Nucleophilic reactivity of a copper(II)-superoxide complex

Article abstract of DOI:10.1002/anie.201311152

Metal-bound superoxide intermediates are often implicated as electrophilic oxidants in dioxygen-activating metalloenzymes. In the nonheme iron α-ketoglutarate dependent oxygenases and pterin-dependent hydroxylases, however, Fe^III-superoxide intermediates are postulated to react by nucleophilic attack on electrophilic carbon atoms. By reacting a Cu ^II-superoxide complex (1) with acyl chloride substrates, we have found that a metal-superoxide complex can be a very reactive nucleophile. Furthermore, 1 was found to be an efficient nucleophilic deformylating reagent, capable of Baeyer-Villiger oxidation of a number of aldehyde substrates. The observed nucleophilic chemistry represents a new domain for metal-superoxide reactivity. Our observations provide support for the postulated role of metal-superoxide intermediates in nonheme iron α-ketoglutarate dependent and pterin-dependent enzymes. Nucleophilic superoxide: A copper(II)-superoxide complex has been found to be a highly reactive nucleophile. The complex reacts readily with certain electrophiles and is capable of the nucleophilic deformylation of electron-rich aldehydes (Baeyer-Villiger oxidation). These observations provide experimental support for the postulated nucleophilic reactivity of metal-superoxide intermediates in the catalytic cycles of certain nonheme iron enzymes.

Full text of DOI:10.1002/anie.201311152

Angewandte
Chemie
DOI: 10.1002/anie.201311152
Reactive Intermediates
Nucleophilic Reactivity of a Copper(II)–Superoxide Complex**
Paolo Pirovano, Adriana M. Magherusan, Ciara McGlynn, Andrew Ure, Amy Lynes, and
Aidan R. McDonald*
[
7]
Abstract: Metal-bound superoxide intermediates are often
implicated as electrophilic oxidants in dioxygen-activating
metalloenzymes. In the nonheme iron a-ketoglutarate depen-
dent oxygenases and pterin-dependent hydroxylases, however,
atom of a-KG by nucleophilic attack. Likewise, in the
III
pterin-dependent hydroxylases, a nucleophilic Fe –super-
oxide is proposed to attack an electrophilic carbon atom of
pterin. An Fe –superoxide intermediate in a Rieske dioxy-
genase mutant was recently trapped and spectroscopically
[8]
III
III
Fe –superoxide intermediates are postulated to react by
[
9]
nucleophilic attack on electrophilic carbon atoms. By reacting
characterized, however, rather than display electrophilic
HAA or nucleophilic reactivity, this species decayed through
electron transfer. Overall, strong experimental support for
the role of enzymatic metal–superoxide intermediates that act
as electrophilic oxidants exists, whereas little to no support for
their postulated roles as nucleophiles has been reported to
date.
A number of mononuclear Cu –superoxide model com-
plexes have been trapped and characterized, allowing an
assessment of the reactivity of the metal-bound superoxide
II
a Cu –superoxide complex (1) with acyl chloride substrates,
we have found that a metal–superoxide complex can be a very
reactive nucleophile. Furthermore, 1 was found to be an
efficient nucleophilic deformylating reagent, capable of
Baeyer–Villiger oxidation of a number of aldehyde substrates.
The observed nucleophilic chemistry represents a new domain
for metal–superoxide reactivity. Our observations provide
support for the postulated role of metal–superoxide intermedi-
ates in nonheme iron a-ketoglutarate dependent and pterin-
dependent enzymes.
II
[1c,10]
ligand.
These complexes displayed the ability to effect
a variety of transformations (HAA, electron transfer, O-atom
transfer) that mimic the electrophilic chemistry of copper
M
etal–superoxide species have been implicated as reactive
III
intermediates in the catalytic cycles of a variety of Cu- and Fe-
hydroxylases. Mononuclear Fe –superoxide complexes
[
1]
II
containing metalloenzymes.
enzymes, dopamine-b-hydroxylase (DbH), and peptidylgly-
cine a-hydroxylating monooxygenase (PHM), a Cu –super-
oxide moiety is postulated to act as an electrophilic hydrogen-
atom abstraction (HAA) reagent. X-ray diffraction charac-
terization of a Cu –superoxide species in PHM provided
structural support for this hypothesis. In the nonheme iron
enzyme superfamily, Fe –superoxide intermediates have
In the Cu–hydroxylase
remain elusive, while a single example of a dinuclear Fe -
III
[11]
(OH) -Fe –superoxide complex exists. This complex was
2
II
capable of acting as an electrophile in the oxidation of
III
phenols. Evidence for the involvement of Fe –superoxide
[2]
II
intermediates in the activation of dioxygen by Fe model
II
III
complexes exists, in one case the postulated Fe –superoxide
[3]
[12]
species acted as an electrophilic HAA reagent, in the other
III
[13]
as a presumed nucleophile.
Valentine and Sawyer also
been ascribed roles as both electrophilic and nucleophilic
extensively investigated the chemistry of superoxide and
[
1a,4]
[14]
reactants.
For example, in isopenicillin N synthase (IPNS),
metals.
In general, metal–superoxide model complexes
2
-hydroxyethylphosphonate dioxygenase (HEPD), 2-
display electrophilic reactivity. To the best of our knowledge,
no direct evidence for a metal-bound superoxide that reacts as
a nucleophile has been described to date. As such, no
experimental verification of the postulated nucleophilic
hydroxypropylphosphonic acid epoxidase (HppE), 1-amino-
cyclopropane-1-carboxylic acid oxidase (ACCO), an Fe –
superoxide unit is proposed to perform HAA during O
activation. In ring-cleaving dioxygenases, the Fe–superoxide
III
2
[5]
III
reactivity of Fe –superoxide species in the a-KG and
moiety is believed to undergo radical CÀO bond formation
pterin-dependent nonheme iron enzymes exists. Herein we
describe our investigations into the nucleophilic reactivity of
a metal–superoxide model complex toward electrophilic
carbonyl groups.
[6]
with metal-bound catecholate. In contrast, in the a-keto-
III
glutarate (a-KG) dependent oxygenases, an Fe –superoxide
intermediate is postulated to react with the a-keto carbon
Of the metal–superoxide complexes we tested, only
Tolmanꢀs [N,N’-bis(2,6-diisoproylphenyl)-2,6-pyridinedicar-
[*] P. Pirovano, A. M. Magherusan, C. McGlynn, A. Ure, A. Lynes,
Dr. A. R. McDonald
School of Chemistry and CRANN/AMBER Nanoscience Institute,
Trinity College Dublin
College Green, Dublin 2 (Ireland)
E-mail: aidan.mcdonald@tcd.ie
Homepage: http://www.tcd.ie/Chemistry/staff/people/mcdonald/
[**] This publication has emanated from research supported in part by
the European Union (Marie Curie Career Integration Grant, FP7–
333948) and a research grant from Science Foundation Ireland (SFI)
under Grant Number SFI/12/RC/2278.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311152.
Scheme 1. Complex 1 and reactions that were investigated.
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[
10h]
R
H
boxamido]-superoxo-copper(II) complex
(1, Scheme 1)
plot of the log( k / k ) versus the para-substituent (s ) would
2 2 p
was suitably reactive. Indeed, Tolman and co-workers sur-
mised that 1 was likely a good nucleophile, given that it was
readily protonated and displayed poor HAA reactivity. The
nucleophilic character of 1 was first tested in its reaction
toward acyl chloride substrates, electrophiles that commonly
be linear and result in a positive 1 value, providing proof of
a nucleophilic attack by 1 on p-R-PhC(O)Cl. Indeed, Nam
and co-workers utilized this approach to demonstrate the
strong nucleophilic character that certain metal–peroxide
[16c–f]
complexes possess.
However, the Hammett plot gave
[
10a,15]
react with metal–peroxide complexes.
Complex 1 was
a 1 value close to 0 (Figure S7, all substrates displayed
reacted with benzoyl chloride (PhC(O)Cl, 10 equiv) at À808C
in THF/DMF (3:1). An immediate reaction occurred, result-
ing in the disappearance of the characteristic electronic
comparable k values). These observations provide a strong
2
indication that the rate-determining step in the reaction
between 1 and acyl chlorides is not the nucleophilic attack of
the superoxide ligand on the electrophilic carbonyl group.
For a better understanding of the nucleophilic reactivity of
absorption feature (l = 627 nm) assigned to 1 within 40 s
max
1
(
Figure 1). H NMR and GCMS analysis of the products
1, we investigated its reactivity in aldehyde deformylation
reactions. Previous reports demonstrated that metal-bound
[
15e,16]
peroxide ligands are proficient deformylating reagents.
These studies provided an understanding of the nucleophilic
properties of a variety of metal–peroxide complexes. Com-
plex 1 reacted with 100 equivalents of 2-phenylpropionalde-
hyde (PPA) at À808C in THF/DMF (3:1; Figure S8). The
1
reaction was complete within 400 s, and GC-MS and H NMR
analysis of the reaction mixture showed the formation of
1
8
acetophenone. When 1 was prepared with K O and reacted
2
with PPA, the resulting acetophenone displayed near-quanti-
1
8
tative O incorporation. Complex 1 also reacted with
00 equivalents of cyclohexanecarboxaldehyde (CCA) at
1
À808C in THF/DMF (3:1; Figure S11). The reaction was
1
complete within 20 s, and GC-MS and H NMR analysis of
the reaction mixture showed the formation of cyclohexanone.
The k values determined for the reactions between 1 and
2
À1 À1
À1 À1
PPA and CCA at À808C were 0.062m
s
and 1.43m s
Figure 1. UV/Vis spectral changes observed in the reaction between
(1.5 mm, solid black trace) and PhC(O)Cl (15 mm) in THF/DMF
respectively (Figures S9 and S12). Further insight into the
reaction between 1 and PPA/CCA was obtained by determin-
ing the activation enthalpy and entropy of the reactions. The
1
II
(
3:1) at À808C to give [Cu X(L)] (gray trace). Inset: Plot of the
pseudo-first order rate constant (k ) versus [PhC(O)Cl].
obs
°
À1
À1
DH values (PPA = 40 kJmol ; CCA = 35 kJmol ) were
comparable to those determined for the reaction between
indicated the formation of benzoic acid. A pseudo
first-order rate constant (kobs) for the reaction was
calculated by plotting the change in absorbance
intensity of the lmax = 627 nm feature of 1 against
time and fitting the resulting curve (Figure S1 in the
Supporting Information). The second-order rate
constant (k ) was determined by plotting k values
Table 1: Rate constants and activation enthalpy and entropy values for the
deformylation of PPA by metal–dioxygen complexes.
[a]
k2 [mÀ1 À1
°
À1
°
À1
À1
s
]
DH [kJmol
]
DS [JK mol
(T [8C])
]
(T [8C])
(T [8C])
2
obs
[
b]
determined under a series of substrate concentra-
tions followed by calculating the slope of the
1
0.062
40
À63
(
À80)
(À90 to À60)
(À90 to À60)
resulting linear plot (Figure 1, inset). The k value
2
III
+[c,d]
[
Fe (h -OO)(TMC)]
0.041
13
À24
2
determined for the reaction between
1 and
(15)
(0 to +20)
(0 to +20)
À1 À1
PhC(O)Cl (4.49m s ) was relatively high com-
pared to k2 values determined for the reaction
between aldehyde electrophiles and nucleophilic
III
2+[e]
[Fe (h -OOH)(TMC)]
0.13
(À40)
1
[
15e,16]
peroxide complexes (Table 1).
This observation
III
+[f]
[
[
Co (h -OO)(14-TMC)]
0.058
55
À90
is not unexpected as the acyl chloride is anticipated
to be more electrophilic than an aldehyde. Complex
2
(0)
(À10 to +20)
(À10 to +20)
1
is thus a capable nucleophile that reacts rapidly
III
+[f]
Co (h -OO)(13-TMC)]
0.015
25)
62
À77
2
with an electrophilic acyl chloride substrate at low
temperatures.
(
(+5 to +35)
(+5 to +35)
III
+[g]
In the reaction between 1 and acyl chlorides, we [Ni (h
-OO)(TMC)]
0.04
25)
2
(
determined k values for a series of para-substituted
2
benzoyl chloride substrates (p-R-PhC(O)Cl, R =
[a] PPA=2-phenylpropionaldehyde. [b] This work. [c] TMC=tetramethylcyclam.
tBu, H, F, Cl, NO ). We hypothesized that a Hammett [d] Ref. [15e]. [e] Ref. [16g]. [f] Ref. [16c]. [g] Ref. [16d].
2
2
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III
III
À1 À1
PPA/CCA and Fe –peroxide and Co –peroxide complexes
k2 = 0.41m s , Figures S13 and S14). In summary, the rates
of aldehyde deformylation by 1 were controlled by the degree
of substitution of the a-C atom, but not by the availability of
an a-H atom in the aldehyde substrate.
°
(
Tables 1 and S1). The entropy of activation values (DS ,
À1
À1
À1
À1
PPA = À63 JK mol ; CCA = À80 JK mol ) were large
and negative, indicative of a bimolecular reaction (see
Figures S10 and S13). The obtained kinetic and thermody-
namic parameters clearly demonstrate that 1 is an effective
nucleophilic deformylating reagent that displays reactivity
properties similar to those reported for nucleophilic defor-
mylation reactions performed by metal–peroxide complexes.
Interestingly, a comparison of the k values determined
for the reaction between metal–peroxide complexes and PPA/
CCA with those established for 1 suggests that 1 is a very
The degree of a-C substitution controls how electron-rich
the a-C atom is. All of the more electron-rich a-C substrates,
PPA, CCA, and TMA, were reactive toward 1. All of the
electron-poor aldehyde substrates (p-R-PhC(O)H, EtA,
PrA) showed poor reactivity. In contrast, electron-poor p-R-
PhC(O)Cl substrates were very reactive toward 1. We put
these contrasting observations down to one of the following:
different reaction mechanisms exist for acyl chloride and
aldehyde substrates; or the rate-determining step is not
influenced by the electrophilicity of the carbonyl-C atom; or
both.
2
reactive oxidant (Tables 1 and S1). For PPA, at À808C
À1 À1
1
displayed a k value (0.062m s ) comparable to those
2
III
III
III
determined for Fe –peroxide, Ni –peroxide, and Co –
peroxide complexes at significantly higher temperatures
We propose mechanisms for the reactions between 1 and
acyl chloride or aldehyde substrates (Schemes 2 and S1)
À1 À1
(
between À40 and + 258C, k = 0.015–0.13m s , Table 1).
2
The only model complex that displayed higher deformylation
based on mechanisms proposed for metal–peroxide Baeyer–
III
À
[20]
rates than 1 is [Fe (h -OO )(TMCS=2-mercaptoethyl)-
Villiger oxidations.
We determined that the superoxide
1
4
,8,11-trimethyl-1,4,8,11-tetraazacyclotetradecane),
which
ligand in 1 does not dissociate in order to perform the
contains a peroxide dianion ligand that reacted with PPA at
À908C at such high rates that accurate kinetic analysis was
[
17]
not possible. We assume the two anionic nitrogen donors of
the dicarboxamide ligand in 1 render the superoxide ligand
very basic/nucleophilic. Complex 1 is thus highly reactive
compared to its metal–peroxide counterparts.
Previous studies demonstrated that para-substituted benz-
aldehydes (p-R-PhC(O)H) can provide mechanistic insights
[
16c–f]
III
into nucleophilic deformylation reactivity.
For Mn –
III
III
peroxide, Fe –peroxide, and Co –peroxide complexes, a plot
of log( k / k ) versus s was linear with a positive 1 value.
R
H
2
2
p
This observation indicated that the peroxide ligand in these
complexes was reacting as a nucleophile. With this in mind,
we investigated the reactivity of 1 toward p-R-PhC(O)H (R =
H, NMe , OMe, Me, Cl, NO ). However, no reaction was
Scheme 2. Mechanisms for the initial steps in the reaction between
1 and a) PhC(O)Cl and b) PPA/CCA/TMA.
2
2
observed upon exposure of 1 to up to 100 equivalents of p-R-
[18]
PhC(O)H at À808C in THF/DMF (3:1). p-R-PhC(O)Hꢀs
would be considered more electrophilic than PPA or CCA,
therefore these observations were unexpected. Metal–perox-
ide complexes that were previously found to be reactive
toward PPA or CCA showed higher reaction rates toward p-
[
21]
oxidation of aldehyde substrates (Figure S16). Importantly,
II
we assumed electron transfer from the Cu center to the
superoxide ligand upon attack on the electrophilic carbonyl
group, giving a Cu –peroxide intermediate. As in Baeyer–
III
[16c–f]
R-PhC(O)Hꢀs.
Villiger oxidations, we assumed the initial nucleophilic attack
of the superoxide ligand is reversible. We tentatively suggest
that the experimental evidence supports this, because the
Hammett plot (Figure S7) indicated that the nucleophilic
attack was not rate-determining in the decay of 1. For the acyl
chloride reaction (Scheme 2a), we believe the superoxide
By comparing the aldehyde substrates that were reactive
toward 1 (PPA/CCA) and those that were poorly reactive (p-
R-PhC(O)Hꢀs), we postulated that the a-H or a-C atoms in
the aldehyde substrates play a critical role. We investigated
the role of the a-H atom by determining the kobs value for the
reaction between 1 and a-deutero-cyclohexanecarboxalde-
III
ligand simply displaces the chloride, giving a Cu –peracetate
[
19]
hyde (a-D-CCA). No difference in rate constants for a-H-
CCA and a-D-CCAwas observed. This would suggest that no
acid–base or HAA process involving the a-H atom occurred
in the deformylation reaction. We then reacted 1 with
aldehyde substrates with varying degrees of a-C substitution.
No reaction was observed upon addition of 100 equivalents of
acetaldehyde (EtA, primary a-C) or propanal (PrA, secon-
dary a-C) to 1 at À808C in THF/DMF (3:1). As discussed
above, PPA/CCA (tertiary a-C) were reactive toward 1.
Finally, 1 reacted with 100 equivalents of trimethylacetalde-
hyde (TMA, quaternary a-C) at À808C in THF/DMF (3:1;
complex, rather than undergoing a Criegee-type rearrange-
ment, because chloride is a good leaving group. The
peracetate complex likely decays through OÀO bond scission
to give benzoic acid. Despite the fact that the acyl chloride
substrates are likely quite electrophilic, we believe the driving
force in their reaction with 1 is not a nucleophilic attack, but
rather the readiness of the chloride to act as a leaving group.
In contrast, in the reaction between 1 and aldehyde
substrates, we believe Criegee rearrangement must occur in
order to give the ketone products (Schemes 2b and S1). The
Criegee rearrangement, in which the a-C atom attacks the
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.
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Communications
distal O atom resulting in OÀO bond scission, is presumably
irreversible. We believe the Criegee rearrangement step
determines the substrate selectivity observed in deformyla-
tion reactions performed by 1. Our observations mirror trends
observed in Baeyer–Villiger oxidation reactions where the
migration of substituents during rearrangement is usually
determined according to the trend: tertiary alkyl > cyclohex-
yl > secondary alkyl > primary alkyl. The migrating group
is formally an anion, however, a transient cation forms during
the rate-determining migration step. We propose that elec-
tron-rich a-C aldehyde substrates will readily undergo
Criegee rearrangement because the transient cation is
stabilized. In contrast, electron-poor a-C substrates will not
undergo Criegee rearrangement, because the transient cation
will not be stabilized. In conclusion, aldehyde substrates with
electron-rich a-C atoms are susceptible to deformylation by
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strates giving carboxylic acids. Complex 1 was also found to
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toward understanding the postulated Cu –peroxide species
(
Scheme 2) and their decay products.
2
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Received: December 23, 2013
Revised: February 17, 2013
Published online: && &&, &&&&
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Keywords: bioinorganic chemistry · dioxygen activation ·
.
nucleophilic reactivity · reaction mechanisms ·
superoxide complexes
1
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
Angewandte
Communications
Communications
Reactive Intermediates
P. Pirovano, A. M. Magherusan,
C. McGlynn, A. Ure, A. Lynes,
A. R. McDonald*
&&&& — &&&&
Nucleophilic Reactivity of a Copper(II)–
Superoxide Complex
Nucleophilic superoxide: A copper(II)-
superoxide complex has been found to be
a highly reactive nucleophile. The com-
plex reacts readily with certain electro-
philes and is capable of the nucleophilic
deformylation of electron-rich aldehydes
(Baeyer–Villiger oxidation). These obser-
vations provide experimental support for
the postulated nucleophilic reactivity of
metal-superoxide intermediates in the
catalytic cycles of certain nonheme iron
enzymes.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!