
Reagents for production of F C radicals in pulse radiolysis
3
Experiments with Langlois’ reagent and trifluoroacetate
yielded unsatisfactory results for different reasons but serve as
valuable references due to the reagents’ commercial avail-
•
ability. The oxidation of trifluoroacetate with HO is simply too
•
slow for fast production of F C needed in time-resolved
3
5
−1 −1
mechanistic studies. We find k11 = (6 − 7) × 10 M
s
in
agreement with published data from flash photolysis experi-
6
−1 −1 33
ments (<10 M
for our purposes, k10 = 5 × 10 M
salt (Baran modification) is stable and available in high purity,
s ). Langlois’ reagent is kinetically ideal
9
−1 −1
s
. The corresponding Zn-
2
+
however, Zn has a rich complex chemistry that distinctly
limits the use of this compound. In our case, the low solubility
of Zn[Fe(CN) ] precluded certain measurements. On the
13
6
other hand, the sodium salt proved to be either unstable or
not pure: experiments yielded distinctly differing kinetics
traces for timescales >20 µs from day to day, which is not
Fig. 4 GC-MS chromatograms of organic extracts of oxidative caffeine
functionalization in aqueous, buffered media with Fenton’s reagent and acceptable for future mechanistic investigations. In addition,
DMSO (A) or DMSO-F (B).
earlier experiments with reductive activation of CF I showed
several disadvantages associated with this gas, such as the
6
3
3
4
necessity of signal deconvolution.
DMSO-F has the drawback of not being commercially avail-
bases. Thus, the well-established oxidative activation of DMSO able. Its rate of reaction with HO is lower than that of
site for radical addition and is reminiscent of purine nucleo-
6
•
by the Fenton protocol for methylating adenine and guanidine Langlois’ reagent by half an order of magnitude. On the other
2
9
should provide an ideal blue print. To mixtures of caffeine, hand, liquid handling is comparatively easy, and the reagent
ascorbic acid, Na EDTA and Fe(II)SO ·7H O in phosphate proved to be robust in daily use. This makes DMSO-F the cur-
buffer we added at 0 °C a DMSO derivative followed by drop- rently best, though not optimal, choice for time-resolved
wise addition of H . Products were extracted with ethyl mechanistic studies. We therefore investigated the mechanism
acetate and analyzed by GC-MS (Fig. 4). Besides unreacted of the oxidative activation more closely, because in principle,
2
4
2
6
2 2
O
•
−
starting material (t = 11.0 min; 194m/z, grey) only the functio- fragmentation of the oxidized intermediate [(CF ) S(OH)O]
R
3 2
3 R
nalized products occur, i.e. CF -caffeine (t = 9.8 min; 262m/z, may not only occur via reaction (14), but also via reactions (20)
green) or CH
well as minor amounts of a decomposition product likely
arising from oxidative imidazole cleavage (t = 11.6 min, 112m/
z). The product CF -caffeine was quantified by F NMR spec-
3 R
-caffeine (t = 11.6 min; 208m/z, magenta), as and (21), also producing a moderately oxidizing radical.
•
•ꢀ
½
ðCF3Þ SðOHÞOꢁ ! ½ðCF3Þ SðOÞOꢁ þ Hþ
ð20Þ
ð21Þ
2
2
R
1
9
•ꢀ
•
ꢀ
3
½
ðCF3Þ SðOÞOꢁ ! CF3SO2 þ F3C
2
troscopy through addition of PhCF as internal standard to the
3
Kinetics experiments as well as product analysis were
carried out to confirm the hypothesis of fragmentation via
reaction (14). Product analysis, demonstrating trifluoromethyl-
organic extract and furnished a value of approximately 16%.
ation of caffeine after oxidative activation of DMSO-F by the
6
Discussion
•
Fenton reagent, indeed supports the notion of F
3
C radical pro-
•
−
Rates constants for the reaction of DMSO-F with e
6
aq
duction, reaction (14), very clearly, albeit at low yield. In this
regard, it is noteworthy that the addition of ascorbate proved
•
and HO
Perfluorination has two distinct effects on the reactivity of critical to observing the functionalized product. However,
•
3
DMSO. The inductive effect exerted by fluorine will decrease ascorbate (“antioxidant”) may reduce the F C radical, thereby
35
electron density around the sulfur center. Additionally, the preventing oxidative functionalization of caffeine. Because
C–F bond is easier to reduce than the C–H bond because of perfluoroalkyl radicals exhibit a very low molar absorptivity, we
3
0
2−
the very low lying σCF* orbital, and the resulting instability of decided to monitor kinetics with a reporter molecule, ABTS
.
perfluorinated materials towards strongly reducing conditions In the presence of oxygen, we observe a double-exponential be-
9740 | Org. Biomol. Chem., 2019, 17, 9734–9742
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Paper
havior (Fig. 3), i.e. two sequential (pseudo)-first order reactions anionic vs. neutral) or whether it also features a (pronounced)
•
•
can be resolved. In aqueous environment F C and Cl C rad- steric component cannot be deduced from the data at hand.
3
3
3
4,36
•
icals have a similar electronegativity.
Similarly, F
3
COO
•
37
and Cl
3
COO show comparable kinetic behavior. While the
former is a stronger oxidant, the overall reactivity of both mole-
cules is dominated by the electron-withdrawing effect exerted
Conclusions
•
by the halogen substitution pattern. With the ascorbate anion In analogy to the oxidative activation of DMSO with HO pro-
•
•
(
trihalogen)methylperoxyl radicals have a reactivity H COO ≪ viding H
3
C , we explored the feasibility of using DMSO-F
6
as a
3
•
•
•
Cl
3
COO ≤ F
3
COO with corresponding relative rate constants precursor to F
of 1 : 100 : 100. For the reaction with Trolox C the corres- laboratory experiments corroborated that DMSO-F undergoes
6
3
C . Pulse-radiolysis studies in conjunction to
3
8
•
9
−1 −1
ponding rate constants have
: 2400 : 4700. Oxygen will cause formation of F
reaction (15), which we expect to exhibit a comparable reactiv- parison to other commercially available precursors (Langlois’
a
relative magnitude of a rapid reaction with HO with k
7
= (0.6 − 2.5) × 10 M
s ,
•
•
1
3
3
COO radicals, followed by a fragmentation reaction to furnish F C . In com-
•
9
−1 −1 28
ity as Cl COO , k = (1.2 − 1.9) × 10 M
s
.
This is indeed reagent, trifluoroacetate), DMSO-F
the case: k17 = (1 − 3) × 10 M
. (Table 2) Is the remaining handle and overall more robust and therefore, is well suited
rate constant, with kcalc = (0.5 − 3) × 10 s , to be attributed to for time-resolved kinetics studies of F
6
proved stable, easier to
3
16
9
−1 −1
s
5
−1
•
C . The major caveat is
3
reaction (14) or reaction (15)? Based solely on our data we the requirement for its laboratory synthesis and hitherto time-
cannot decide unequivocally. Nevertheless, reaction (15) is the consuming purification.
more probable candidate for two reasons: (A) given [O
2
] ≈
, in
3
9
9
−1 −1
2
00 µM, we would calculate k15 = (0.3 − 1.5) × 10 M
s
agreement with the corresponding rate constants for the reac-
Conflicts of interest
•
•
9
−1 −1
tions of H
and 3.3 × 10
3
C and Cl
3
C with O
2
of (3.0 − 4.7) × 10 M
s
9
−1 −1
40
M
s
, respectively. (B) Compared to a There are no conflicts to declare.
7
−1
reported value of k21 = 1.5 × 10 s we consider a value of k14
=
5
−1
41
(0.5 − 3) × 10 s too low.
Acknowledgements
ðCH3Þ SðOHÞOꢁ ! CH3SO2 þ H3C þ Hþ
•
ꢀ
•
ð21Þ
½
2
This work was generously supported by the Swiss National
The [S → C] substitution from Langlois’ reagent to trifluor- Science Foundation (N. S.; P3P3P2_167744), the National
oacetate underpins the importance of a nucleophilic central Science and Engineering Research Council of Canada (B. J. J.)
•
atom to achieve significant scavenging rates of the HO radical. and ETH Zürich (Prof. D. Günther, Prof. A. Togni).
A loss in reactivity of over three orders of magnitudes was
observed and this innocuous substitution was likely
accompanied by a fundamental change in mechanism.
Furthermore, the comparison of trifluoroacetate with acetate is
Notes and references
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−
•
7
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