Conversion of Aldehyde to Alkane by a Peroxoiron(III) Complex: A Functional Model for the Cyanobacterial Aldehyde-Deformylating Oxygenase

Article abstract of DOI:10.1021/jacs.5b01053

Cyanobacterial aldehyde-deformylating oxygenase (cADO) converts long-chain fatty aldehydes to alkanes via a proposed diferric-peroxo intermediate that carries out the oxidative deformylation of the substrate. Herein, we report that the synthetic iron(III)-peroxo complex [Fe^III(η²-O₂)(TMC)]⁺ (TMC = tetramethylcyclam) causes a similar transformation in the presence of a suitable H atom donor, thus serving as a functional model for cADO. Mechanistic studies suggest that the H atom donor can intercept the incipient alkyl radical formed in the oxidative deformylation step in competition with the oxygen rebound step typically used by most oxygenases for forming C-O bonds. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b01053

Article
pubs.acs.org/JACS
Conversion of Aldehyde to Alkane by a Peroxoiron(III) Complex: A
Functional Model for the Cyanobacterial Aldehyde-Deformylating
Oxygenase
Alireza Shokri and Lawrence Que, Jr.*
Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota, Minneapolis, Minnesota 55455, United
States
S
* Supporting Information
ABSTRACT: Cyanobacterial aldehyde-deformylating oxygenase (cADO) con-
verts long-chain fatty aldehydes to alkanes via a proposed diferric-peroxo
intermediate that carries out the oxidative deformylation of the substrate. Herein,
we report that the synthetic iron(III)-peroxo complex [FeIII(η2-O2)(TMC)]+
(TMC = tetramethylcyclam) causes a similar transformation in the presence of a
suitable H atom donor, thus serving as a functional model for cADO. Mechanistic
studies suggest that the H atom donor can intercept the incipient alkyl radical
formed in the oxidative deformylation step in competition with the oxygen
rebound step typically used by most oxygenases for forming C−O bonds.
INTRODUCTION
■
The biosynthesis of diesel-chain alkanes and alkenes has
attracted interest in recent years1−4 because of their potential to
serve as a drop-in replacement for fossil fuels.5 Although it is
quite challenging for a cell to make unfunctionalized paraffins,6
nature synthesizes them by employing a wide variety of
biochemical reactions such as dehydrations, double bond
reductions, and decarboxylations. Of particular interest is the
conversion of long-chain fatty aldehydes to corresponding
alkanes that is catalyzed by cyanobacterial aldehyde-deformylat-
ing oxygenase (cADO).7,8 From a structural perspective, the
cADO enzyme belongs to the family of ferritin-like nonheme
diiron-carboxylate enzymes that include methane monooxyge-
nase (MMO), class I ribonucleotide reductase (RNR), and
stearoyl-acyl carrier protein Δ9-desaturase (Δ9D), all of which
share a common Fe2(His)2(O2CR)4 active site.9,10 At first
glance, it seems odd for the C−H-bond-forming cADO to be
Figure 1. (A) cADO-catalyzed reaction. (B) Proposed mechanism,
part of a family of O2-activating enzymes that in many examples
cleave C−H bonds, but it has been shown to require O2 to
carry out the oxidative deformylation of substrate to form
alkane and formate (Figure 1A). In fact, isotope labeling
studies11−14 have shown that the formate product derives an O
atom from O2 and retains the aldehyde C−H bond and that the
terminal methyl group of the alkane product incorporates an H
atom from solvent. These observations have led to the
proposed mechanism shown in Figure 1B,15 in which O2
binds initially to the reduced diiron center to form an adduct
best described as a peroxodiiron(III) species designated as B.
Intermediate B carries out a nucleophilic attack at the aldehyde
carbon of the substrate to generate peroxyhemiacetal species C.
Decay of C by O−O bond homolysis leads to C−C bond
scission to form formate and the corresponding Cn−1 alkyl
radical, which in turn is converted to the alkane product by
proton-coupled electron transfer from an iron-bound water.
adapted from ref 15.
Support for the formation of a substrate-derived radical has
been obtained from a substrate analog that has a cyclopropyl
moiety adjacent to the putative carbon radical site and affords a
ring-opened product.16
To date, B is the only intermediate in the cADO mechanism
that has been trapped.17 Its spectroscopic properties resemble
those of peroxo intermediates of AurF and CmlI, diiron
enzymes that catalyze the oxidation of aminoaryl substrates to
nitroaryl products.18,19 These three peroxo intermediates are
distinct from corresponding intermediates of MMO, RNR, and
Received: January 30, 2015
© XXXX American Chemical Society
A
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Δ9D, which exhibit broad visible absorption maxima near 700
nm that is associated with a (μ-1,2-peroxo)diiron(III)
species.20−22 The three more recently characterized intermedi-
ates have significantly more blue-shifted visible features near
500 nm that suggest a different peroxo binding mode.17−19
Recently reported resonance Raman data on the CmlI-peroxo
intermediate reveal a ν(O−O) at much lower energy than that
found for peroxo intermediates of other nonheme diiron
enzymes, for which a novel (μ−η1:η2-peroxo)diiron(III) unit
has been proposed.19 The mechanism proposed for cADO15
suggests the possibility of a similar binding mode for the bound
O2 in the cADO-peroxo intermediate to endow it with
sufficient nucleophilic character to attack the substrate
aldehyde.
Peroxoiron(III) intermediates involved in biological trans-
formations can have ambiphilic character.23−27 For example,
the cytochromes P450 that are involved in steroid biosynthesis
generally carry out C−H bond hydroxylations via an electro-
philic oxidant called compound I, derived from the activation of
a peroxoiron(III) intermediate. In some reactions, however, this
intermediate is proposed to be involved in the nucleophilic
attack of substrate carbonyl groups resulting in C−C bond
cleavage,24,25 namely progesterone 17α-hydroxylase-17,20-lyase
in the cleavage of the C17 side chain of progesterone to form
androstenedione and aromatase in the conversion of testoster-
one to estradiol. By analogy to the latter cytochromes P450, the
cADO-peroxo intermediate is proposed to carry out a
nucleophilic attack on the fatty aldehyde carbonyl group to
initiate its oxidative deformylation and afford the corresponding
cADO and has allowed us to gain mechanistic insights into this
novel transformation.
EXPERIMENTAL SECTION
■
General. All reagents and solvents were purchased from Sigma-
Aldrich Company and were used as received except tributyltin
deuteride, which was obtained from Alfa Aesar Company. THF was
degassed and stored inside of the glovebox to keep the oxygen away
from it. All solution preparations were carried out under N2
atmosphere in a glovebox. The FeII(TMC)(OTf)2 complex was
prepared as previously reported.45 Reactions were carried out in
septum-sealed 1 dram vials. For product analysis, the reaction mixture
was passed through a short plug of silica gel prior to the GC or GC-
MS analysis to remove the iron complex. Products were identified by
comparing with authentic samples, and yields were determined by
comparison against standard curves prepared with authentic samples
and using dodecane as an internal standard.
Instrumentation. GC-MS spectra were obtained with an HP 6890
GC (HP-5 MS column, 30 m) with an Agilent 5973 mass analyzer, an
Agilent Technologies 7890AGC system, and 5975C VL MSD.
Ammonia was used as the ionization gas for chemical ionization
analysis. A PerkinElmer AutoSystem gas chromatograph (AT-1701
column, 30 m) with a flame ionization detector was used to record gas
chromatograms. UV−vis spectra were recorded on a Hewlett-Packard
(Agilent) 8453 diode-array spectrophotometer (190−1100 nm range)
using a Unisoku cryostat cooled by liquid nitrogen. High-resolution
mass spectra were obtained via an electrospray ionization−time-of-
flight mass spectrometer. 31P NMR spectra were recorded on a VI-300
MHz instrument.
RESULTS AND DISCUSSION
■
Reactivity of PPA with [FeIII(TMC)(η2-O2)]+. Complex 1
was generated in situ using the reported procedure by treating
1.0 mM FeII(TMC)(OTf)2 with 2.5 equiv of Et3N followed by
5.0 equiv of H2O2 at −10 °C under N2,31 but with THF as the
solvent instead of the more commonly used acetonitrile
(MeCN) or trifluoroethanol (TFE) solvents. Because of the
solvent change, the λmax of 1 was red-shifted to 880 nm (Figure
2). This solution was quite stable at −10 °C, but the 880 nm
Cn−1 alkane as the final product. This outcome is different from
that observed for the heme enzymes, where the substrate has
undergone partial oxidation to form a CC or a CO bond,
rather than reduction to the alkane produced by cADO.
There is no biomimetic example to date of the reaction
catalyzed by cADO. Our goal has been to test the viability of
the key mechanistic step in the proposed cADO mechanism
that generates alkane, where the incipient alkyl radical produced
in the oxidative deformylation step is reduced to the alkane
product. So far, no synthetic peroxodiiron(III) complex has
been identified to have the (μ−η1:η2-peroxo) binding mode
proposed for cADO intermediate B in Figure 1.28,29 We thus
initiated our cADO modeling effort with the well-characterized
[FeIII(TMC)(η2-O2)]+ complex (1) (TMC = tetramethylcy-
clam; Figure 3),30−32 which is one of several examples of
synthetic mononuclear nonheme ferric complexes with a side-
on-bound peroxo ligand.33−42 Some [MIII(η2-O2)]+ complexes
have been shown to convert 2-phenylpropionaldehyde (PPA)
to acetophenone,31,43,44 but alkane formation has not been
reported. Following precedents in heme chemistry, oxidative
deformylation of an aldehyde by 1 may proceed by initial
formation of a peroxohemiacetal adduct analogous to that
shown for C in Figure 1, followed by O−O bond homolysis to
generate formate, an alkyl radical, and an FeIV(O) moiety; the
latter two would then combine in a rebound step to form an
alcohol product. With this mechanistic hypothesis in mind, we
have sought to define reaction conditions under which the
incipient alkyl radical may be intercepted to afford an alkane
product before undergoing rebound. In this report we
demonstrate that the reaction of aldehydes with 1 in THF
solvent in the presence of suitable H atom donors results in the
conversion of aldehydes into corresponding (n − 1) alkanes.
This system thus represents the first functional model for
Figure 2. UV−vis spectrum of 1 obtained upon addition of 5.0 equiv
of H2O2 to a solution containing [Fe(TMC)]2+ (1.0 mM) and Et3N
(2.5 equiv) at −10 °C in THF. Inset: exponential decay of 1 upon
addition of 100 equiv of PPA.
chromophore decayed exponentially upon treatment with PPA,
resulting in the concomitant formation of 0.6 equiv of
acetophenone. This amount of product was obtained with as
little as 3.0 equiv of H2O2 and did not increase with more equiv
of H2O2. The acetophenone likely derives from the 2e−
oxidation of an initially formed α-phenethanol product
B
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generated from the combination of a nascent α-phenethyl
radical (Bn·) with the FeIV(O) moiety generated in the course
of the reaction.
We then sought to identify conditions under which this
putative radical may be intercepted and reduced to the
corresponding alkane and found that ethylbenzene formed in
addition to acetophenone upon addition of n-Bu3SnH (125
equiv, BDE(Sn−H) = 76 2 kcal mol−1)46,47 to the reaction
mixture (Figure S1). This product was identified by GC-MS
analysis of the reaction mixture, which revealed a new peak in
the GC trace that coeluted with ethylbenzene and gave rise to a
protonated molecular ion at m/z = 107.2 (Figure S2A). A
control experiment consisting of a mixture of n-Bu3SnH and
PPA did not generate any ethylbenzene. When the reaction was
carried out with n-Bu3SnD (96% D), deuterium was
incorporated into the ethylbenzene product as indicated by
GC-MS analysis (Figure S2B). The ethylbenzene yield
decreased by 40%, and the mass spectral analysis showed a
1:3 ratio of the all-protio and the monodeuterio products.
Analysis of these results suggests an H/D KIE of 7 for the
cleavage of the Sn−H/D bond by the incipient Bn· radical.
Interestingly, the formation of ethylbenzene was observed
only with THF as solvent, and the use of other solvents such as
TFE, 1-butanol, acetone, or acetonitrile did not result in PhEt
formation and formed acetophenone as sole product. Thus,
only in THF was the lifetime of the incipient alkyl radical
sufficiently lengthened to allow its interception by n-Bu3SnH.
To the best of our knowledge, this is the first report of a
peroxo-iron(III) complex that can convert RCHO to R−H
(Figure 3) as proposed for cADO (Figure 1).
Figure 4. Product yields upon addition of n-Bu3SnH (black) or Ph3P
(blue) to the reaction of 1 (1.0 mM) and PPA (20 mM) in THF at
−10 °C. Circles represent the amount of acetophenone formed,
squares represent the amount of ethylbenzene; and triangles represent
the amount of Ph3PO. See Table 1 for a complete list of product
yields.
ethylbenzene. As found in the n-Bu3SnH trapping experiments,
the PhEt yield increased as the PhNHNHPh concentration
increased (Table 1). A control experiment showed that this
reagent also reacted quickly with 1 in the absence of the
aldehyde, which may account for the lower alkane yields in
these reactions relative to those obtained by n-Bu3SnH
interception.
Nam has demonstrated that the oxygen atom incorporated
into the acetophenone product of PPA oxidation derives from
the peroxo group of 1 using 18O-labeling experiments.31 To
ascertain that the incipient [FeIV(O)(TMC)]2+ species was the
likely O atom source, we employed Ph3P as a trapping
nucleophile and observed the formation of Ph3PO at the
expense of acetophenone. No Ph3PO was formed in the
absence of the aldehyde. As shown in Figure 4, the [Ph3PO]/
[acetophenone] ratio increased with increasing [Ph3P] and
leveled off above 20 mM. As with n-Bu3SnH, the observed
saturation is consistent with a solvent cage effect48−51 because
increasing [Ph3P] should increase the ratio until all the free
(escaped) FeIV(O) complex has been scavenged. Similar
behavior was observed by Groves and Su for the decay of the
adduct between metmyoglobin and peroxynitrite, which forms
a [FeIV(O)porphyrin/NO2] pair upon rate-determining O−O
bond homolysis that can undergo either NO2 rebound to form
NO3 or NO2 escape and trapping by a nearby tyrosine
residue.53,54 Our results thus indicate that Ph3P intercepts the
incipient FeIV(O) complex generated during the deformylation
reaction.
Figure 3. Reaction of [FeIII(TMC)(η2-O2)]+ (1) with PPA (2) in the
presence of n-Bu3SnH.
The effect of n-Bu3SnH concentration on the reaction was
explored. The [ethylbenzene]/[acetophenone] ratio increased
with n-Bu3SnH concentration and was maximized above 50
mM (Figure 4A), strongly suggesting that there is a
competition between n-Bu3SnH and the FeIV(O) intermediate
for trapping of the incipient Bn· radical, undergoing either H
atom transfer from n-Bu3SnH or recombination with the
FeIV(O) species in the “oxygen rebound” step. The saturation
behavior observed as a function of n-Bu3SnH concentration
may be rationalized by a solvent cage effect,48 where the
amount of ethylbenzene formed reflects the fraction of nascent
Bn· radical that can break through the cage wall and be trapped
by the radical scavenger. The fraction of escaped radical
depends on properties such as shape, size, and mass as well as
solvent viscosity. Such radical−cage effects are well docu-
mented in organotransition metal chemistry.49−51
Because the above reactions were carried out in the presence
of excess of H2O2 and Et3N, the reaction of PPA with isolated
crystals of 132 was also investigated (Table 1). Acetophenone
was also formed but at half the yield, demonstrating that 1 was
by itself capable of providing the four oxidizing equivalents
1
required for the formation of ketone from PPA. H NMR
analysis of the solution at the end of the reaction showed no
evidence for either the iron(II) or the oxoiron(IV) complex,
leading us to surmise the likely formation of NMR-silent
iron(III) byproducts.
All of the above experimental observations are consistent
with the stoichiometry and the mechanism shown in Figure 5.
Attack of 1 at the aldehyde carbonyl forms the peroxy-
hemiacetal intermediate. Facile homolytic cleavage of the O−O
bond followed by homolytic scission of the C−C bond yields
The putative Bn· intermediate could also be trapped by
another potential H atom donor, PhNHNHPh, which has an
N−H bond dissociation energy of 73.1 kcal mol−1.52 GC-MS
analysis of the reaction mixtures revealed formation of
C
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Table 1. Deformylation of Aldehydes (RCHO, 20 mM) by FeIII(TMC)(η2-O2) (1.0 mM) in THF at −10 °C
a
a
b
a
aldehyde
conditions
[aldehyde/ketone] (mM)
[alkane] (mM)
[OPPh3] (mM)
8 (mM)
normal
0.59
0.33
0.51
0.46
0.43
0.40
0.35
0.36
0.26
0.20
0.14
0.50
0.47
0.42
0.29
0.30
0.29
0.09
0.05
0.13
0.06
c
crystals of 1
n-Bu3SnH (10 equiv)
n-Bu3SnH (25 equiv)
n-Bu3SnH (37.5)
n-Bu3SnH (50 equiv)
n-Bu3SnH (75 equiv)
n-Bu3SnH (125 equiv)
PhNHNHPh (15 equiv)
PhNHNHPh (100 equiv)
PhNHNHPh (300 equiv)
PPh3 (5 equiv)
0.06
0.11
0.21
0.22
0.24
0.25
0.07
0.14
0.15
PPA
0.08
0.10
0.14
0.27
0.26
0.30
PPh3 (10 equiv)
PPh3 (15 equiv)
PPh3 (20 equiv)
PPh3 (40 equiv)
PPh3 (60 equiv)
normal
0.26
0.06
0.15
0.26
0.21
0.28
0.06
0.16
0.28
0.07
c
crystals of 1
undecanal
THF-d8
n-Bu3SnH (250 equiv)
PPh3 (60 equiv)
0.31
a
b
c
Determined by GC analysis. Determined by 31P NMR. Crystals of 1 were obtained by the procedure reported in ref 45. Determination errors are
approximately 10%.
formation of a brown precipitate in the reaction mixture and
the appearance of the [TMC-H]+ ion in the mass spectrum
taken at the end of the reaction. The nascent alkyl radical can
also react with a suitable H atom donor if present in the
reaction mixture to form the observed R−H product.
Reactivity of Undecanal with [FeIII(TMC)(η2-O2)]+. The
relatively weak Cα−H bond of PPA makes it a common
substrate for the oxidative deformylation reaction. However,
cADO enzyme substrates are linear aldehydes with much
stronger Cα−H bonds than PPA. Consequently, undecanal was
used as the model substrate in the reaction. Addition of
undecanal to 1 resulted in the disappearance of its 880 nm band
at a rate comparable to that for the PPA reaction. GC-MS
analysis of the reaction mixture revealed three peaks, which
respectively coeluted with authentic standards of decane (6),
decanal (7), and γ-butyrolactone (8) (Figure 6 and Table 1).
Although addition of excess n-Bu3SnH to the reaction mixture
did not affect the decane yield, substitution of THF by THF-d8
as the reaction solvent reduced the yield of decane and resulted
in deuterium incorporation into the hydrocarbon product, as
determined by mass spectrometry (Figure S3). These results
are consistent with the hydrogen atom coming from the
solvent. Also, addition of Ph3P to the reaction mixture
prevented formation of decanal and significantly decreased
the yield of the lactone derived from THF oxidation, consistent
with the trapping of the FeIV(O) intermediate that serves as the
O atom source for these products. We were not able to
establish the fate of either the decyl or the THF-derived radical
in this experiment.
Figure 5. (A) Stoichiometry and (B) proposed mechanism for the
deformylation of PPA by 1 in THF.
the FeIV(O) complex, formate, and Bn·. The incipient radical
then undergoes oxygen rebound with the newly formed
FeIV(O) species to form an alkoxoiron(III) complex, which is
further oxidized to the ketone by a second equivalent of 1 or
H2O2. Reaction of the alkoxoiron(III) moiety with trace water
present in the solution leads to formation of FeIII(OH)-
(TMC)]2+, which is proposed as the byproduct of the reaction.
This unstable and yet uncharacterized species very likely decays
to Fe2O3 and free TMC, as indicated respectively by the
Formation of 6 and 7 in the undecanal experiments implies a
reaction mechanism analogous to that proposed for PPA
(Figure 5). However, the decyl radical (CH3(CH2)8CH2·) is
much more reactive than Bn· and powerful enough to abstract
an H atom from THF to generate decane. The newly formed
THF radical then combines with the FeIV(O) complex to form
D
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this species then undergoes O−O bond homolysis to afford R·,
formate, and [FeIV(O)(TMC)]2+. At this stage, the presence of
a suitable H atom donor intercepts R· to make R−H, instead of
forming a C−O bond with the FeIV(O) complex. The success
of our cADO modeling efforts has hinged on a shift in solvent
from TFE,31 used in previous studies of aldehyde deformylation
by 1, to THF. We speculate that the change in solvent may
tune the rate at which the incipient alkyl radical undergoes
rebound with [FeIV(O)(TMC)]2+ to allow the incipient alkyl
radicals to be intercepted by an H atom donor. These results
support the basic premise of the mechanism proposed for the
cADO-catalyzed reaction,11−13 i.e., that the aldehyde substrate
is attacked by a nucleophilic iron-peroxo species formed in the
cADO active site such as the (μ−η1:η2-peroxo)diiron(III)
moiety C proposed for cADO in Figure 1. Subsequent injection
of an electron concomitant with O−O bond cleavage in the
decay of C avoids formation of an oxoiron(IV) center with
which the incipient alkyl radical can undergo rebound. Instead,
the radical abstracts an H atom from an iron-bound water to
form the desired alkane product.
Figure 6. GC-MS traces of the products from the reaction of 1 with
undecanal.
γ-butyrolactol, which in turn is oxidized to 8. The ability of the
decyl radical to abstract H· from THF is related to its
thermodynamic affinity for H·, reflecting the relative strengths
of the C−H bonds involved. The Cα−H bonds of THF and the
primary C−H bonds of decane have respective bond
dissociation energies of 92 and 98 kcal mol−1,55 so H atom
transfer from THF to decyl radical is favored.
ASSOCIATED CONTENT
* Supporting Information
Figures as described in the text. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/jacs.5b01053.
■
S
Kinetic studies of the reactions of 1 with PPA or undecanal
in THF at −10 °C reveal that the rate of 1 decay is
independent of the nature of the aldehyde and of the
concentration of the aldehyde. As shown in Figures S4 and
S5, the observed kobs values fall within the range of 6−10 ×
10−4 s−1 under all conditions studied, with similar rates
obtained using the peroxo crystals as the starting point. This
behavior differs from that found by Nam for the reactions of 1
with PPA in TFE solvent, the rates of which depend on the
PPA concentration.31 We speculate that the reactivity differ-
ences of 1 in the two solvents derive from the accessibility of its
more nucleophilic end-on-bound isomer. In the less polar THF
solvent, formation of the end-on-bound isomer is not so
favored, so the isomerization of 1 is rate-determining. However,
in the more polar and hydrogen-bonding TFE solvent,
isomerization is more facile, and the rate-determining step
becomes the attack of 1 on the carbonyl group of the aldehyde.
The importance of an end-on peroxo moiety for oxidative
deformylation is emphasized by the much higher reactivity of
[FeIII(TMC)(η1-OOH)]2+ relative to that of 1 at −40 °C as
demonstrated by Nam32 and the very rapid oxidation of PPA by
[FeIII(TMCS)(η1-OO)]+ even at −90 °C, where TMCS is a
pentadentate analog of TMC with a pendant thiolate donor.44
A similar argument has been used to rationalize the significantly
enhanced reactivity of [FeIII(F20TPP)(η2-O2)]+ (H2F20TPP =
tetrakis(pentafluoro-phenyl)porphin) upon addition of DMSO,
which is proposed to bind to the site trans to the peroxo ligand
and promote the isomerization of the side-on bound peroxo
moiety to its end-on-bound form.56
AUTHOR INFORMATION
Corresponding Author
*larryque@umn.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support from the National Institutes of Health (GM-
38767) is gratefully acknowledged.
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DOI: 10.1021/jacs.5b01053
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX