Download containing complexes of aromatic amino acids

PAPER
www.rsc.org/pccp | Physical Chemistry Chemical Physics
Dissociations of copper(II)-containing complexes of aromatic amino
acids: radical cations of tryptophan, tyrosine, and phenylalaninew
Chi-Kit Siu, Yuyong Ke, Yuzhu Guo, Alan C. Hopkinson and K. W. Michael Siu*
Received 6th May 2008, Accepted 25th June 2008
First published as an Advance Article on the web 11th August 2008
DOI: 10.1039/b807692h
The dissociations of two types of copper(II)-containing complexes of tryptophan (Trp), tyrosine
(Tyr), or phenylalanine (Phe) are described. The first type is the bis-amino acid complex,
[CuII(M)2] 2+, where M = Trp, Tyr, or Phe; the second [CuII(4Cl-tpy)(M)] 2+, where 4Cl-tpy is
the tridendate ligand 4 0 -chloro-2,2 0 :60 ,200 -terpyridine. Dissociations of the Cu(II) bis-amino acid
complexes produce abundant radical cation of the amino acid, M +, and/or its secondary products.
By contrast, dissociations of the 4Cl-tpy-bearing ternary complexes give abundant M + only for
Trp. Density functional theory (DFT) calculations show that for Tyr and Phe, amino-acid
displacement reactions by H2O and CH3OH (giving [CuII(4Cl-tpy)(H2O)] 2+ and
[CuII(4Cl-tpy)(CH3OH)] 2+) are energetically more favorable than dissociative electron transfer
(giving M + and [CuI(4Cl-tpy)]+). The fragmentation pathway common to all these
[CuII(4Cl-tpy)(M)] 2+ ions is the loss of NH3. DFT calculations show that the loss of NH3
proceeds via a ‘‘phenonium-type’’ intermediate. Dissociative electron transfer in
[CuII(4Cl-tpy)(M–NH3)] 2+ results in [M–NH3] +. The [Phe–NH3] + ion dissociates facilely by
eliminating CO2 and giving a metastable phenonium-type ion that rearranges readily into the
styrene radical cation.
Introduction
Protein radicals are important transient intermediates in enzymatic activities in biological systems. Generation of many of
these radicals involves oxidation of an amino acid residue by a
metal co-factor. The radical generated is commonly centered at
a tryptophan (Trp) or tyrosine (Tyr) residue; for examples in
ribonucleotide reductases, cytochrome c peroxidase, prostaglandin H synthase, and galactose oxidase.1 The traditional
means of producing a radical cation in the gas phase is electron
ionization (EI).2 A gas-phase examination is advantageous in
that it reveals the intrinsic chemistry of the species, unencumbered by solvation. Efficient EI requires prior evaporation of
neutrals into the gas phase, which is difficult, if not impossible,
for peptides and proteins.2 Recently, copper(II)-containing
ternary complexes [CuII(L)(M)] 2+, where L is typically an
amine ligand and M is the peptide or amino acid, have been
employed as a source for peptide and amino acid radical cations
in the gas phase.3–14 Collision-induced dissociation (CID) of the
complex results in dissociative electron transfer, leading to the
observation of M + under appropriate conditions. M + is most
efficiently formed if it contains or is an amino acid that has a
Department of Chemistry and Centre for Research in Mass
Spectrometry, York University, 4700 Keele Street, Toronto, Ontario,
Canada M3J 1P3
w Electronic supplementary information (ESI) available: CID spectra
(Fig. S1); potential energy scan (Fig. S2); possible reactions of the
tyrosine radical cation (Fig. S3); possible reactions of the phenylalanine radical cation (Fig. S4); Cartesian coordinates for the geometries
optimised at the UB3LYP/6-31++G(d,p) level Table S1). See DOI:
10.1039/b807692h
5908 | Phys. Chem. Chem. Phys., 2008, 10, 5908–5918
low ionization energy (IE). These amino acids include Tyr and
Trp, in which the unpaired electron and charge are stabilized by
the aromatic functional groups (phenol and indole, respectively). The dissociative electron transfer reaction is competitive
with other processes, including dissociative proton transfer in
which a proton migrates either from the auxiliary ligand to the
peptide to produce a protonated peptide [M+H]+, or vice versa
to produce a protonated ligand [L+H]+.3,4,7,9–13 These competitive dissociations can be controlled and tuned by judicious
choice of the auxiliary ligand. For example, dissociative proton
transfer from the ligand to the peptide is suppressed when
ligands devoid of acidic hydrogens, e.g., 2,2 0 :6 0 ,200 -terpyridine
(tpy), are employed.3,9,11 Chu and co-workers12 have shown
that certain ligands with considerable steric crowding, including
1,4,7-triazacyclononane and 1,4,7,10-tetraoxacyclododecane
(12-crown-4 ether), favor dissociative electron transfer; indeed,
formation of M + from peptides with only aliphatic residues
has been demonstrated.
Recently, Barlow et al.15 reported the CIDs of a large number
of amino acids, including the aromatic and basic amino acids.
Ke et al.16 described the CIDs of several [CuII(L)n(M)] 2+ of the
basic amino acids; a variety of ligands were examined, including
diethylenetriamine, 1,4,7-triazacyclononane, tpy, bipyridine,
histidine (where L = M = histidine), and acetone. A key
finding is that the ratio of the two types of M + that can be
generated—Type 1 that is stable on the mass spectrometer time
scale and Type 2 that is metastable—is controllable and can be
tuned by judicious choice of the auxiliary ligand. The use of a
weak ligand, acetone, produces exclusively metastable M +,
whereas the use of a strong ligand, tpy, produces primarily
‘‘stable’’ M + that can be isolated for subsequent CID. This is
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not the only report that described observation of M + from the
CID of a complex that contains only Cu2+ and M; an earlier
communication, also by Ke et al.13 had described the observation of M2 + and M + from the CIDs of [CuII(M)n] 2+, where
n Z 4 and M was an N-acetyl and C-methyl ester or
C-amidated derivative of tryptophan or tyrosine. Here, we
report the CIDs of [CuII(M)2] 2+ and [CuII(4Cl-tpy)(M)] 2+,
where 4Cl-tpy is 4 0 -chloro-2,2 0 :6 0 ,200 -terpyridine and M is
tryptophan, tyrosine or phenylalanine (Phe), that complement
and extend the work of Barlow et al.15 and Ke et al.13,16
Experimental
Mass spectrometry
Experiments were performed on a prototype of a commercially
available triple–quadrupole mass spectrometer (MDS SCIEX
API 3000) or an ion-trap mass spectrometer (Finnigan-MAT
LCQ), both equipped with an ESI source. The typical electrospray voltage was 4.5 kV. Nitrogen was used as the sheath gas
at a flow rate of 0.3 L min1, and the capillary temperature
was 120–160 1C. The metal complexes were infused at a flow
rate of 2–3 mL min1. Ion lineage was determined using the
MSn scan functions of the LCQ instrument.
Materials
Copper complexes were prepared in 1 mL 1 : 1 water/methanol
solutions, by mixing copper(II) perchlorate hexahydrate, the
auxiliary ligand 4Cl-tpy, and the amino acid Trp, Tyr, or Phe
to a final concentration of 100 mM [CuII(L)(M)] 2+. All
chemicals and solvents were commercially available from
Sigma (St. Louis, MO, USA) and were used as received.
Isotopically labeled DL-phenylalanine-a-d1, DL-phenyl-d5alanine, and DL-phenyl-d5-alanine-b,b-d2 were from CDN
Isotopes (Pointe-Claire, Quebec, Canada; all 498% purity).
Density functional theory (DFT) computations
All calculations were performed using the Gaussian03 quantum
chemical program.17 The total energies of Cu(II) complexes and
radical cations were calculated by the unrestricted open-shell
formalism within the framework of Becke’s three-parameter
DFT hybrid functional, B3LYP, which is based on a mixture of
Hartree–Fock exchange and the Becke and Lee–Yang–
Parr exchange–correlation functional.18 The standard Pople
Gaussian-type double-zeta basis set including polarization and
diffuse functions on all atoms, 6-31++G(d,p), was employed.
Local minima and transition structures were optimized and
verified by harmonic frequency analyses. Zero-point vibration
energies were evaluated directly using the normal-mode frequencies without anharmonic scaling. The local minima associated with
each transition structure were identified using the intrinsic reaction
coordinates (IRC) method.19 Atomic charges and spin densities
have been evaluated using natural population analysis (NPA).20
Results and discussion
As described earlier, the two most common and competitive
channels in the dissociation of Cu(II)-containing ternary complexes are dissociative electron transfer and dissociative
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proton transfer. An intriguing case is one in which the ternary
complex contains two molecules of the amino acids (or
peptides) as ligands; here, in proton transfer, one amino acid
is the proton donor while the other, identical amino acid is the
proton acceptor. Fig. 1 shows the dissociation of the
63
Cu(II)-containing bis-complex of (a) tryptophan, (b) tyrosine, and (c) phenylalanine (unspecified Cu isotope will hereafter be understood to be 63Cu; the dissociation chemistries of
the 65Cu-containing complexes were used for verification). The
CID of [CuII(Trp)2] 2+ (Fig. 1a) reveals only products of
dissociative electron transfer, giving Trp + at m/z 204 and
[CuI(Trp)]+ at m/z 267. The product ion at m/z 130 is
probably the protonated 3-methyleneindolenine cation formed
via Ca–Cb bond cleavage7,15,21 with the neutral product being
the a-glycyl radical, H2NC HCOOH.21,22 The 70 eV EI mass
spectrum of Trp shows only one prominent ion, the protonated 3-methyleneindolenine cation at m/z 130.23 By contrast,
the dissociation of [CuII(Phe)2] 2+ (Fig. 1c) displays an abundant dissociative proton-transfer product: the [Phe+H]+ ion
at m/z 166. The prominent product ions at m/z 120 and m/z 91
are attributable to the dissociation of [Phe+H]+;24 the
former has been assigned as the a1 or iminium ion,
H2N+QCHCH2C6H5, the latter the benzyl cation,
C6H5CH2+. However, dissociation of [Phe+H]+ is also expected to give a prominent product ion at m/z 103, which is
absent; in addition, the abundant ion at m/z 74 in Fig. 1c is
non-prominent in the dissociation of [Phe+H]+.24 The three
most abundant ions in the 70 eV EI spectrum of phenylalanine
are m/z 74, 91, and 120.23 It is noteworthy that the most
abundant Cu-containing ion in Fig. 1c is the [CuI(Phe)]+ ion
at m/z 228, the complementary ion of Phe +; by contrast, the
abundance of the [CuII(Phe–H)] + ion, the complementary
product of [Phe+H]+ is small. Taken together,
[CuII(Phe)2] 2+ appears to dissociate efficiently to give hot
Phe +, which dissociates to give the signature product ions at
m/z 120, 91, and 74. The m/z 74 product ion is probably
H2N+QCHCOOH with the benzyl radical, C6H5CH2 , being
the neutral product.
The dissociation of [CuII(Tyr)2] 2+ (Fig. 1b) gives both
Tyr + at m/z 181 and [Tyr+H]+ at m/z 182. The abundant
product ion at m/z 107, attributable to the p-hydroxybenzyl
cation, HOC6H4CH2+, is present both in the 70 eV EI mass
spectrum of Tyr23 as well as in the CID spectrum of
[Tyr+H]+.24 The ion at m/z 108, the p-cresol radical cation,
[HOC6H4CH3] +, is also present in the EI spectrum of Tyr.
Both the m/z 107 and 108 product ions were observed in the
dissociation of [CuII(L)(Tyr)] 2+.7,15 However, the relative
ratio of the m/z 244 and 243 product ions, assigned as
[CuI(Tyr)]+ and [CuII(Tyr–H)] +, respectively, strongly suggests that the branching ratio is greatly in favor of the
production of Tyr + over that of [Tyr+H]+. A significant
fraction of hot Tyr + dissociates to give the signature product
ions at m/z 107 and 108.
Fig. 2 shows the CID spectra of [CuII(435Cl-tpy)(M)] 2+
where M is (a) Trp, (b) Tyr, and (c) Phe (unspecified Cl isotope
hereafter is 35Cl; the chemistries of the 37Cl-containing ions
were identical). In all spectra, the most abundant product ion
is the [CuI(4Cl-tpy)]+ ion at m/z 330. The radical cation M +
is only apparent in (a) for M = Trp, in which the Trp + ion is
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Fig. 1 Product ion spectra of (a) [63CuII(Trp)2] 2+, (b) [63CuII(Tyr)2] 2+, and (c) [63CuII(Phe)2] 2+: collision energies Elab = 4, 8, 10 eV,
respectively.
fairly abundant and so is its signature product ion, the
protonated 3-methyleneindolenine cation, at m/z 130. The
relatively low-abundance ion at m/z 258.5 is probably a doubly
charged radical cation formed as a result of the loss of
ammonia from [CuII(4Cl-tpy)(Trp)] 2+. This product ion,
[CuII(4Cl-tpy)(M–NH3)] 2+, is in fact common in the CIDs
of all three complexes. In the dissociations of the (b) Tyr- and
(c) Phe-containing complexes, the [CuII(4Cl-tpy)(M–NH3)] 2+
ions at m/z 247 and 239, respectively, are even more abundant.
These [CuII(4Cl-tpy)(M–NH3)] 2+ ions, in turn, fragment to
give secondary product ions: [M–NH3] + at (b) m/z 164 and
(c) m/z 148, and the complementary [CuI(4Cl-tpy)]+ ion at m/z
330. The [M–NH3] + ion can subsequently dissociate to give
[M–NH3–CO2] + at (b) m/z 120, the 4-hydroxystyrene radical
cation; and (c) m/z 104, the styrene radical cation.15 A second
prominent dissociation pathway of [CuII(4Cl-tpy)(Phe)] 2+
(Fig. 2c) gives the Phe iminium ion at m/z 120 and
the [CuII(4Cl-tpy)(COOH)] + ion at m/z 375, which is
fragile and, in turn, fragments to give the abundant
[CuII(4Cl-tpy)(OH)] + ion at m/z 347 by eliminating CO.
Alternatively, the Phe iminium ion at m/z 120 can also be
formed by loss of a CO via the Phe b1 ion at m/z 148,25 which is
5910 | Phys. Chem. Chem. Phys., 2008, 10, 5908–5918
isobaric to the [Phe–NH3] + ion. This m/z 148 ion is a mixture
of b1 and [Phe–NH3] + ions, revealed clearly by the CID of
[CuII(4Cl-tpy)(15N-Phe)] 2+ from which the two ions appeared at m/z 149 and 148, respectively (see Fig. S1 in the
ESI).w These dissociation pathways are also evident for
[CuII(4Cl-tpy)(Tyr)] 2+ (Fig. 2b) though less prominently.
There is no evidence for dissociative proton transfer—no
[M+H]+, no unambiguous products attributable only to
[M+H]+, and no [CuII(4Cl-tpy–H)]+—in any of the spectra
shown in Fig. 2. Apparently, the absence of acidic hydrogens
in 4Cl-tpy effectively suppresses this channel evident in Fig. 1
and in the dissociations of [CuII(diethylenetriamine)(M)] 2+.7
The m/z 174 and 181 ions in Fig. 2b and c are probably
[CuII(4Cl-tpy)(H2O)] 2+ and [CuII(4Cl-tpy)(CH3OH)] 2+, respectively, formed by nucleophilic displacement of the amino
acid by a solvent molecule. The corresponding ions
[CuII(tpy)(H2O)] 2+ and [CuII(tpy)(CH3OH)] 2+ were noted
by Barlow et al.15 who attributed these to the solvation
products of [CuII(L)] 2+ after the latter was formed from
[CuII(L)(M)] 2+ by loss of the amino acid as a neutral. All
of the product ions noted in the paragraph above have
corresponding ions in the CIDs of the [CuII(tpy)(M)] 2+
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Fig. 2 Product ion spectra of (a) [63CuII(435Cl-tpy)(Trp)] 2+, (b) [63CuII(435Cl-tpy)(Tyr)] 2+, and (c) [63CuII(435Cl-tpy)(Phe)] 2+: relative
collision energies, all 10%.
complexes examined by Barlow et al.,15 although there are minor
differences in interpretations. The [CuII(tpy)] 2+ ion, at m/z 148,
is isobaric with the [Phe–NH3] + ion; as no [CuII(4Cl-tpy)] 2+
ion (m/z 165) is evident in Fig. 2, the contribution of
[CuII(tpy)] 2+ to the signal observed at m/z 148 was probably
minor.15 It may also be of note that the [Tyr–NH3] + at m/z
164 is isobaric with the [CuII(tpy)(CH3OH)] 2+ ion.15
The product assignments in Fig. 2c are supported by CIDs of
deuterated [CuII(4Cl-tpy)(Phe)] 2+ in which Phe is d1-Phe[NH2CD(CH2C6H5)COOH], d5-Phe[NH2CH(CH2C6D5)COOH], or
d7-Phe[NH2CH(CD2C6D5)COOH]. The product ion spectrum
of [CuII(4Cl-tpy)(d5-Phe)] 2+ is shown in Fig. 3. Replacing five
hydrogens with deuteriums results in an increase of m/z 2.5 in
the mass-to-charge value of the precursor ion from m/z 247.5 to
250.0. The most abundant ion, [CuI(4Cl-tpy)]+, does not contain deuterium and, therefore, remains at m/z 330. El Aribi
et al.24 showed that there is considerable scrambling between
the aromatic hydrogens and the hydrogens in the NH3+– and
–COOH groups in protonated Phe. Similar scrambling in
protonated Trp has also been reported by Lioe et al.26 The
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m/z 347 and 348 ions in Fig. 3 are, therefore, assigned, respectively, as [CuII(4Cl-tpy)(OH)]+ and [CuII(4Cl-tpy)(OD)]+, the
latter having its original hydroxyl hydrogen exchanged with a
phenyl deuterium. Likewise, H/D scrambling is also evident in
the loss of ammonia: the cluster of m/z 241.5, 241, and 240.5
ions in Fig. 3 (shown more clearly in the relevant inset)
are [CuII(4Cl-tpy)(d5-Phe–NH3)] 2+, [CuII(4Cl-tpy)(d5-Phe–
NH2D)] 2+, and [CuII(4Cl-tpy)(d5-Phe–NHD2)] 2+, respectively, which in turn undergo dissociative electron transfer to
give [d5-Phe–NH3] + (m/z 153), [d5-Phe–NH2D] + (m/z 152),
and [d5-Phe–NHD2] + (m/z 151). A similar degree of H/D
scrambling is also evident in the cluster of m/z 109, 108, 107,
and 106 ions: [d5-Phe–NH3–CO2] +, [d5-Phe–NH2D–CO2] +,
[d5-Phe–NHD2–CO2] +, and [d5-Phe–ND3–CO2] +. The m/z
125 and 124 ions are the iminium ions, formally
H2N+QCHCH2C6D5 and H2N+QCHCH2C6HD4.
Amino-acid binding modes in [CuII(tpy)(M)] 2+
The copper(II) ion has a d9 electronic configuration and forms
four strong metal–ligand dative bonds in a square-planar
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Fig. 3 Product ion spectrum of [63CuII(435Cl-tpy)(d5-Phe)] 2+: relative collision energy = 10%.
arrangement at the equatorial positions.27,28 Upon binding to
tpy, three of the coordination sites of the Cu(II) ion are
occupied by three pyridyl nitrogen atoms and one remaining
coordination site is available for an electron-rich ligand,
assuming a four-coordinate complex; five-coordinate complexes of Cu(II) are known, although the fifth bond is typically
quite weak.27,28 For Phe, Tyr and Trp, the probable electrondonating sites are the carboxylic group and the amino group
resulting in complex structures 1 and 2, as shown in Fig. 4. The
Phe in 1 (Fig. 4a) is in the zwitterionic form with the carboxylic
proton having migrated to the amino group and the
carboxylate anion is stabilized by the Cu(II). This effect
lowers the enthalpy (DH10) of structure 1 by 6.8 kcal mol1
(6.4 kcal mol1 in terms of DG1298) relative to structure 1 0 , the
lowest energy form of canonical Phe, where the proton is on
the carboxylic oxygen, but forms a strong hydrogen bond to
the amino nitrogen with a distance of 1.651 Å (versus the
H O distance of 1.949 Å in 1). The transition structure 1TS1 0
that separates the two minimum structures is only at
5.6 kcal mol1 (1.2 kcal mol1 lower than 1 0 ), which means
that 1 0 is at a minimum on the electronic energy surface
(DE = 8.1 kcal mol1 compared to DE = 8.4 kcal mol1 for
1TS1 0 ); however, when zero-point energy is included, it collapses to 1 without a barrier.
Structures 2 and 2 0 have NH2 in the fourth equatorial
position of [CuII(tpy)] 2+; in addition, the carbonyl or hydroxyl oxygen can bind to one of the axial positions to form 2 or
2 0 , respectively. This fifth coordination, however, is weak and
cannot compensate for loss of the strong coordination between Cu(II) and the carboxylate of the zwitterionic Phe that
exists in 1. DFT calculations show that 2 and 2 0 lie 9.4 and
17.7 kcal mol1, respectively, above 1, the structure at the
global minimum.
Elimination of neutral Phe from [CuII(tpy)(Phe)] 2+, determined by taking the difference between the energy of structure
1 (Fig. 4a) and the sum of the energies of [CuII(tpy)] 2+ and
the lowest-energy conformer of the neutral amino acid,29–32 is
endothermic by 63.0 kcal mol1 (Table 1). Neutral amino acid
loss is not observed in the CID of [CuII(tpy)(M)] 2+; nucleophilic displacement of the amino acid by a solvent molecule
5912 | Phys. Chem. Chem. Phys., 2008, 10, 5908–5918
gives [CuII(tpy)(H2O)] 2+ or [CuII(tpy)(CH3OH] 2+,15 with
smaller endothermicities of 34.0 kcal mol1 (H2O) and
29.8 kcal mol1 (CH3OH). Similar ligand-displacement reactions have been observed in hydrated Cu 2+ with methanol33
and in [PtII(tpy)(pyridine)]+ with pyridine or acetonitrile.34
The process here with [CuII(tpy)(M)] 2+ involves first a solvent association reaction which is slightly exothermic by 10.8
and 12.9 kcal mol1 for the addition of H2O and CH3OH,
respectively. Addition of the solvent molecule is barrierless,
forming a penta-coordinated complex with the interaction of
Cu Phe being weakened by the Cu solvent bond formed at
the equatorial position ([1+H2O] and [1+CH3OH] in
Fig. 4a). The solvated products are prominent in this study
of [CuII(4Cl-tpy)(Phe)] 2+. It is noteworthy that the chloro
substitution in 4Cl-tpy has a minimal effect on the thermochemistry. The endothermicity for eliminating Phe in
[CuII(4Cl-tpy)(Phe)] 2+ is 63.5 kcal mol1 (Table 1), which
is virtually identical to that in [CuII(tpy)(Phe)] 2+. The energetics of amino-acid displacement and dissociative electrontransfer reactions are also comparable (Table 1).
Structures analogous to 1 and 2 of [CuII(tpy)(Phe)] 2+ exist
also for [CuII(tpy)(Tyr)] 2+ and [CuII(tpy)(Trp)] 2+ (see Fig. 4
and Table 1). The energies of 2 relative to 1 for Phe, Tyr, and
Trp are very comparable, about 9.5 kcal mol1. It is also of
note that the energetics of the amino-acid elimination and
displacement reactions vary only slightly with M and with only
a small increase in the order of Phe o Tyr o Trp (Table 1).
This is consistent with the fact that the Cu O distance in 1 is
almost identical, regardless of the amino acid involved.
Dissociative electron transfer is competitive with aminoacid elimination and displacement reactions in the CID of
[CuII(4Cl-tpy)(M)] 2+ and [CuII(tpy)(M)] 2+.15,21 The intramolecular, one-electron oxidation reaction yielding M + is the
most chemically interesting reaction that has spawned considerable attention and subsequent investigations following
the initial discovery.3,21,35 Table 1 lists also the energetics for
the dissociative electron-transfer reactions from structure 1 to
give [CuI(tpy)]+ (or [CuI(4Cl-tpy)]+) and the most stable
p-radical of M + (see, for example, Trp1 in Fig. 5). In contrast
to the amino-acid elimination and displacement reactions, the
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Fig. 4 Low-energy structures of (a) [CuII(tpy)(Phe)] 2+, [CuII(tpy)(Phe)(H2O] 2+ and [CuII(tpy)(Phe)(CH3OH] 2+, (b) [CuII(tpy)(Tyr)] 2+, and
(c) [CuII(tpy)(Trp)] 2+. The relative energies DH10 (DG1298) are evaluated at the UB3LYP/6-31++G(d,p) level and are in kcal mol1. The bond
distances are in ångström.
energy changes in the dissociative electron-transfer reaction
are heavily dependent on the amino acid involved and follow
the trend in the ionization energies of the side-chain functional
groups in the order of Trp o Tyr o Phe.23 The dissociative
electron-transfer reaction is less endothermic than the
amino-acid elimination and displacement reactions for
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[CuII(tpy)(Phe)] 2+ (with the former having a value of
14.7 kcal mol1) and [CuII(tpy)(Tyr)] 2+ (7.1 kcal mol1), and
is even exothermic for [CuII(tpy)(Trp)] 2+ (2.9 kcal mol1).
The barrier against the dissociative electron-transfer reaction
can conceptually be determined by locating the crossing of the
two dissociation-energy surfaces;36 this calculation, however,
Phys. Chem. Chem. Phys., 2008, 10, 5908–5918 | 5913
Table 1 Reaction energies of the competitive reactions of [CuII(L)(M)] 2+. The energies (kcal mol1) are evaluated at the UB3LYP/631++G(d,p) level
L = tpy
L = 4Cl-tpy
M = Trp
Amino acid elimination
[CuII(L)(M)] 2+ - [CuII(L)] 2+ + M
Amino acid displacement
[CuII(L)(M)] 2+ + H2O [CuII(L)(H2O)] 2+ + M
[CuII(L)(M)] 2+ + CH3OH [CuII(L)(CH3OH)] 2+ + M
Solvent association
[CuII(L)(M)] 2+ + H2O [CuII(L)(M)(H2O)] 2+
[CuII(L)(M)] 2+ + CH3OH [CuII(L)(M)(CH3OH)] 2+
Dissociative electron transfer
[CuII(L)(M)] 2+ - [CuI(L)]+ M +
Barrier
a
M = Tyr
M = Phe
M = Phe
DE
DH10
DG1298
DE
DH10
DG1298
DE
DH10
DG1298
DE
DH10
DG1298
68.3
66.6
54.8
65.5
63.8
52.1
64.5
63.0
51.3
65.1
63.5
51.9
37.2
37.6
34.7
34.4
34.9
31.9
33.4
34.0
31.2
33.7
34.3
31.5
33.6
33.4
31.7
30.8
30.7
29.0
29.8
29.8
28.2
30.1
30.1
28.6
13.2
10.8
1.1
14.3
12.9
2.1
18.9
41a
14.7
1.3
18.0
13.9
1.9
0.2
27a
2.9
16.1
9.6
7.1
5.3
Value estimated from potential energy scan.
is nontrivial even for systems as small as [CuII(H2O)] 2+ and
[CuII(NH3)] 2+.37–39 Here, we estimated the barrier against
dissociating [CuII(tpy)(M)] 2+ by performing a potentialenergy scan along the Cu O distance, starting from a configuration in which the [CuI(tpy)]+ complex and the amino
acid radical cation are well separated (Cu O = 10 Å): a full
geometry optimization, except for the restrained Cu O distance, is performed. The Cu O distance is then decreased
with a step size of 1 Å, and followed by a geometry optimization at each Cu O distance (see Fig. S2 in the ESI).w The
accuracy of this procedure was estimated by comparing the
barriers against dissociative electron transfers in
[CuII(NH3)] 2+ and [CuII(H2O)] 2+ calculated this way with
those obtained by full optimizations of the transition-state
structures as published in the literature.37,38 The barriers
determined using potential-energy scans were 8.2 and 9.1 kcal
mol1, respectively; those using published transition-state
structures were 10.9 and 10.4 kcal mol1. Thus, a conservative
estimate of the accuracy of the potential-energy scan methodology is 3 kcal mol1.
Returning to the current investigation of [CuII(tpy)(M)] 2+,
the trend is that the potential energy increases slightly
with decreasing Cu O distance (due to increasing Coulombic
repulsion) as the two charge separated products are
brought together, until around 6 Å. The Cu–amino acid
attraction then becomes dominant and the potential energy
drops significantly. As the Cu O bond distance decreases
from around 6 Å, the charge and spin on [Cu(tpy)] increase
while that on M decrease dramatically (see Fig. S2 in the ESI).w
Comparing the estimated barrier against the dissociative
electron transfer in [CuII(tpy)(Trp)] 2+ thus determined
(DE = 27 kcal mol1) with that in [CuII(tpy)(Phe)] 2+ (DE =
41 kcal mol1), and with the endothermicities of the amino-acid
elimination reactions (DE = 64–68 kcal mol1) and amino-acid
displacement reactions (DE = 30–38 kcal mol1) (see Table 1),
the results are clearly in agreement with experimental observations that in the CID of [CuII(tpy)(Trp)] 2+ fragmentation to
give Trp + is favored, while in that of [CuII(tpy)(Phe)] 2+
5914 | Phys. Chem. Chem. Phys., 2008, 10, 5908–5918
amino-acid displacements to give [CuII(tpy)(H2O)] 2+ and
[CuII(tpy)(CH3OH)] 2+ are preferred.
Energy surfaces of the amino-acid radical ions
The CIDs of the Cu(II)-containing complexes produce observable quantities of Trp + and Tyr +. The structures of Trp +
have been examined here by DFT calculations. Dissociating the
Trp from structure 1 would presumably produce a distonic
ion40 with the radical residing on the carboxyl group and the
charge on the protonated amino group. For amino acids that
have a basic side-chain, e.g., histidine and arginine, the carboxyl
radical is unstable against CO2 loss.15,16 Geometry optimization
shows that the carboxyl radical cation of Trp + is not at a local
minimum and converts to a p-radical form in which both the
radical and the charge are located in the aromatic side-chain,
Trp1 (Fig. 5 and Table 2). This is in agreement with the fact that
CO2 loss is not observed in the CID of [CuII(L)(Trp)] 2+. This
difference is probably due, in part, to the difference in proton
affinities (PAs) between the NH2– group in [Trp–H] and the
imidazole group in [His–H] [cf. PA(Trp) = 226.8 kcal mol1
o PA(His) = 236 kcal mol1].23 Migration of the alphahydrogen to the carboxylic group produces Trp2, a radical
cation with the radical and charge formally located on the alpha
carbon and the protonated carboxylic group, respectively. The
radical on Ca is thus stabilized captodatively (Trp2 is only
1.0 kcal mol1 above Trp1) with the amino group serving as an
electron donor and the protonated carboxylic group as an
acceptor.41,42 This tautomerization is, however, kinetically disfavored by a large barrier of 56.3 kcal mol1 (Table 2). Distonic
radical cation, Trp3, with a relative energy of 6.9 kcal mol1 can
be formed by transferring a proton from the CH2 of the side
chain to the amino group, leaving the radical delocalized over
the beta carbon and the p-system. Formation of Trp3 can
follow two pathways: (a) direct 1,3-proton transfer via the
transition structure Trp1TS3, or (b) two sequential 1,4-proton
transfers via transition structures Trp1TS4, Trp4TS5 (a rotation
about the Ca–C(OH)2+ bond) and Trp5TS3, and intermediates
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Fig. 5 Possible reactions of the tryptophan radical cation. The relative energies (DH10) are evaluated at the UB3LYP/6-31++G(d,p) level and
are in kcal mol1.
Trp4 and Trp5 (Fig. 5). The critical barriers in the two pathways
are almost identical and are about 30 kcal mol1 (Table 2). Trp3
is unlikely to form (due to competition to give the protonated
3-methyleneindolenine ion, see later) as it is expected to be
fragile against the fragmentation to give the indolylpropenoic
acid radical cation and NH3 (6.1 kcal mol1 versus Trp1), which
is not observed in the CID of Trp + (Fig. 1a and 2a). Starting
from Trp5, a 1,2-hydrogen shift from the Ca to Cb gives
Trp2 via the transition structure Trp5TS2. The energy
barrier of 46.7 kcal mol1 is lower than that of direct Trp2
formation via Trp1TS2, but still significantly higher than those
against the formation of Trp3, Trp4, and Trp5 (Fig. 5 and
Table 2).
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For comparison, the geometric optimizations for Tyr + and
Phe + have also been performed. The relative energies are
tabulated in Table 2 and the optimized structures are shown in
the ESI.w As with Trp +, the carboxyl radical cations are
metastable and proton transfer to give the p-radical cation
structures. The relative stabilization of the aromatic
delocalization in M1 against the captodative effect in M2
decreases with decreasing size of the aromatic system,
which is evident in the decreasing relative energy of the
three M2 structures from Trp (1 kcal mol1) to Tyr
(8.9 kcal mol1) and to Phe (16.3 kcal mol1), as well as
that of the three transition structures M1TS2. The same
decreasing trend is also apparent in the energies of the benzylic
Phys. Chem. Chem. Phys., 2008, 10, 5908–5918 | 5915
Table 2 Tautomerization and reaction energies (kcal mol1) of Trp +, Tyr +, and Phe +. The values were evaluated at the UB3LYP/631++G(d,p) level. The geometric structures are shown in Fig. 5 for M = Trp and in the ESIfn1w for M = Tyr and Phe
Relative energy/kcal mol1
Spin and charge density on the side chain R
M = Trp
M = Tyr
M = Phe
M = Trp
M = Tyr
M = Phe
M
DH10
DG1298
DH10
DG1298
DH10
DG1298
Spin
Charge
Spin
Charge
Spin
Charge
M1
M2
M3
M4
M5
M1TS2
M1TS3
M1TS4
M4TS5
M5TS2
M5TS3
M3-NH3
[H2NC HCOOH] + R+
[H2N+QCHCOOH] + R
0.0
1.0
6.9
30.0
18.2
56.3
30.2
28.8
30.9
46.7
17.3
6.1
20.5
45.5
0.0
1.5
6.6
29.9
18.6
56.6
30.3
29.2
31.5
47.4
17.8
3.7
8.4
33.4
0.0
8.9
2.6
21.2
9.3
47.0
23.8
20.8
21.5
38.3
8.2
5.1
18.5
32.4
0.0
8.1
2.4
21.5
10.0
47.4
24.3
21.7
22.5
39.4
9.2
4.5
6.8
20.8
0.0
16.3
7.8
16.1
3.9
39.2
21.8
17.7
16.1
33.3
3.3
8.3
22.0
24.3
0.0
15.4
8.0
16.3
4.5
39.8
22.3
18.7
17.1
34.4
4.5
1.5
10.8
13.3
0.89e
0.01e
0.92e
0.92e
0.78e
+0.88
+0.15
+0.22
+0.15
+0.33
0.68e
0.02e
0.92e
0.93e
0.82e
+0.68
+0.13
+0.20
+0.13
+0.28
0.54e
0.02e
0.93e
0.93e
0.88e
+0.55
+0.12
+0.18
+0.11
+0.22
+
radical cations M3, M4, and M5. All these observations are
consistent with the fact that the p-system on the side-chain of
Trp + is better able to stabilize the radical and the charge
than those of Tyr + and Phe +. It is also reflected by the
spin and charge density on the p-system of the side chain R in
M1, in which both exhibit the trend Trp1 4 Tyr1 4 Phe1
(Table 2).
As reported above, Trp + fragments prominently to give the
protonated 3-methyleneindolenine ion at m/z 130, a product of
side-chain cleavage involving the Ca–Cb bond. A potential
energy scan increasing the Ca–Cb bond distance in Trp1 resulted
in a monotonic increase in energy and the energy barrier against
this fragmentation is thus determined by its reaction energy. In
general, cleavage of the Ca–Cb bond can result in either
H2NC HCOOH+R+ (for Trp, R+ is the protonated 3-methyleneindolenine ion) or H2N+QCHCOOH+R . The competition between these two channels depends largely on the
ionization energy of the radical fragment, which is the major
contributor to the reaction energy.42,43 The adiabatic IEs of R
determined in this study are Trp, 142.4 kcal mol1; Tyr,
153.5 kcal mol1; and Phe, 165.1 kcal mol1. With the large
difference between the IE of the R for Trp and that of the
glycyl radical (167.4 kcal mol1 43 and determined as such at the
B3LYP/6-31++G(d,p) level), the reaction energy to give
H2NC HCOOH+R+ (20.5 kcal mol1) is considerably lower
than that to give H2N+–CHCOOH+R (45.5 kcal mol1)
(Table 2). For Phe, the comparable IEs of the benzyl
radical and the glycyl radical result in comparable reaction
energies to give H2NC HCOOH+R+ (22.0 kcal mol1) and
H2N+QCHCOOH+R (24.3 kcal mol1). These calculated
dissociation energies are consistent with the fact that both
H2N+QCHCOOH and the benzyl cation are observed in the
CID spectrum of [CuII(Phe)2] 2+ (Fig. 1c). For [CuII(Tyr)2] 2+
(Fig. 1b), in addition to the abundant R+ ion, the p-hydroxybenzyl cation, at m/z 107, the p-cresol ion at m/z 108 is
also evident.
To shed some light onto the appearance of this [R+H] +
ion, the proton affinities at the benzylic carbon of the three sidechain radicals (R ) are evaluated using DFT calculations
and compared with the PA at the imine nitrogen of
HNQCHCOOH (Table 3, not all PAs are available in the
NIST Chemistry WebBook;23 those that are listed are comparable). The proton affinity of C6H5CH2 (203.6 kcal mol1) is
slightly larger than that of HNQCHCOOH (202.4 kcal mol1).
This difference in the PAs of 1.2 kcal mol1 for phenylalanine
increases significantly to 15.4 kcal mol1 for tyrosine and to
29.6 kcal mol1 for tryptophan. Combining the DFT results for
Tyr suggests that the dissociation of Tyr + giving
H2NC HCOOH+R+ is energetically more favorable than that
giving H2N+QCHCOOH+R ; if this latter channel is open,
Table 3 Proton affinities DH1298 (kcal mol1) of HNQCHCOOH
and the side-chain radical (R ) of Trp (3-metheneindolenine radical),
Tyr (p-hydroxylbenzyl radical), and Phe (benzyl radical)a
This workb
Literature valuesc
HNQCHCOOH R (Trp)
R (Tyr) R (Phe)
202.4
217.8
214.3
232.0
a
203.6
198.7
Protonation sites at the imine nitrogen for HNQCHCOOH and the
benzylic carbon for R . b At UB3LYP/6-31++G(d,p) level. c NIST
Chemistry WebBook.23
5916 | Phys. Chem. Chem. Phys., 2008, 10, 5908–5918
Fig. 6 Transition structures of [CuII(tpy)(Phe)] 2+ that lead to loss of
NH3. The transition energies DHz0(DGz298) are relative to the most
stable structure 1 as shown in Fig. 4. All energies are evaluated at the
UB3LYP/6-31++G(d,p) level and are in kcal mol1.
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an internal proton transfer is likely between the incipient
products thereby yielding HNQCHCOOH and [R+H] +
(due to the large difference of 15.4 kcal mol1 in the PAs
between HNQCHCOOH and R ). The [R+H] + ion is
expected in the dissociation of Phe +, as the R has a larger
PA than HNQCHCOOH, and the dissociation channel giving
H2N+QCHCOOH+R is open as shown by the presence of
H2N+QCHCOOH in Fig. 1c. The fact that the toluene
radical cation is absent signifies that proton transfer within
the H2N+–CH(COOH) R complex does not occur. We
attribute this to the relatively high internal energy and high
dissociation rate of this complex under CID conditions. In a
recent photodissociation experiment of Phe +, both the benzyl
cation (m/z 91) and the toluene radical cation (m/z 92) were
observed.44 The presence of [R+H] + in the photofragmentation of Phe +, but not in our CID experiment of
[CuII(Phe)2] 2+ is probably because the former was performed
under conditions in which little excess energy was imparted
onto the dissociating Phe +.
Elimination of NH3 from [CuII(tpy)(Phe)] 2+
As previously shown, the loss of NH3 is a common channel in
the CIDs of [CuII(4Cl-tpy)(M)] 2+ (Fig. 2) and that of
[CuII(tpy)(M)] 2+.15 For Tyr and Phe, the resulting
[CuII(4Cl-tpy)(M–NH3)] 2+ product ion further dissociates
to give [CuI(4Cl-tpy)]+ and [M–NH3] +, the latter of which
subsequently eliminates CO2 to yield [M–NH3–CO2] +. The
loss of NH3 is a facile reaction in the dissociations of the
[M+H]+ ions of Trp, Tyr, and Phe.24 The critical transition
structure that leads to the dissociation products has been
proposed to involve a ‘‘phenonium-type’’ ion.24,25,45–47 In
investigating the mechanism for the elimination of NH3 from
[CuII(4Cl-tpy)(M)] 2+ and subsequent dissociations, we chose
to center our examination on [CuII(tpy)(Phe)] 2+ as the prototypical complex. The Phe component in the lowest-energy
structure of [CuII(tpy)(Phe)] 2+, structure 1 (shown in
Fig. 4a), closely resembles the structure of [Phe+H]+.24 For
protonated Phe, elimination of NH3 can be achieved via two
reaction pathways: (a) a 1,2-hydride shift from Cb to Ca
thereby forming a benzyl cation and displacing NH3, or (2)
a neighboring-group displacement by the phenyl ring thereby
giving a phenonium-type ion.24,25,45–47 The analogous transition structures for [CuII(tpy)(Phe)] 2+ are shown here in Fig. 6
(all energies are relative to structure 1). As for protonated Phe,
the energy of the transition structure for the 1,2-hydride shift
(44.7 kcal mol1) is higher than that involving the phenoniumtype ion (36.1 kcal mol1). A third possible competing channel
that we investigated involves a different type of neighboringgroup displacement that begins with a nucleophilic attack on
the Ca carbon by the free carboxylic oxygen thereby yielding a
lactone intermediate; this mechanism was proposed for the
minor NH3 loss in the CID of protonated arginine.48
The transition structure for this third pathway has the
highest energy (46.5 kcal mol1). As a result, the most
plausible structure for [CuII(tpy)(Phe–NH3)] 2+ involves a
phenonium-type ion.
The energy surface for the dissociation of the [Phe–NH3] +
ion (m/z 148) is shown in Fig. 7. The most probable
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Fig. 7 Energy surface for the dissociation of [Phe–NH3] +. The
relative energies DH10 (DG1298) are evaluated at the UB3LYP/631++G(d,p) level and in kcal mol1. The spin and charge densities
are calculated by natural population analyses.
[Phe–NH3] + ion formed via dissociative electron transfer in
[CuII(tpy)(Phe–NH3)] 2+ is structure I (Fig. 7). Structure I is a
distonic radical cation with the radical located at the COO
group and the positive charge mainly on the 6-membered ring
(+0.6). The carboxyl radical in I has limited stability against
CO2 loss (with a barrier of only 5.2 kcal mol1) to give a
second metastable phenonium-type radical cation II. This
latter radical cation undergoes very facile ring-opening to give
the styrene radical cation III (m/z 104).
Conclusion
The CIDs of [CuII(M)2] 2+ produce abundant M + and/or its
secondary products. By contrast, the CIDs of [CuII(4Cltpy)(M)] 2+ produce abundant M + only for Trp. The common
dissociation channel is one that gives [CuII(4Cl-tpy)(M–NH3)] 2+,
which for Tyr and Phe further produces [M–NH3] + and
[M–NH3–CO2] +. For Phe, the dissociation of [CuII(4Cltpy)(M)] 2+ to give abundant H2N+QCHCH2C6H5, the iminium ion, and [CuII(4Cl-typ)(COOH)] + is also evident; the latter
loses CO facilely to give abundant [CuII(4Cl-typ)(OH)] +. DFT
calculations show that in [CuII(tpy)(M)] 2+ the lowest-energy
structure contains a zwitterionic amino acid. Dissociative electron
transfer in [CuII(tpy)(M)] 2+ results in immediate, intramolecular
proton transfer giving the canonical M + with the charge and the
radical delocalized on the aromatic ring. This is the preferred
reaction for Trp. For Phe, the amino-acid displacement reactions
leading to the observation of [CuII(tpy)(H2O)] 2+ and
[CuII(tpy)(CH3OH)] 2+ have lower barriers than dissociative
electron transfer. Neighboring-group displacement by the aromatic ring in [CuII(tpy)(M)] 2+ results in a phenonium-type
[M–NH3] +. The [Phe–NH3] + radical cation loses CO2 facilely
to give [Phe–NH3–CO2] +, a metastable phenonium-type ion that
opens up readily to give the styrene radical cation.
Acknowledgements
This work was made possible by funding from the Natural
Sciences and Engineering Research Council (NSERC) of
Phys. Chem. Chem. Phys., 2008, 10, 5908–5918 | 5917
Canada and by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET: http://
www.sharcnet.ca).
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