Reactivity of adrenaline toward alkoxyl radicals and carbonyl triplet states

Article abstract of DOI:10.1039/b810765c

The reactivities of adrenaline toward hydrogen abstraction by the tert-butoxyl radical and the excited triplet state of benzophenone have been examined in solution using laser flash photolysis techniques. The rate constants obtained in acetonitrile-rich solvents are 13 and 1.5 × 10⁸ M^-1 s^-1 for benzophenone triplet and the tert-butoxyl radical, respectively. Adrenaline is a better hydrogen donor than phenol, but not as efficient as α-tocopherol.

Full text of DOI:10.1039/b810765c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Reactivity of adrenaline toward alkoxyl radicals and carbonyl triplet states
Gonzalo Cosa*a and J. C. Scaiano*b
Received 26th June 2008, Accepted 1st September 2008
First published as an Advance Article on the web 31st October 2008
DOI: 10.1039/b810765c
The reactivities of adrenaline toward hydrogen abstraction by the tert-butoxyl radical and the excited
triplet state of benzophenone have been examined in solution using laser flash photolysis techniques.
The rate constants obtained in acetonitrile-rich solvents are 13 and 1.5 ¥ 108 M-1 s-1 for benzophenone
triplet and the tert-butoxyl radical, respectively. Adrenaline is a better hydrogen donor than phenol, but
not as efficient as a-tocopherol.
Introduction
Adrenaline, together with noradrenaline and dopamine, belongs
to the general class of compounds known as catecholamines.
These molecules act both as neurotransmitters in the brain, and as
hormones in the blood system. They are produced in the organism
by the enzyme tyrosine hydroxylase, which transforms tyrosine
into dopa, a first intermediate in their synthesis (see Fig. 1).1
Scheme
1
Oxidation of adrenaline. 1 adrenaline, 2 adrenaline
semiquinone radical, 3 adrenoquinone, 4 leucoadrenochrome, 5 leucoa-
drenochrome semiquinone radical, 6 adrenochrome, 7 adrenoleutine.
The oxidation of catecholamines may be initiated by free radical
attack on the dihydroxybenzene moiety resulting in H-abstraction
and formation of an aryloxyl or semiquinone radical.17,18 The
kinetics of formation of the different transients involved in the
oxidation of dopa semiquinone radical (dopa equivalent of 2) to
dopachrome (dopa equivalent of 6), as well as their spectroscopy,
have been described following pulse radiolysis studies in water.12,15
The reactivity of catecholamines has also been analyzed in the
presence of peroxyl radicals.18
Here we report absolute rate constants for the reaction of the
catecholamine adrenaline with t-butoxyl radicals and carbonyl
triplets, specifically, triplet benzophenone. Our goal is to learn
on the reactivity of adrenaline towards these highly reacticve
intermediates in order to explore the feasibility of radical mediated
degradation of catecholamines. The choice of t-butoxyl radicals
and triplet benzophenone as the oxidating agents of adrenaline
is not casual. Previous results existing in the literature, where the
former are quenched by well known radical scavengers such as
phenol,19,20 a-tocopherol,21,22 aminoleutins7 or melatonin,23 will
allow us to compare the free radical scavenging activity of these
phenols to that of adrenaline.
Fig. 1 Structure of various catecholamines.
Catecholamines may readily undergo oxidation ultimately lead-
ing to melanin pigments which are known for their protection
against solar radiation.2–6 The protective effect is due not only to a
screening effect of the solar radiation, but also the antioxidant
effect of melanin plays an important role as a scavenger of
radicals.3,7–9 In the case of dopamine it is also worth noting that
the immediate products following its oxidation are precursors of
the potent neurotoxin 6-hydroxydopamine, a compund involved
in oxidative stress neuronal degeneration.10
Catecholamines share a common oxidation pathway; Scheme 1
illustrates it with adrenaline.11–16 It is initiated by the oxidation of
the dihydroxybenzylamine (1) to the amine semiquinone radical
(2); the latter disproportionates to form aminoquinone (3) and
1. Upon cyclization aminoquinone forms leucoaminochrome (4).
Leucoaminochrome further oxidizes to form leucoaminochrome
semiquinone radical (5), which upon disproportionation gener-
ates aminochrome (6) and 4. Aminochrome then rearranges to
aminoleutine (7).
Experimental section
Materials
aDepartment of Chemistry, McGill University, 801 Sherbrooke St. West,
Montreal, QC, H3A 2K6, Canada. E-mail: gonzalo.cosa@mcgill.ca;
Fax: (514) 398-3797; Tel: (514) 398-6932
Adrenaline (( ) 4-[1-hydroxy-2-methylamino) ethyl]-1,2-benzene-
diol), benzhydrol, di-tert-butyl peroxide (treated in alumina col-
umn before use) and 1,4-cyclohexadiene (distilled before use) were
purchased from Sigma-Aldrich Canada (Oakville, ON, Canada).
bDepartment of Chemistry, University of Ottawa, 10 Marie Curie,
Ottawa, ON, K1N 6N5, Canada. E-mail: tito@photo.chem.uottawa.ca;
Fax: (613)562-5633; Tel: (613)562-5896
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Halostachine (( )1-hydroxy-1-phenyl-2-methylaminoethane) was
purchased from Lancaster (Windham, NH, USA). Benzophenone
from BDH Chemicals Ltd. (Poole, England) was recrystallized in
ethanol before use. Acetonitrile was HPLC-grade and purchased
from OmniSolv (Gibsstown, NJ, USA), it was used without further
purification. Acetic acid, glacial, was purchased from Anachemia
(Montreal, QC, Canada).
Nanosecond Laser Flash Photolysis
The laser flash photolysis (LFP) system has been previously
described.24,25 Samples were excited with a Molectron UV-24 nitro-
gen laser generating pulses at 337 nm of 6 ns and < 6 mJ output at
the source, or with the third harmonic of a Surelite Nd/YAG laser
generating pulses at 355 nm of 8 ns duration and 25 mJ output. The
signals from the monochromator/photomultiplier system were
initially captured by a Tektronix 2440 digitizer and transferred
to a PowerMacintosh computer that controlled the experiment
with a software developed in the LabVIEW 4.1 environment from
National Instruments (Austin, TX, USA).
All transient spectra, kinetics, and power dependence studies
were recorded employing a flow system with a 7 ¥ 7 mm, 2 ml
capacity, fused silica cuvettes from Luzchem Research (Ottawa,
Canada). Samples were purged in a storage tank for 30 minutes
with N2. A minimum of 8 shots were acquired at each wavelength
to record transient absorption spectra. For the power dependence
studies 40 to 60 shots were accumulated for each measurement, to
improve the signal to noise ratio due to the low intensity of the
signals. The quenching rate constant for hydrogen abstraction by t-
butoxyl radical was determined from the signal growth monitored
at 370 nm. Up to 30 shots were accumulated. In the case of studies
performed with benzophenone, the 355 nm laser was employed.
In this case no more than 4 shots were accumulated to obtain each
kinetic trace. Details of the techniques employed and related data
analysis are available in recent reviews.26,27
Scheme
consumption.
2
Steps involved in t-butoxyl radical formation and
LFP the appearance of a transient with an absorption band
shoulder at 380 nm (see Fig. 2). This transient also presents a
band in the visible region which extends in the near IR, i.e., from
500 nm and over 700 nm. We assign the observed spectrum to the
semiquinone radical resulting from H-abstraction from adrenaline
(Step 3 in Scheme 2). The spectrum obtained here matches spectra
obtained following pulse radiolysis studies of dopa in aqueous
solution containing NaN3 at pH 6,15 and of 3,5-di-tert-butyl-1,2-
benzoquinone under N2O atmosphere at pH 3.28
Fig. 2 Transient absorption spectra of 2.9 ¥ 10-3 M adrenaline under
N2 atmosphere, in 38:60:2 di-tert-butyl peroxide:acetonitrile:acetic acid.
Laser wavelength 337 nm. Time windows: (●) 0.56 ms; (ꢀ) 4.72 ms; and
(ꢀ) 17.00 ms after the laser pulse.
Fresh solutions were prepared every day before experiments.
The solvent employed in all cases was prepared by mixing 60
parts in volume of acetonitrile with 2.25 parts in volume of acetic
acid glacial, and bringing to 100 parts with di-t-butyl peroxide
(approximately 38 parts in volume). These values ensured an
absorbance of 0.3–0.5 for di-t-butyl peroxide in the laser cell at
the excitation wavelength. Sample stability was checked under
nitrogen atmosphere. There was no observed change after 3 hours,
as determined by steady state absorption spectroscopy.
The rate constant for the reaction of t-butoxyl radicals with
adrenaline (kH) was estimated using Equation 1, where kexp is the
observed growth rate constant of the semiquinone radical, and k1
is the rate constant for t-butoxyl radical b-cleavage.
kexp = k1 + kH ¥ [AdrO - H]
(1)
By plotting kexp values for increasing adrenaline (Adr-OH)
concentrations (Fig. 3), we obtained a kH value of 1.5 ¥ 108 M-1 s-1
from the slope of the plot and a k1 value of 2.6 ¥ 105 s-1 from
its intercept. Given that t-butoxyl radicals are rapidly quenched
by adrenaline the formation of methyl radicals via b -cleavage
and their subsequent reaction with adrenaline is negligible under
our experimental conditions. Thus our measured reactivity is
characteristic for the reaction of t-butoxyl radicals with adrenaline
(Step 3 in Scheme 2).
We have previously shown that in alkylamines the C-H bond
in position a to the amino group is reactive towards t-butoxyl
radicals.29 It is therefore important to establish which role, if any,
the amino group plays in the oxidation of the catecholamines.
In fact, the methodology we employ in our experiments provides
kinetic, not mechanistic information.27,30 Although we only ob-
serve the semiquinone radical spectra, we cannot rule out on this
Results
Reaction with t-butoxyl radicals
The irradiation of di-tert-butyl peroxide (di-t-butyl peroxide),
with a short wavelength nanosecond laser pulse produces t-
butoxyl radicals within the duration of the pulse. Upon their
formation these radicals undergo slow b-cleavage with elimination
of acetone and production of a methyl radical (Step 2 in Scheme 2).
Alternatively, in the presence of a hydrogen donor (H-donor) t-
butoxyl radicals will be reduced to t-butanol concomitant with the
oxidation of the H-donor (Step 3, 4 or 5 in Scheme 2).
Following irradiation of di-t-butyl peroxide with 337 nm laser
pulses in the presence of adrenaline we can readily monitor via
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Fig.
3
Observed growth rate constant for the formation of the
adrenaline semiquinone radical measured at 370 nm, in the presence
of different concentrations of adrenaline in 38:60:2 di-tert-butyl per-
oxide:acetonitrile:acetic acid as solvent. Laser wavelength 337 nm, N2
bubbled. The inset shows the time dependence of the absorption at 370 nm
for an adrenaline concentration of 1.09 ¥ 10-3 M.
Scheme 3 Deactivation mechanism for triplet benzophenone in the
presence of adrenaline.
sole basis the possibility of hydrogen abstraction at the a-amino
position, which would in turn result in a transparent radical in
our system, and an overestimation of the reactivity at the phenol
moiety.
Scheme 4 Disproportionation of adrenaline semiquinone radical.
In order to establish if H-abstraction in position a to the amino
group is viable in our system, we performed kinetic measure-
ments with 1-hydroxy-1-phenyl-2-methylaminoethane (halosta-
chine, Step 4, Scheme 2) in the presence of a constant concentration
of benzhydrol, employed as a signal carrier (Step 5, Scheme 2).29,31
Even at concentrations as high as 42 mM on halostachine, the
observed growth rate (monitored at 330 nm) was the same as
that obtained with no halostachine, ca. 3.3 ¥ 105 M-1s-1. At the
same concentration of adrenaline, the observed rate would be ca.
6.3 ¥ 106. Thus we estimate an upper limit of 5% for hydrogen
abstraction at centers other than the phenylhydroxy moiety (Step
4 in Scheme 2).
the same conditions. The latter is a good hydrogen donor, and
the allylic radical obtained following its oxidation is transparent
over the whole visible range.35 The decay traces obtained for both
quenchers are shown in Fig. 4.
Reaction with triplet benzophenone
Following excitation, benzophenone (Bp) undergoes efficient
intersystem crossing to the n,p* lowest excited triplet state.32 The
triplet state is very reactive towards hydrogen abstraction, rate
constants for benzophenone triplet quenching by phenols ranging
between 8 ¥ 107 to 5 ¥ 109 M-1s-1 have been measured in acetonitrile
and benzene.19 However, not only hydrogen abstraction, but also
electron transfer,33 energy transfer and other type of physical de-
activation may be operational in the case of triplet benzophenone,
as shown in Scheme 3.19,22
Fig. 4 Transient absorption spectra obtained 0.9 ms after the laser pulse,
in the presence of (ꢀ) adrenaline 5.9 ¥ 10-4 M, and (ꢀ) 1,4-cyclohexadiene
2.05 ¥ 10-2 M. Also shown is the difference between both traces,
which were normalized at 500 nm (ꢁ). Inset: Time dependence for
the absorption at 500 nm following excitation of benzophenone in the
presence of (+) adrenaline 5.9 ¥ 10-4 M, and (᭺) 1,4-cyclohexadiene
2.05 ¥ 10-2 M. Experiments were performed under N2 atmosphere, in 98:2
acetonitrile:acetic acid V:V. The Laser wavelength employed was 355 nm.
The quenching rate constant of triplet benzophenone is 1.3 ¥
109 M-1s-1. In order to establish to which extent the observed
quenching is due to hydrogen abstraction (Step 10), and how im-
portant are the other possible mechanisms proposed in Scheme 3
(Steps 7 to 9), we evaluated the ratio of absorbances from the
triplet state and from the ketyl radical at 500 nm in order to
establish how much of the triplet state is converted to ketyl radical
following H-abstraction. The triplet state absorption was obtained
immediately after the laser pulse, and the ketyl radical absorption
was measured after the decay of the triplet state is complete.22,34
Given that the absorption of adrenaline semiquinone radical has
a band extending from ca. 500 nm and to the red, (Fig. 2), we used
the ratio of absorbances measured at 500 nm. We then compared
the value obtained following 95% quenching by adrenaline, to that
obtained following 95% quenching by 1,4-cyclohexadiene, under
Fig. 5 Transient absorption spectra obtained for 3.0 ¥ 10-3 M adrenaline
under N2 atmosphere in 38:60:2 di-t-butyl peroxide:acetonitrile:acetic acid
v:v:v. Spectra correspond to time windows recorded (᭺) 23 ms, (●) 113 ms,
(ꢀ) 449 ms and (᭢) 812 ms after a 337 nm laser pulse.
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Table 1 Hydrogen abstraction rate constants from different radical
scavengers by benzophenone and t-butoxyl radical in units of 10-8 M-1 s-1
Based on our results we conclude that over 95% of the reaction
with adrenaline is due to hydrogen abstraction by benzophenone
triplet state. Thus, we obtained values of 2.21 and of 2.33 for
the triplet absorption/ketyl radical absorption when employing
adrenaline and 1,4-cyclohexadiene as hydrogen donors, respec-
tively. These values are within a 5% error difference, that for
adrenaline being smaller than that for the alkene, where hydrogen
abstraction is the only operational mode of quenching.
A comparison of the ketyl radical spectra obtained with 1,4-
cyclohexadiene to that obtained with adrenaline evidences the
presence of the semiquinone radical of adrenaline, as can be
observed following the subtraction of both spectra in Fig. 4. From
the data in Fig. 4 we can determine the molar absorptivity for the
semiquinone radical at 370 nm (eSQ 370) employing the known
Benzophenone triplet
t-butoxyl radical
Substrate
Benzene
CH3CN
0.819
Benzene
Polar sv.
phenol
p-methoxyphenol
adrenaline
aminoleutin
melatonin
a-tocopherol
1319
4519
—
3.320
1620
—
a0.2220
a1.120
b1.5
3919
13
697
—
847
7623
6021
—
b8.17
—
b0.3423
b6.622
5122
3822
a In methanol and di-t-butyl peroxide; b in acetonitrile and di-t-butyl
peroxide. To perform our experiments it was necessary the addition of
acetic acid (2.2% V:V; ca. 0.4 M) in acetonitrile to increase adrenaline
solubility. The latter is insoluble in benzene, and therefore we could not
determine the kinetics of hydrogen abstraction in this solvent.
value for the ketyl radical at 550 nm i.e., 3,300 700 M-1cm-1.36
A
value of 1400 300 M-1cm-1 is obtained for eSQ 370. This value is
within experimental error, the same as that previously determined
for catechol in benzene at 383 nm, ca. 1500 300 M-1 cm-1.20
The rate constants for H-abstraction obtained here can further
be compared to those obtained under similar experimental
conditions for well known free radical scavengers such as a-
tocopherol,.21,22 aminoleutins7 or melatonin,23 These values are
listed in Table 1 together with the rate constants for H-abstraction
from phenol and p-methoxyphenol.
Decay of the semiquinone radical
As part of our experiments we also monitored the fate of the
semiquinone radical over time. Fig. 5 shows the transient absorp-
tion spectra at long times following excitation. Note the drop and
increase in absorption at 370 nm and 400 nm, respectively. In
this case the experimental traces are best fitted by a second order
function. The transient spectra obtained at 0.812 ms after the laser
pulse matches that reported for aminoquinones formed following
the oxidation of their respective catecholamines (not shown).12,15
These aminoquinones are formed following disproportionation of
two semiquinone radicals,12,13,15,16,37 as exemplified in Scheme 1 for
adrenaline.
A disproportionation is supported in our case both by the ob-
served temporal evolution of the semiquinone radical absorbance,
fitted with a second order rate expression, and by the quadratic
power dependence for the absorbance measured at 400 nm, 1.7 ms
after the laser pulse (data not shown).27
Reaction with t-butoxyl radicals
Under our experimental conditions reactions involved solely the
phenol moiety and we did not observe hydrogen abstraction on
the CH2 position a to the amino group. This can be rationalized
on the basis that the lone pair of electrons in the nitrogen atom
is protonated. The resonance stabilization of the a-amino radical
by this lone pair of electrons will not be operational under this
condition,29 neither is the stabilization of the transition state
leading to this radical.
Quantitative predictions have been formulated for kinetic
solvent effects (KSE) that permit the extrapolation of the data for
hydrogen atom abstraction by a radical (for example t-butoxyl)
from a phenol in a given solvent, based on the known value
in a different media.40,42 These predictions are based on three
assumptions; each substrate hydrogen bonds to only one solvent
molecule; the equilibrium rate constant for this bonding is
independent of the surrounding media; and finally, due to steric
reasons, the hydrogen atom of the donor cannot be directly
abstracted by the acceptor, rather the acceptor has first to replace
the solvent molecule in the complex formed by the hydrogen
donor-solvent molecule.40,42
The disproportionation rate constant kdisp, may be obtained
from Equation 2:
kdisp
kobs
=
(2)
eSQ ¥ l
where eSQ is the molar absorptivity for the semiquinone radical,
(l) is the optical path length of the cell, kobs is the observed dispro-
portionation rate constant, determined by changes in transient
absorbance, and kdisp is the rate constant of disproportionation,
which accounts for the actual changes in the concentration of the
semiquinone radical (rather than changes in absorbance).
From the eSQ determined at 370 nm, and from the observed
decay second order rate constant kobs monitored at 370 nm, we
calculate a kdisp value of 35 0.8 ¥ 108 M-1s-1. The value reported
in the literature for dopa in buffer at pH 7.7 is 0.98 ¥ 108 M-1s-1.12
The three assumptions account for the difference observed in the
reactivity of phenol and p-methoxyphenol with t-butoxyl radicals
in methanol vs. benzene. Qualitatively, we would expect a similar
increase in the radical scavenging activity of adrenaline in going
from acetonitrile (where hydrogen bonding is strong) to benzene.
The low solubility of adrenaline in benzene however did not permit
us to test this hypothesis.
Discussion
Reaction with triplet benzophenone
The antioxidant effect of phenols has received considerable
attention, where a major emphasis has involved the free radical
scavenging reactivity of phenols.38–46 We have employed t-butoxyl
radicals and benzophenone in its excited triplet state to establish
the activity of adrenaline as a radical scavenger.
The kH value in acetonitrile for benzophenone is roughly an
order of magnitude larger than that for t-butoxyl radical. This
difference has been previously described with other phenols.20,22
Thus we observe in Table 1 that an order of magnitude difference
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in reactivity in acetonitrile also applies to a-tocopherol, phenol
and p-methoxyphenol, as well as melatonin, an indole derivative of
similar structure to aminoleutines, although lacking the dihydroxy
functionality of the latter. This is explained by the stabilization,
due to polar effects, of the transition state leading to the
photoreduction of benzophenone, which in this case may involve
charge transfer and offsets the strong hydrogen bonding of the
radical scavengers with acetonitrile.20,22 These polar effects are less
important in the case of hydrogen abstraction by t-butoxyl radical
and other radicals.40
Our results show that the consequence of quenching of the
benzophenone triplet state is only hydrogen abstraction. Under
the conditions employed the nitrogen atom in the catecholamine
is protonated (vide supra), and therefore electron transfer from
this species to benzophenone does not occur. As in the case
of the reaction with t-butoxyl radicals, no reaction to form a-
aminoradicals takes place in our media. This is due to protonation
of the nitrogen atom at the amine functional group.
We have been able to determine the molar absorptivity of
adrenaline semiquinone radical at 370 nm following its reaction
with benzophenone triplets, and from this value we have calculated
the second order rate constant for disproportionation. Our value
for this disproportionation is ca. 35 fold larger than that in water.
At the present time we cannot determine if this difference is due
to solvent effects, or whereas the accummulated errors with which
the values have been obtained also play a role.
An analysis based on the reactivity of these molecules with
t-butoxyl radicals presents a much clearer picture; thus from the
values measured for dopaleutine we establish that its reactivity is as
high as that of a-tocopherol, and ca. 5 times higher than that of the
catecholamine (Table 1). The low reactivity of melatonin, an indole
analog of dopaleutine that lacks the hydroxyl groups, further
illustrates that the radical scavenging reactivity of dopaluetine
relies on its hydroxyl moiety.
Conclusions
We report the reactivity of the catecholamine adrenaline towards
t-butoxyl radicals and benzophenone triplets. Adrenaline is a
reasonably good hydrogen donor, however we predict that the
reactivity of the products of its oxidation will exhibit an enhanced
radical scavenging activity. This in view of the good overlap
existing between the lone pair of electrons in the nitrogen atom of
the newly formed heterocyclic ring, and the hydroxy group in the
benzene moiety. This overlap (and the heterocycle) is nonexistent
in adrenaline and the other catecholamines, previous to their
oxidation. In the presence of large free radical concentrations we
believe that the oxidation of adrenaline into melanin will proceed
towards complete polymerization following the steps shown in
Fig. 1, where each new hydroxybenzene species will have enhanced
antioxidant power compared to its immediate precursor. This
enhanced reactivity would ensure the complete elimination of
undesired intermediates in adrenaline oxidation, following radical
mediated lesions.
Free radical scavenging activity, a comparison
We consider it worth analyzing at this time subsequent in-
termediates formed in the oxidation of adrenaline and other
catecholamines. In this sense, both leucoadrenochrome and
aminoleutin pose very interesting structures in terms of radical
scavenging potential.
Acknowledgements
This work was generously supported by the Natural Sciences and
Engineering Research Council of Canada and by the Canadian
Foundation for Innovation. J.C.S. is grateful to the Government
of Ontario for support and to McGill University for its hospitality
during the sabbatical leave when this work was completed. G.C. is
additionally thankful to Le Fonds Que´be´cois de la Recherche sur
la Nature et les Technologies and McGill University for funding.
The rate constants for hydrogen abstraction from phenols
depend on the strength of the O–H bond, i.e., on the O–H
bond dissociation energy (BDE).46 Electron donating groups
substituted ortho or para to the reactive hydroxyl group stabilize
the aryloxyl radical formed, and also the transition state leading
to its formation.45 This stabilization accounts for the higher
reactivity of adrenaline and p-methoxyphenol in comparison
to that of phenol which lacks an electron donating group. In
the case of a-tocopherol, a 6 member heterocyclic ring reduces
the dihedral angle existing between the lone pair of the p-
oxygen atom in the heterocyclic ring and the hydroxyl group,
this results in its enhanced antioxidant activity.44 A similar rigid
structure with an electron donating N atom located in position
para to a hydroxyl group can be observed both in the case of
adrenoleutine (7) and leucoadrenochrome (4) (see Scheme 1), we
may therefore anticipate that these species will be more reactive
radical scavengers than their catecholamine precursors.39
The reactivity of aminoleutine as a hydrogen donor has been re-
ported with quenching experiments done with benzophenone and
fluorazophore-P.7 From the results obtained with benzophenone
we observe that aminoleutine is about as reactive as a-tocopherol
in acetonitrile, and ca. 6.5 times more reactive than adrenaline
(Table 1). However care should be taken in analyzing the reactivity
of these molecules with benzophenone, given that they are affected
by charge transfer effects.23
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