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Template for Electronic Submission to ACS JournalsMay 15, 2014
Volume 4 Number 1
Arizona Computational Students
projects of the students in the chemistry
course C518, Computational Chemistry, in
the spring semester of 2014. This
document is solely for the use of the
instructor and students in this course and
all other uses are strictly forbidden without
the consent of the instructor.
i
Computational Studies on the Mechanism of Stereospecific Alcohol
Addition to
Acetonitrile Activated [Re6(µ3-Se)8] 2+
Melissa C. Fairley*, Dennis L. Lichtenberger, Zhiping Zheng Pages
1-4
Department of Chemistry and Biochemistry, The University of
Arizona, Tucson, Arizona 85721
Structure Stability Based on Isomerization of a Tm (III) Complex of
Pyridine-N-Oxide
Analogue of DOTA as Investigated by DFT
Adwoa K. Sasu*, Dennis L. Lichtenberger, Mark Pagel Pages 5-8
Department of Chemistry and Biochemistry, University of Arizona,
1306 E. University Blvd., Tucson, AZ 85721
Theoretical Search Using NMR as a Tool for Finding dia-CEST
Contrast Agents with
Highly Shifted Exchangeable Protons
Luis A. Montano, Julio C. Cardenas-Rodriguez, Dennis L.
Lichtenberger, Mark Pagel Pages 9-13 aDepartment of Chemistry and
Biochemistry, University of Arizona, Tucson, AZ, USA bArizona
Cancer Center, University of Arizona, Tucson, AZ 85724-5024, USA
cDepartment of Biomedical Engineering, University of Arizona,
Tucson, AZ, USA
Dennis
Dennis
pKa change of cis-retinalidene with the rotation of β-ionone
ring
Soohyun Lee, Dennis L. Lichtenberger, Michael F. Brown Pages
14-16
Department of Chemistry and Biochemistry, The University of
Arizona, Tucson, Arizona 85721, United States
Computational Study on Electron Reduction of Disulfides and
Peroxides
Seyed A. M. Fathi and Dennis L. Lichtenberger Pages 17-20
Department of Chemistry and Biochemistry, The University of
Arizona, P.O. Box 210041, Tucson, Arizona 85721, United
States
µ
Department of Chemistry and Biochemistry, The University of
Arizona, Tucson, Arizona 85721
KEYWORDS: chalcogenide and halide clusters, Z and E isomers,
alcohol addition, Amsterdam Density Functional (ADF)
ABSTRACT: The [Re6(µ3-Se)8] 2+
cluster core has been studied for potential catalytic
schemes as a highly efficient and recyclable catalyst. The core’s
lewis acidity allows
for the activation of the acetonitrile ligand on
{Re6(µ3-Se)8(PEt3)5[NH=CH3]} 2+
to go
through alcohol addition forming predominantly the Z-isomeric imino
ester complex
with the E-isomer in low yield. This alcohol addition proposed
mechanisms were
studied using Density Functional Theory (DFT) by Amsterdam Density
Functional
(ADF) to explain the specificity and the factors that control it.
This computational
results show that the Z-isomer is slightly more prominent, but not
to the extent of
what has been experimentally observed. The solvent and gas phase
calculations show
that the solvent does not change the outcome of the computations
drastically. The
thermodynamic equilibrium is close to one suggesting that the
difference is not a
thermodynamic explanation.
Se)8] 2+
cluster is one of the transition chalcogenide and halide
clusters that is being studied due to its high synthetic
yields,
aerobic stability and reactivity to solution-phase ligand
substi-
tution for altering properties 2 .
The [Re6(µ3-Se)8] 2+
octahedron geometry composed of metal-metal Re atoms face-
capped with Se atoms. Due to the multiple reactive metal
sites
ligand substitution reactions via site specific
functionalization
allows for an altered electronic structure, physical
properties,
and chemical reactivity 3 . The lewis acidity of this cluster
al-
lows for the activation of otherwise inert ligands to
chemical
reactions 1 .
Se)8(PEt3)n(CH3CN)6-n] 2+
. The iodo ligand is reactive, but can
be substituted by a stronger ligand; due to the inert core,
the
cluster is stereochemically fixed in a given isomer 2 .
It has previously been found that the cis- and transaddition
of
alcohols, methanol and ethanol, to the [Re6(µ3-
Se)8(PEt3)n(CH3CN)6-n] 2+
dance. Previous studies using similar chemical systems for
alcohol addition to metal-activated acetonitrile clusters
have
resulted in similar Z/E ratio with the E-isomer being
slightly
favored. An example of this is the addition of alcohols to
[PtCl3(RCN)] where the Z-isomer isomerizes to the E-form
with the exception of HOtBu 4,5
. Another example is with
[Pd(C6F5)2{NH=C(OMe)Me}2] was isolated in pure E-isomer
form 4 . It has been explained with a proposed mechanism for
the [Re6(µ3-Se)8] 2+
structures.
Figure 1. Structure and Mechanism of cis- and trans- alcohol
addition resulting in Z- and E-isomers (PEt3 groups are not
included for simplicity) 1
These mechanism shows that in the Z-isomer is formed more
predominantly because of hydrogen-bonding involving the
1
alcohol –OH group and the Se atoms of the cluster 3 . When
increasing the steric bulk of the alcohol it reduces the
effec-
tiveness of the addition but the Z/E-isomer ratio remains
con-
stant 1 . Each isomer Gibbs free energy has been reported to
support the experimental observations 6 . These studies were
inconclusive as to why the Z-isomer is predominantly present
because similar energies were calculated for each isomer with
no further studies into other factors of this specificity.
This
computational study is to further investigate the observed
iso-
meric predominance taking into account the acetonitrile iso-
mers free from the complex specificity.
BACKGROUND
The core has been structurally described and understood, but
there is restricted amount of structural data with respect to
the
Z- and E-isomers. The Z-isomer crystal structure is shown in
Figure 2 while the crystal structure for the E-isomer is still
not
determined 2 .
Se)8(PEt3)5[NH=(OCH3)(CH3)]} 2
using 1 H-NMR and
proximately 94.5% Z-isomer and 5.5% E-isomer 1 . The NMR
peaks do no change in standing solution indicating that
inter-
conversion of isomers does not occur under ambient condi-
tions on an NMR scale 3 .
Two different computational studies have been completed
previously using the ADF method. The reported difference in
energies where the more stable isomer, Z-isomer in both
cases,
is the zero point energy are shown in Table 1.
Table 1. Previously reported calculated difference in en-
ergies for Z- and E-isomers
These studies did not distinguish the E- and Z- isomers with
a
small Gibbs free energy difference between the two different
isomers 6,7
. The fraction in the E-isomer for the first study is
0.35 and for the second is 0.20. To have a ratio of 95:5,
Z:E-
siomer, at room temperature there would need to be an energy
difference of 0.08 eV. These studies did not solvation ener-
gies, dispersion energies, or frequency calculations
therefore
fewer assumptions are being made here than in previous stud-
ies.
Density Functional ADF 2010.2 code. The xyz coordinates
for the Z-isomer were obtained from the crystallographic data
and the E-isomer’s were obtained Livera, et al. To account
for
scalar relativistic functions the Zero Order Regular Approxi-
mation (ZORA) method was used. Geometry optimization of
these clusters was completed using small frozen using a
triple-
γ polarization functions (TZP) for all atoms. Electron
correla-
tion effects were treated using Generalized Gradient Approx-
imation (GGA) using the exchange correlation made by
Perdew-Burke-Ernzerhof in 1996 (PBE). A dispersion correc-
tion was used to the total bonding energy (Grimme3
BJDAMP). For the samples with solvent, a single point sol-
vent calculation was completed using solv=methanol. These
were all calculated again for the free molecule Z and
E-isomer
as well as analytical frequencies were also computed for both
isomers in solvent and gas phase. The free isomers were also
optimized in solvent, MeOH, as well as the gas phase for
comparison. This was completed by using solvation, solv
name=methanol, with the geometry optimization 8 . The xyz-
coordinates were obtained using Spartan’ 14 Student Edition,
version 5.01 9 .
RESULTS AND DISCUSSION
The geometry was optimized for both isomers and the Z-
isomer optimization is compared to the crystal structure in
Table 2.
Table 2. Bond lengths and bond angles for (a) crystal and
(b) calculated structures of Z-isomer
Thes
e
cal-
cu-
lated
val-
ues
are
with
in
0.03
3- 0.07 Å for bond length and 2.99- 3.66 for the bond angles
when compared to the crystallographic data. The crystallo-
graphic data is not available for the E-isomer therefore there
is
no comparison available.
The frequency calculations were completed for the Z and E-
isomers of the cluster as well as the free Z and E-isomers of
acetonitrile in different conformations and are shown in
Tables
S2-S5 in the Supporting Information.
The frequency calculations are shown for the free isomers
in solvent and gas phase are displayed in Table 3.
Reference Energy
C-O ( Å) 1.385 1.334
Re-N-C () 137.84 134.18
C-O-C () 122.41 119.42
and gas phase
c Methanol solvent, COSMO model
The data shown in Table 3 shows the difference between the
isomers in solvent and gas phase are very small.
This frequency calculations shows that there is very little
difference in energy stability between the two isomers of the
cluster which has previously been shown. The most stable
conformers were used to find the thermodynamic equilibrium
constant. Thermodynamic equilibrium was also calculated for
the Z and E-isomers of the cluster; both are shown in Table
4.
Table 4. Thermodynamic equilibrium constant for both
Z- and E-isomers free and cluster based
The ΔG difference is between the Z and E-isomer single point
solvent. The thermodynamic equilibrium constant are close to
one showing the isomers both in free form and cluster-based
are calculated to be at equal concentrations which does not
explain the difference in the experimental observations be-
tween the Z and E-isomers.
CONCLUSION
This computational study explored the differences between the
Z and E-isomers of {Re6(µ3-Se)8(PEt3)5[NH=(OCH3(CH3)]} 2+
via analytical frequency calculations to determine the
thermo-
dynamic equilibrium constants. These constants show that the
Z-isomer is favored slightly in each the free isomer and
cluster
bound. The complexation improves the stability of the Z-
isomer slightly. The other aspects explored in this study
com-
pared to previous works were solvation effects and dispersion
energies. Both of these do not distinguish between the two
isomers. The difference in energy difference is not large
enough (0.07 eV) to explain the 95:5 ratio that is observed
experimentally.
Future work that is suggested to explain the specificity of
this chemical system would be to explore other similar
transi-
tion metal activations for methanol addition such as in the
case
of the Pd and Pt examples. The next would be to explore the
transition state proposed by the mechanisms in Figure 1.
These possible intermediates are proposed to be stabilized by
hydrogen bonding between the alcohol group with the two Se
atoms of the cluster.
two conformers of each isomer and geometry optimized xyz-
coordinates for Z and E-isomers free and attached to cluster.
This
material is available free of charge via the Internet at
http://pubs.acs.org.
*Email address: fairley@email.arizona.edu
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
Gas Phase
ZPE(g) 2.68 2.68 0.00
H(v,T,g)b 2.83 2.83 -0.0
-TS(T,g,total) -0.95 -0.94 0.00
-TS(T,g,translational) -0.50 -0.50 0.00
-TS(T,g,rotational) -0.33 -0.33 0.00
-TS(T,g,vibrational) -0.12 -0.11 0.00
ZPE(solv) 2.67 2.67 0.00
H(v,T,solv)b 2.82 2.82 0.00
-TS(T,solv) -0.95 -0.95 0.00
3
The author would like to thank students in CHEM 518 class as
well as members of the Zheng group at University of Arizona.
(1) Orto, P.; Selby, H. D.; Ferris, D.; Maeyer, J. R.; Zheng,
Z.
Inorg. Chem. 2007, 46, 4377-4379.
(2) Zheng, Z.; Long, J. R.; Holm, R. H. J. Am. Chem. Soc.
1977, 119, 2163.
(3) Zheng, Z. Dalton Trans. 2012, 41, 5121-5125.
(4) (a) Kukushkin, Y. V.; Pombeiro, A. J. L. Chem. Rev. 2002,
102, 1771; (b) Pombeiro, A. J. L.; Kukushkin, Y. V.
Compr. Coord. Chem. II 2004, 1, 639.
(5) (a) Kaminskaia, N. V.; Guzei, I. A.; Kosti, N. M. J.
Chem.
Soc., Dalton Trans., 1998, 3879; (b) Chin, C. S.; Chong,
D.; Lee, B.; Jeong, H.; Won, G.; Do, Y.; Park, Y. J. Or-
ganometallics, 2000, 19, 638.
(6) Livera, V. S.; Lichtenberger, D. L.; Zheng, Z.; J. Ariz.
Comp. Chem. Stud.
Andres Bello, Santiago, Chille, unpublished results.
(8) Amsterdam Density Functional (ADF) program, Release
2010.02, SCM, Theoretical Chemistry, Vrije Universiteit,
Amsterdam, The Netherlands, 2010.
CA, Except for molecular mechanics and semi-empirical
model, the calculation methods used in Spartan have been
documented in: Y. Shao, L.F. Molnar, Y. Jung, J. Kuss-
mann, C. Ochsenfeld, S. T. Brown, A. T. B. Gilbert, L. V.
Slipchenko, S. V. Levchenko, D. P. O’Neil, R. A. DiStasio
Jr., R. C. Lochan, T. Wang, G. J. O. Beran, N. A. Besley, J.
M. Herert, C. Y. Lin, T. Van Voorhis, S. H. Chien, A. Sodt,
and R. P. Steele
Department of Chemistry and Biochemistry, University of Arizona,
1306 E. University Blvd., Tucson, AZ 85721
KEYWORDS: Lanthanide, Density Functional Theory, Contrast
Agents
ABSTRACT: Lanthanide (III) complexes that are stable in aqueous
solution have received a considerable amount of atten- tion
recently because of their important application as contrast agents
in magnetic resonance imaging (MRI). Particularly of interest are
lanthanide (III) complexes with macrocyclic ligands derived from
1,4,7,10-tetraazacyclododecane (cyclen) due to their high
thermodynamic stability and kinetic inertness. Therefore, a better
understanding of the structure and
dynamics of these systems in solution will aid in the rational
design of more efficient contrast agents. In this work, densi- ty
functional theory (DFT) calculations were preformed to optimize the
geometry and frequency calculations of Tm(III) H3do3apyNO. It was
found that the square antiprism (SA) and the twisted square
antiprism (TSA) isomers were similar in
thermodynamic stability based on thermodynamic data found in
frequency calculations. The key bond lengths and angles for the SA
isomers were, found to be in good agreement with crystallographic
data of the SA isomer found in literature.
INTRODUCTION
In the last twenty years, gadolinium (III) complexes with
poly(aminocarboxylate) ligands have been of great interest because
of their common use as contrast agents (CAs) in MRI. For example,
the macrocycle cyclen- 1,4,7,10-tetraacetic acid (DOTA) Figure 1 is
commonly
used ligand designed for this purpose. 1 The efficiency of
Gd (III)- based CAs is dependent on relaxivity, therefore a large
variety of related compounds have been carefully investigated and
have revealed the basic relationships between the molecular
structure of ligands and complex-
es and how they function as CAs. 2 with this understand-
ing, new possibilities to improving the low efficiency of the
first-generation CAs have emerged. One challenge that is
encountered in the development of high-efficiency CAs is the
optimization of the exchange rate of the water molecule bound to
the Gd (III) ion with the bulk water
molecules. The two factors that affect water exchange are the
charge of the complex and the steric strain at the wa-
ter coordination site. 3 Varying the charge of the complex
has two drawbacks, there are a limited number of options and
intravenous application of highly charged complexes is problematic.
For this reason, tuning the steric strain has become the main focus
of increasing water exchange.
5
2
(III) metal ions for MRI. 12
Monohydrated Ln (III) chelates go through a dissocia- tion or
dissociative interchange mechanism during water
exchange. 4 Hence, marginally increasing steric strain at
the water-binding site accelerates the dissociation of the water
molecules and therefore, increases the exchange rate. The steric
strain can be altered either directly or in- directly based on the
method of modification of the lig- and. For instance, the direct
approach employs sterically more demanding pendant arms or produces
the steric strain by increasing the number of atoms in the
macrocy-
cle. 5 On the other hand; the indirect approach modulates
steric strain via isomerism of the complexes.
The coordination of DOTA and other related octaden- tate ligands to
the Ln (III) ions are known to demonstrate two stable arrangements,
a square antiprism (SA) and a twisted square antiprism (TSA) Figure
2. The TSA struc- ture was found to have a water exchange rate 50
times faster than that of the SA isomer, therefore ways to
favor
the formation of the TSA isomer has been investigated. 5
The isomer typically exists in a dynamic equilibrium via the
inversion of the macrocycle and a rotation of the pen- dant arms.
Yet, proper modification of the ligand back- bone can hinder the
equilibrium and thus, lock the geom-
etry in either the TSA or SA arrangement. 5 In this work,
DFT calculations will be employed to confirm the stability of the
TSA and SA isomers through thermodynamic data of the
complexes.
Figure 2: Illustration of isomerization between SA and TSA isomers.
Metal center has been removed for clarity.
EXPERIMENTAL SECTION
formed using the Gaussian 09 package. 6 The Density
Functional Theory method was used in these computa- tions. A
combination of an exchange functional with the desired correlation
functional was employed SVWN5. The (S) request the slater exchange
functional and the VWN5 correlational functional fits the
Ceperly-Alder solution to
the uniform electron gas. 7 The basis set the was used was
SDD, which is the combination of the Huzinaga-Dunning double ζ
basis set on lighter elements with the Stut- gart/Dresden basis set
relativistic effective core potential
for the metal. 8
from published crystallographic data. 9 The input geome-
try for the TSA isomer was generated with the student Spartan
program. Geometry optimizations were carried out without symmetry
restrictions. To confirm that the geometry optimizations were at a
true minimum, vibra- tional analysis was conducted.
RESULTS AND DISCUSSION
Geometry optimizations performed on the SA isomer at the SVWN5/SDD
level provided Tm-N bond distances between 2.5-2.6 angstroms and
Tm-O bond distances be- tween 2.25-2.27 angstroms (Table S1 in the
supporting information). These bond lengths were in good
SA isomer TSA isomer
6
3
Table 1: Comparative energies (eV) of the SA and TSA isomers at
298.15 K.
Gas Phase
ZPE -74208.07 -74208.09 0.02
G(g) = Ee + H – TS -74194.99 -74190.06 -4.93
agreement with the X-ray crystal structure. The key bond angles
that were measured were also found to be agreement with the X-ray
data. The small difference in measured bond lengths and angles
between the opti- mized structure and X-ray data, illustrates that
the SVWN5 functional and SDD basis set are reasonable for these
types of calculations.
Through vibrational analysis and statistical thermo- dynamics, the
standard thermodynamic parameters; entropy, enthalpy and Gibbs free
energy were calculated at 298.15 K at the SVWN5/SDD level Table 1.
The iso- mers were found to be similar in thermodynamic stabil- ity
yet, the SA isomer, is slightly favored by -4.93 eV. This is due to
the release of steric strain when the pen- dant arms and macrocycle
rotated and inverted during isomerization between SA and TSA form.
The basis of
these calculations was confirmed by literature data of 1 H
NMR spectra. 9 Due to a large sensitivity of the lantha-
nide-induced-shift (LIS) effect to structural changes,
thus confirming thermodynamic data with 1 H NMR data
is reasonable. It shown that the SA isomer in the 1 H
NMR spectra was more dominant in comparison to the TSA
isomer.
CONCLUSION
In conclusion the optimized geometries of the SA and TSA isomers
were determined to have similar thermo- dynamic stability. The SA
isomer was slightly favored by -4.93 eV respectively. Key bond
lengths and angles were in agreement with X-ray data for the SA
isomer, thus illustrating the accuracy of the SVWN5 functional and
SDD basis set used. In future work a higher level func- tional the
takes into account the unpaired electrons of
the system will be employed in order to determine spec- troscopic
data, such as 1H NMR spectra of the isomers.
ACKNOWLEDGEMENT
The author thanks Dr. Dennis Lichtenberger for all of his support
and help with the computations for this pro- ject. The author would
also like to thank CHEM 518 stu- dents at The University of
Arizona, spring 2014 for their help and guidance.
SUPPORTING INFORMATION
Computational input files, XYZ coordinates of studied molecules and
experimental results are available in sup- porting
information.
REFRENCES
1. Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauf-
fer, R. B. Chem. Rev.1999, 99, 2293–2352.
2. Aime, S.; Botta, M.; Fasano, M.; Terreno, E.
Chem. Soc. ReV. 1998, 27, 19–29.
3. Parker, D.; Puschmann, H.; Batsanov, A. S.; Se-
nanayake, K. Inorg. Chem. 2003, 42, 8646–8651.
4. Merbach, A. E.; To´th,E´ . The Chemistry of
Contrast Agents in Medical Magnetic Resonance
Imaging; John Wiley & Sons: Chichester, U.K.
5. Ruloff, R.; Scopelliti, R.; Tripier, R.; Handel, H.;
Merbach, A. E. Chem. Commun. 2002, 2630–
2631.
6. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
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Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
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R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
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Morokuma, V. G. Zakrzewski, G. A. Voth, P.
Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J.
Cioslowski, D. J. Fox, Gaussian, Inc., Walling-
ford CT, 2009.
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48, 466-475.
Department of Chemistry and Biochemistry, The University of
Arizona, Tucson, Arizona 85721, United States
Department of Chemistry and Biochemistry at The University of
Arizona P.O. Box 210041, 1306 East University Blvd., Tucson, AZ
85721-0041.
Email: keivin7shlee@email.arizona.edu
ABSTRACT: Bacteriodopsin uses 13 cis-retinalidene as a proton pump.
We ran MP2 6-31G* calculation to examine the pKa change of 13
cis-retinalidene as a function of the β- ionone ring rotation.
Gaussian09 with semi-relaxed energy scan method was used to obtain
the energy at every 15o of C5=C6-C7=C8 dihedral angle. Later,
single point energy of each rotated structure was calculated to get
the energy of the water solvated molecule. Calculation showed that
the β- ionone ring rotation changed pKa from 18.5 to 19.3, but the
pKa of the aspartic acid was 14.6. This suggests that better
solvation model and that information on some other con- formational
change is needed in order to study bacteriodop- sin proton transfer
pathway.
Bacteriorhodopsin, embedded in the inner membrane of the
halobacteria, is known to convert the light energy to the pro- ton
gradient energy [1]. This proton gradient energy is then used by
the ATP synthase to provide energy in halobacteria. The
bacteriodopsin proton transfer pathway in halobacteria is well
known. First, the trans-retinalidene inside the protein is first
protonated by the proton from the intracellular side. Upon the
light activation, the bacteriorhodopsin’s trans- retinalidene
changes its conformation to 13 cis-retinalidene [1]. After the
change in conformation, proton is donated by the 13
cis-retinalidene to a nearby aspartic acid located on the
extracellular side. Then finally, the proton is released by the
rhodopsin to the extracellular side. The pKa change of the
trans-retinalidene as a function of β-ionone ring rotation is
already calculated by Scott F. et. al., and it is shown that the
trans-retinalidene changes pKa from 7 to 9 with the β-ionone ring
rotation [2]. In the same manner, pKa change of the 13
cis-retinalidene is calculated in this paper. For this calcula-
tion, Gaussian09’s semi-relaxed energy scan method is used. All the
calculation is done at the MP2 6-31G* level. MP2 is used because
only MP2 is capable of reproducing experi- mental pKa of
trans-retinalidene’s Schiff base,7.4±0.1 [2]. The C6=C7-C8=C9
dihedral angle that cis-retinalidene is going to have when it is
releasing the proton to the other side of the membrane can be shown
by the study of the pKa change as the function of the β-ionone ring
rotation. Similarly, it has been found that that a tryptophan
replaces and rotates away
the β-ionone ring in bovine rhodopsin during the rhodopsin
activation process [3].
Figure 1 Picture of the protonated 13 cis-retinalidene
Figure 2 Picture of the changing from trans- to cis- configu-
ration. Deprotonation to extracellular matrix is expected to
follow. Picture from wikipedia
BACKGROUND: Brian Kobilka of Stanford received a Nobel Prize for
correctly predicting the mechanism of rhodopsin activation process
in bovine rhodopsin. Notable changes of the rhodopsin activation
included the rotation of the β- ionone ring. Due to the functional
importance in vision pro- cess, numerous studies were done on the
structure of rho- dopsin, both bovine and bacteriodopsin. UC Irvine
crystal- lographers found out that the activated bacteriodopsin had
11 cis-retinalidene. Researchers figured out the retinalidene’s
role as a proton pump when they first found the bacteri- orhodopsin
in halobacteria. For the pKa of aspartic acid cal- culation,
L-aspartic acid was used. Since the aspartic acid is part of the
bacteriodopsin, which is a transmembrane pro- tein, and most
transmembrane proteins are in alpha helix, the aspartic acid was
assumed to be part of the alpha helix as well. Therefore the two
dihedral angles, φ and ψ, of the as- partic acid were fixed to -48
and -57 (from the Ramachan- dran plot). Hydrogens were connected to
the N terminal and the C terminal of the aspartic acid. For the
chemical model, the protein that surrounds the ligand was ignored.
Lastly, there exists hydrogen bonding between Schiff base and
as-
14
2
partic acid which could facilitate the proton transfer process.
Møller-Plesset 2, is an ab-initio method that includes Møller-
Plesset electron interaction energy term to the second order. Basis
set 6-31G*, for Carbon, uses six Gaussian functions to mimic S-type
shell, 3 Gaussian functions to mimic SP-type valence orbital, and
another 1 Gaussian function to SP-type valence orbital. Star
indicates that the 6-31G carbon is aug- mented with one s- and one
p-type diffusion functions.
EXPERIMENTAL: First, the structure of 13 cis-retinalidene was drawn
using Spartan student. After drawing the struc- ture, all double
bonds were made coplanar so that all dihe- dral angles with double
bonds at both ends were set to 0o. Then the 13 cis-retinalidene
geometry in xyz coordinates was copied to the data section of the
Gaussian input file. After the geometry information, a Gaussian
command was given that the dihedral angles that were set to 0o stay
at that angle throughout the geometry optimization. However, C5=C6-
C7=C8 (C5=C6 is the double bond in the β-ionone ring) di- hedral
angle was not fixed but a Gaussian command was given that
C5=C6-C7=C8 bond was rotated by 15o for 15 times and geometry
optimization followed after each rotation. Then the same procedure
was followed with protonated 13 cis-retinalidene. However, both the
spin multiplicity and the charge of the protonated molecule were
set to 1 instead of 1 and 0. The Gaussian calculation was done in
the gas phase using 6-31G* basis set and at MP2 level of theory.
Solvation calculation was done using Gamess 2013 and SM8 solvent
model. SM8 solvent calculation was not only based on the optimized
geometry but also on the gas phase energy of the structure. In
total 15x2 input files were generated. Specific commands to run the
SM8 solvent model were given in the manual of GAMESSSPLUSS. SM8
solvent model calculation was done using 6-31G* basis set and B3LYP
level of theory. Solvation calculations were done on a local
machine. pKa is calculated using the formula pKa=ΔGaq/(2.303*RT).
Where ΔGaq = Gaq(SB) + Ggas(H
+) + ΔGsolvation(H+) - Gaq(PSB) + RTln(22.4L/1L). SB stands for
Schiff base and PSB stands for protonated Schiff base, Schiff base
is the moiety in the reti- nalidene molecule that gets protonated.
Last term is the change in free energy when the system changes from
1mol in 24.7L to 1mol in 1L at constant temperature and adding it
is necessary because the reference state of Ggas is RTln(24.7L/1L)
higher than Gaq, and ΔGsolvation(H+) = Gaq(H+) - Ggas(H
-). Values of Gaq(H+) and ΔGsolvation(H+) were experi- mentally
obtained as -6.28 kcal/mol and -264.61 kcal/mol respectively [4].
Finally the equation can be simplified as pKa = [Gaq(SB) – Gaq(PSB)
− 269.0]/1.3644. Both Gaq(SB) and Gaq(PSB) can be obtained from SM8
calculation. The units are in kcal/mol and the temperature is at
25oC [2]. Later the calculated pKa was compared to the
experimentally deter- mined pKa of bacteriodopsin, 14.5 [5].
Conversion factor used was 1 hatree = 627.51 kcal/mol.
Results and Discussion:
First, a question that there could be protonation site other than
the nitrogen was asked. Electrostatic potential map from Spartan
student showed that the nitrogen of the Schiff base was the most
likely site to get protonated.
Figure 3 Electrostatic potential map of both deprotonated and pro-
tonated 13 cis-retinalidene. Both were colored on the same energy
scale.
After finding out the likely protonation site, the difference in
free energies of the protonated and deprotonated form was taken to
calculate the pKa of the 13 cis-retinalidene. Two methods were used
to calculate the pKa. First method recal- culates the single point
energy of each optimized structure in an implicit water solvent
using Gaussian.
Figure 4 pKa of the cis-retinalidene versus the degree of rotation
of β-ionone ring. When selecting the dihedral angle, the atom order
was C8, C7, C6, C5.
In second method, solvation energy was calculated using optimized
gas phase geometry and energy. Only some of the calculations were
done. Angles were chosen so that from Figure3, the dihedral angles
that gave the extreme pKa were chosen.
Figure 5 pKa of the cis-retinalidene. Solvation was done using SM8
solvent model. Polynomial trend line was drawn to predict the pKa
at other angles.
The calculated was negative and it was far below the calcula- tion
of the Gaussian method. The negative value in pKa re-
18.5
18.8
19.0
19.3
p K
-10
-8
-6
-4
-2
0
2
4
6
p K
15
3
sulted because the difference in Gaq (SB) and Gaq(PSB+) was small
in SM8, smaller than 0.43 hatree or 269 kcal/mol. Both Gaq values
were negative and charged cation was more nega- tive because of the
favorable interaction between the polar solvent and the cation
despite the energy cost to orient the solvent to accommodate the
positive charge [6]. However, the fact that SM8 solvent model
wasn’t as effective as Gaussi- an in stabilizing the charged
molecule was evident from the smaller difference in Gaq. Both
Gamess and Gaussian solva- tion method were based on the
polarizable continuum model (PCM) [7]. Solvation equation of the
Gamess was further studied to explain the negative pKa. One
possible explanation could be SM8 calculation included the cost of
distorting the charge distribution of molecule to be
self-consistent with the polarization the water [6]. The cost of
distorting the charge distribution of the charged retinalidene
molecule was high because moving positive charge required many
changes in orientation and polarization distribution of the solvent
mol- ecule.
SM8 model predicted pKa change of more than 2 units. This result
was consistent to what was found from the previous study of
trans-retinalidene. (>2 units pKa change) [2]. Fur- thermore it
was noted that the minimum occurs at around 90o. It can be
interpreted that the smaller pKa value means that there is very
small differences between free energies of protonated and
deprotonated species in an aqueous envi- ronment. From this one can
infer that the energy cost to redistribute the positive charge is
highest when C5=C6- C7=C8 bond is at perpendicular to one
another.
Finally it is suspected that bacteriodopsin retinalidene ro- tates
its β-ionone ring after changing its configuration from trans- to
cis-. It is to be noted that 90o rotation is the half of 1800 and
the rotation is large so that it requires some inter- vention from
the protein. Example of the intervention would be the a Tryptophan
replacing β-ionone ring as part of the rhodopsin activation
cycle.
Conclusion
We calculated the pKa as a function of β-ionone ring rota- tion and
found that the range of pKa change of 13 cis- retinalidene is about
2 units. Geometry optimization in MP2 level and solvent energy
calculation using SM8 method re- sulted in pKa values ranging from
-4.3 to -7.1. For more accu- rate results, SM8 solvent model will
be further studied and the semi-relaxed energy surface calculation
will be done again with the input coordinates in z-matrix. This is
expected to give different rotational barriers for some
angles.
Acknowledgement
I would like to thank Suchi Perrera for providing useful tips and
Udeep Chawla for revising the paper.
Re f e re n c e s
[1] "Bacteriodopsin," [Online]. Available:
http://en.wikipedia.org/wiki/Bacteriorhodopsin.
[2] Brown M., Feller S., Zhu S., "Retinal conformation governs pKa
of protonated Schiff base in rhodopsin activation," J. Am Chem Soc,
2013 9391-8.
[3] Soren G. F. Rasmussen, Brian K. Kobilka, Daniel M. Rosenbaum,
"The structure and function of G-protein-coupled receptors,"
Nature, 2009, 459, 356-363.
[4] Liptak M. D., Shields G. C., "Accurate pK a Calculations for
Car- boxylic Acids Using Complete Basis Set and Gaussian-n Models
Combined with CPCM Continuum Solvation Methods," J. Am. Chem. Soc.,
2001, 123, 7314-7319.
[5] [6]
[7]
Sheves M., Albeck A., Friedman N., Ottolenghi M, Proc. Natl. Acad.
Sci. U.S.A, 1986, 83, 3262.
University of Minnesota Truhlar group, "Gamessplus v2010-2 Manual,"
30 September 2010. [Online]. Available:
http://comp.chem.umn.edu/gamessplus/gamessplus-v2010-
2_Manual_SEP30.pdf. [Accessed 15 May 2014].
D. Litchtenberger, "PCM solvent model," [Online]. Available:
http://www.chem.arizona.edu/~lichtend/C518/2014Spring/solva
tion/pcm.html. [Accessed 15 May 2014].
Insert Table of Contents artwork here
16
Seyed A. M. Fathi and Dennis L. Lichtenberger*
Department of Chemistry and Biochemistry, The University of
Arizona, P.O. Box 210041, Tucson, Arizona 85721, United
States
*Email: dlichten@email.arizona.edu
KEYWORDS: Electron transfer, Reduction potential, Peroxide,
Disulfide.
ABSTRACT: Peroxides and disulfides are important compounds in
biological sys- tems. In most of the biological systems they need
to be activated by reductive S-S or O- O bond cleavage to be able
to do their bio- logical functions. Understanding the mech- anism
of this reduction can help provide a better knowledge about
biological systems. Di-tert-butyl peroxide and di-tert-butyl
disulfide were used to theoretically investi- gate the electron
transfer to produce radi- cal anion and dianion. Theoretical
results were compared with experimental cyclic voltammetry results
of these com- pounds that were reported before. We also
investigated the potential energy pattern related to S-S and O-O
distances in these molecules and anions. Our results showed
disulfides can have a loose S-S bond in radical anion intermediate
but peroxides will be dissociated by O-O bond cleavage in the
radical anion form.
INTRODUCTION
Reductive cleavage of the S-S bond in disulfides and the O-O bond
in peroxides is a very important step in biolog- ical systems.
Disulfides are activated by this bond cleav- age to do their
functions in biological systems.1 For exam- ple; disulfide anion
radicals play a key role in the mecha- nism of action of
ribonucleotide reductase in biological systems.3 Similarly,
dioxygen bond cleavage is a necessary step to activatate peroxides
in different oxygen activating enzymes. For example; hemerythin
(Hr) is a diiron en- zyme that initial binding of di oxygen to
diiron active site and hydrolytic cleavage of O-O bond are two
necessary steps to activate this enzyme.2 Understanding the mecha-
nism of this electrochemical reduction can help us to have a better
knowledge of this electron transfer process in biological
systems.
Cyclic voltammetry is the common experimental tech- nique to study
the reduction and oxidation potentials based on the electron
transfer process. Lichtenberger’s group studied the S-S bond
cleavage mechanism by doing the computational studies and comparing
the computa- tional results with cyclic voltammetry experimental
re- sults for 4,4-bipyridyl-3,3-disulfide.3 In that study they
showed a two step electron transfer mechanism to get the
S-S bond cleavage, and had good agreement with experi- mental
results. They showed the S-S bond is elongated at the first step by
doing the first electron transfer to make anion and S-S bond
cleavage was achieved by doing the second electron transfer to make
di-anion.
In this study we used di-tert-butyl disulfide (1) and di-
tert-butyl peroxide (2), shown in Figure 1, as an example of
disulfide and peroxide compounds. We investigated the optimum
geometry and changes in free energy by doing the computational
study on neutral, radical anion and di-anion of each of these
compounds and comparing the theoretical results with experimental
electrochemical results that have been reported
elsewhere.1,4,5
(1) (2)
17
2
Maran and coworkers1 have studied the cyclic voltamme- try
reduction of di-tert-butyl disulfide by using the glassy carbon
electrode in N,N-dimethyl formamide (DMF) solvent. Based on this
study, the reduction of this mole- cule occurred at -2.72 V
relative to ferrocene oxidation potential. They have suggested it
was an irreversible two electron reduction that causes a stepwise
dissociation involves transient radical anion intermediate followed
by S-S bond cleavage.
Cyclic voltammetry reduction of di-tert-butyl peroxide at a glassy
carbon electrode in three dipolar solvents have been reported by
Vasudevan.5 A single irreversible volt- ammetric cathodic peak at
-2.40 and -2.45 V versus Fc+/Fc (for different concentrations) have
been reported in this paper, corresponding to a two electron
transfer reduction process in DMF.
Based on the theory and results of previous research on disulfide3
in this group, we expected to have a weak S-S bond for radical
anion of disulfide but completely O-O bond cleavage for radical
anion of peroxide. After opti- mizing the geometries of these
structures, we did the lin- ear transit calculations as a function
of the S-S and O-O distances in these molecules and anions to
investigate the potential energy with respect to these
distances.
EXPERIMENTAL SECTION
We used the Amsterdam Density Functional Theory pro- gram version
adf2013.01 to do all of the computations. 6-8
PBE functional9 with dispersion corrections according to the method
of Grimme using the BJ damping function (PBE-D3-BJ)10 was used to
do computations. All computa- tions were done by using triple ζ
basis set with polar ioni- zation (TZP). Relativistic effect are
included by the zero order regular approximation (ZORA)12.
Conductor like screening model (COSMO)13 of solvating by using
default parameters for dimethyl formamide was used to estimate the
solvation free energy. All geometry calculations were done in
solution because there was a significant differ- ence in optimum
geometry and energy of charged species in presence of solvent. All
thermodynamic contributions were evaluated at 298.15 K. Cyclic
voltammetry electro- chemical experiments have been done by
different re- search groups1,4,5. Reduction potentials were
calculated by computational calculation the electronic energies in
sol- vent, the zero-point vibrational energies and thermal en-
thalpy and entropy contributions in solution at 298.15 K. The
solution translational and rotational entropy was estimated as
described before1
but it has a little effect on the calculated potential.
RESULTS AND DISCUSSION
Results of 1. Previously reported results of cyclic volt- ammetry4
have shown that a reduction peak potential of this molecule
occurred at -2.71 V vs. Fc+/Fc at scan rate of
1 V/s. tert-butyl sulfide ion produced in initial scan was oxidized
in reverse scan at a significantly more positive potential at -0.13
V.
This result is very similar with the cyclic voltammetry results
that was reported by Lichtenberger’s group for
4,4-bipyridyl-3,3-disulfide3. Just one reduction wave in- stead of
two individual waves followed by an oxidation wave at more positive
potential, suggests that two elec- tron reduction of S-S bond
happened at -2.72 V.
Most common mechanism to illustrate the reduction of S- S bond in
disulfide compounds is a stepwise irreversible electron transfer to
produce radical anion followed by S-S bond cleavage and a second
electron transfer to produce separated anions1,3,4. This mechanism
is shown in equa- tions 1-4.
RSSR +e RSSR (1)
RSSR RS + RS (2)
RS + e RS (3)
RSSR + 2e 2 RS (4)
Changes in potential energy related to the S-S bond dis- tance in
neutral, radical anion and di-anion of molecule 1 was investigated
by doing the linear transit calculation in DMF solvent in this
study. Results of these calculations are shown in figure 2.
Figure 2. Potential energy diagram for 1 related to the S-S bond
distance.
To do more investigation, optimum geometry for each S-S bond
distance of radical anion was investigated and re- sults showed
that S-S bond could be elongated to 2.421 Å while the optimum
distance for neutral molecule is 2.072 Å. These results showed that
S-S bond cleavage occurred by increasing the bond distance to 2.479
Å.
-160
-140
-120
-100
-80
-60
-40
-20
0
20
40
60
1.8 1.9 2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3 3.1
R e
la ti
ve E
n e
rg y
(k ca
l/ m
o l)
1
1•
12
18
3
Based on the CV and calculation results, the second re- duction of
1 occurred at very close to 0.0 V potential while the first
reduction potential is around -2.72 V. When the reduction of
molecule 1 to produce anion occurs at -2.72 V, the second reduction
to produce di-anion will be oc- curred very fast and easy because
it happens at much less negative potential in comparison of first
reduction. Also a big difference between the reduction and
oxidation waves in experimental CV results is related to this
illustration.
In addition, calculated potential energy diagram (Figure 2) and
optimum geometry calculations show that the S-S bond cleavage
occurs by reducing 1 to di-anion and re- sulted tert-butyl sulfide
ions completely fly away from each other in this situation.
Based on these results and explanations, producing the di-anion of
1 and S-S bond cleavage can happen very fast by reducing the
radical anion of 1 to di-anion (second reduction) at much less
negative potential. These results have very good agreement with
previously reported re- sults in Lichtenberger’s group for aromatic
di-sulfide compounds3. So, the same mechanism can be suggested here
that contains an elongated loose S-S bond in radical anion by doing
the first reduction and S-S bond cleavage occurs by doing the
second reduction to produce di- anion. Equations 5 and 6 show this
suggested mechanism.
t-BuS SBu-t + e t-BuS SBu-t (5)
t-BuS SBu-t +e t-BuS + SBu-t (6)
Results of 2. Cyclic voltammetry of di-tert-butyl peroxide have
been studied by Vasudevan5 and Maran13. They have reported the
reduction wave of 2 occurred at -2.40 V and - 2.45 V (for different
concentrations of 1 and 25 mM) at glassy carbon electrode versus
SCE in DMF solvent. Volt- ammogram of 2 in this situation shows a
broad reduction peak by immediate rise in current in negative
direction scan followed by immediately decreasing in current at the
almost same potential to goes back to the background current in
reverse direction scan. This voltammogram is shown in supporting
information figure S1.
Based on these results reduction of 2 occurred at a one broad
reduction peak at -2.45 V but, there is no any oxi- dation peak in
reverse direction scan. Both of these stud- ies showed the same
results and based on that they sug- gested the reduction of 2
occurred irreversibly at a single step electron transfer. Suggested
mechanism is shown in equation 7.
t-BuO OBu-t + 2e t-BuO + OBu-t (7)
Potential energy diagram for neutral, radical anion and di-anion of
molecule 2 based on the O-O bond distance was investigated by doing
the linear transit calculation in
DMF solvent in this study. Results of these calculations are shown
in figure 3.
Figure 3. Potential energy diagram for 2 related to the O-O bond
distance.
Potential energy diagram shows a significant change in energy level
by initial reducing the 2 to radical anion but almost same energy
pattern for radical anion and di-anion of 2. These computational
results show a good agreement with experimental results and
suggested mechanism (equation 7) that have been reported before.
These results support that O-O bond cleavage occurs by doing the
ini- tial reduction followed by second electron transfer imme-
diately at a single step respect to very small difference energy
level between radical anion and di-anion of 2 to produce two
separate stable anions fly away from each other.
The discontinuity in the curve of the dianion between 1.841 and
1.896 Å suggests a geometry change by this dis- tance changing.
Optimum geometry in both sides of this discontinuity was
calculated. Results show this disconti- nuity is related to
rotating of tert-butyl oxyanions from E like (tert-butyls are on
the opposite sides) to Z like (tert- butyls are on the same sides)
structures.
Comparison of obtained results of compound 2 with 1 shows
completely different behavior of peroxides and di- sulfides. Bond
dissociation energies (BDE) of 1 and 2 from neutral and anion
compounds was investigated in this study to obtain a more specific
comparison between S-S and O-O bond cleavage behavior. BDE was
calculated based on the difference between free energy of products
and reactants for each dissociation reaction. Table 1 shows the
results of these calculations.
-180
-160
-140
-120
-100
-80
-60
-40
-20
0
20
40
60
1.3 1.5 1.7 1.9 2.1 2.3 2.5 2.7 2.9 3.1
R e
la ti
ve E
n e
rg y
(k ca
l/ m
o l)
Table 1. Bond dissociation energies (BDE) for 1 and 2
Compound Bond cleavage products
2 RO + OR 38.65
2 + e RO + OR- -24.29
As you can see in table 1, bond dissociation from neutral compound
requires lots of energy to break the bonds for both of these
compounds. But, by looking at the results of BDE for anions,
compound 1 still has a S-S bond in radical anion form but it is
very weak in comparison of neutral molecule (9.56 kcal/mol in
comparison of 69.74 kcal/mol). BDE of anion 2 is dramatically lower
than the neutral molecule and it is a big negative value that con-
firms the O-O bond breakage in radical anion 2 by doing the first
reduction.
Conclusions
In this study we did the computational calculations to investigate
the S-S bond and O-O bond cleavage behavior in disulfide (1) and
peroxide (2) compounds by electron transfer reductions. Comparison
of computational and CV experimental results of these compounds
showed com- pletely different behaviors. These results could
support our hypothesis about the loosely S-S bond in radical anion
di-sulfides and completely dissociate O-O bond in radical anion
peroxides.
Second reduction of 1 that occurs in much less negative potential
than first reduction and calculated potential diagram of neutral,
anion and di-anion 1 supported the two steps reduction mechanism
that produce loose S-S bond for anion (result of initial electron
transfer reduc- tion) and S-S bond breakage for di-anion by doing
second electron transfer reduction step.
On the other hand, just one broad CV reduction peak for 2 and
significant difference calculated potential energy pattern of
radical anion 2 in comparison of neutral mole- cule (and very
similar to di-anion pattern) supported the irreversible single step
two electron reduction mechanism that produce O-O bond
cleavage.
Furthermore, calculated bond dissociation energy (BDE) provided a
strong support for these hypotheses by obtain- ing negative BDE for
radical anion of 2 and very small but still positive BDE for
radical anion of 1.
Next Step
For next step of this study, we can do more computational
calculations in orbital molecular scale to obtain more de- tails
about behavior of these molecules. By the way, simu- lation of
cyclic voltammetry by using these mechanisms and trying to fit the
simulated data with experimental
data can provide more supporting evidence for these
mechanisms.
Acknowledgement
This author wishes to thank Prof. Dennis Lichtenberger for all of
his supports and helps to complete this project and also wishes to
thank CHEM 518 students in The Uni- versity of Arizona, spring 2014
for their helps and guid- ance.
Supporting Information
More details of computational input files, XYZ coordi- nates of
studied molecules and experimental results are available in
supporting information.
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