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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
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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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