uva chemical filters: a systematic study...protection afforded by chemical sunscreen filters in the...
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UVA Chemical Filters:
A Systematic Study
Jacqueline F. Cawthray, B. Science (Hons)
A thesis submitted for the degree of
Doctor of Philosophy
in
The University of Adelaide
Department of Chemistry
February 2009
Chapter 7
321
7 Conclusion
This thesis describes the investigation of methods aimed at improving the level of
protection afforded by chemical sunscreen filters in the UVA (320 - 400 nm) spectral
region. A systematic study into the photophysical properties of the common UVA filter 4-
tert-butyl-4′-methoxydibenzoylmethane (BMDBM) including the metal β-diketonate
complexes formed with Zn2+ and Al3+ and the inclusion complexes formed with βCD and
HPβCD. Additionally, the use of theoretical methods as a complementary tool in the
design and identification of candidate UVA chemical filters has been explored
The acidity constants (pKa) of three β-diketones, DBM, NapPh and BMDBM, and the
stability constants of β-diketonate metal complexes in methanol-water solution were
determined using potentiometric titration methods. The values obtained were consistent
with those expected for weakly acidic β-diketones where the tautomeric equilibrium
strongly favours the enol form. The measured pKas show that the extent of dissociation for
the β-diketones studied follows the order: DBM > NapPh > BMDBM. The trend is
consistent with increasing electron density at the oxygen atoms and correlates with the
proton NMR chemical shift of the enolic proton.
For the divalent metals studied, the general trend in complex stability for the β-diketonate
metal complexes followed that expected by the Irving-Williams series whereby: Cd2+ <
Co2+ ≈ Zn2+ < Ni2+. The stoichiometry derived from potentiometric data for titration of the
β-diketones with Ni2+, Zn2+ Co2+ and Cd2+ corresponds in all cases to a 1 : 1 and a 1 : 2
mole ratio of metal : ligand. For all systems investigated, there was no evidence to support
the formation of a 1 : 3 molar ratio of metal : ligand complex. The differences in the
reported stability of the metal complexes formed by the three β-diketones with a particular
metal ion have been attributed to the differences in basicity of their conjugate β-diketonate.
This was reflected in the correlation found between the acidity and pKas of the β-diketones
with the stability constants, K1 and K2.
The UV-visible absorption and fluorescence emission of the β-diketonate complexes of
BMDBM with Zn2+ and Al3+ were studied. Only slight changes in the absorption spectra
of BMDBM were observed upon the addition of Zn2+ whereas more significant spectral
changes were observed upon the addition of Al3+ to solutions of BMDBM. This has been
attributed to the higher surface charge density of Al3+ that increases the polarisability of
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Al 3+ and, as a consequence, the deformation of the π-electron system in BMDBM. The
extent of the spectral changes observed for BMDBM complexes with Al3+ were strongly
influenced by the speciation of the metal ion. The stoichiometry derived from Job’s
method of continuous variation supports the formation of a metal : ligand complex in a 1 :
3 mole ratio. Only Al3+ complexes with BMDBM were sufficiently fluorescent for
quantitative fluorometric study.
The photochemistry of BMDBM in various environments was explored using laser flash
photolysis and steady state irradiation experiments. This included the photochemistry of
BMDBM alone and in combination with Zn2+, Al3+ and the UVB filter, octyl
methoxycinnamate (OMC). Analysis of the kinetics of these systems showed that the
addition of either Zn2+ or Al3+ with BMDBM prevents formation the transient E- and Z-
isomers of BMDBM. This has been interpreted in terms of the differences in bond strength
between that of the intramolecular hydrogen bond in the enol form of BMDBM with that
of the metal chelated species. Furthermore, the photostability of solutions of BMDBM,
Al 3+ and OMC was enhanced relative to either BMDBM alone or in combination with
OMC. Future investigations into the photostability of BMDBM with the metal ions and
also with OMC in other environments such as less polar solvents would be of interest.
The research presented is encouraging from the point of view of improving both the range
of UVA wavelengths over which BMDBM absorbs and the photostability of the filter. The
results demonstrated that the photostability of BMDBM under laboratory and in vitro
conditions was improved by methods that stabilise the enol form of BMDBM. In
particular, these findings indicate that the photostability of the common UVA absorbing
chemical filter has been substantially improved by chelation with Zn2+ and Al3+. This has
been attributed to a reduction or prevention of photoketonization and subsequent
degradation of BMDBM. Furthermore, the range of UVA wavelengths over which
BMDBM absorbs has been improved by formation of the Al3+ complex.
The significance of this research is the potential for commercialisation with application of
the research presented in the sunscreen industry is expected. This may have positive
implications in the sunscreen industry and in particular to the industry partner, Hamilton
Laboratories. The nature of the technology allows the industry partner to circumvent many
of the restrictions imposed on development of new products such as the lengthy and costly
assessments required for introduction of new chemical filters. Additionally, the expected
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economic and social returns to the broader Australian community may be improved
protection against solar UVA radiation. This should lead to lower skin cancer rates and the
burden imposed on healthcare costs. Examining the photostability of Al3+ complexes with
BMDBM in sunscreen formulations containing the UVB filter, octyl methoxycinnamate,
would be of interest.
An alternative approach to stabilising BMDBM against photodegradation is through
inclusion of the enol form within the annuli of cyclodextrins. The cyclodextrin complexes
formed between BMDBM with either β-cyclodextrin (βCD) or hydroxypropyl β-
cyclodextrin (HPβCD) were characterised using 1H NMR and 1H ROESY NMR
spectroscopy. The results presented show that both the enolate anion and enol tautomer of
BMDBM form inclusion complexes with βCD and HPβCD. The 1H ROESY NMR studies
shows that the inclusion complexes formed in an aqueous environment involve a several
inclusion isomers.
The use of theoretical methods a complementary tool in the design of potentially new
sunscreens has also been investigated. The ground state and excited state properties of a
series of six β-diketones incorporating relevant tautomeric forms has been explored by
computational chemistry. The ground state electronic structures and properties of the
systems investigated were adequately described by computational methods. The results
demonstrate that the information derived from Natural Bond Orbital (NBO) method and
Bader’s Atoms in Molecules (AIM) theory can be used to gain further insight into the
structure-activity relationship of systems such as those studied in this work.
Theoretical excitation energies for the series of β-diketones were obtained using the
symmetry adapted cluster-configuration interaction (SAC-CI) method for excited states.
The comparison of trends between experimentally determined and theoretically calculated
excitation energies shows that in most cases the SAC-CI theoretical spectra accurately
describe the experimental spectra. These results permit a satisfactory level of confidence
in calculated spectra of unknown candidate sunscreen filters based on the β-diketone
moiety. Based on this a candidate UVA filter, IndolePh, has been identified using these
methods.
The methodology used here, i.e. a thorough analysis of the ground state electronic
properties and treatment of excited state by the SAC-CI method, can be used to
complement experimental methods in the rapid identification of potential candidate
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324
sunscreen filters. The size and computational requirements of the SAC-CI method may, in
some cases, be a limiting factor. Utilizing the information obtained by theoretical studies
of the ground state, which are less computationally demanding, may improve the selection
process for candidate filters. This information can then be applied to the future design of
potentially new sunscreen filters having the desired properties.
The future application of the methodology applied in this study in the identification of new
UVA sunscreen filters would benefit from increasing the training set of compounds will
improve the predictive or QSAR model followed by validation of the model using new
chemical entities for checking the reliability and assessing the confidence of prediction of
the model.
Chapter 8
325
8 Experimental
8.1 General
Purification and drying of reagents were carried out according to literature procedures.
Deionised water, purified using a Milli Q Reagent system to give a specific resistance of
> 15 MΩ cm, was used in the preparation of all aqueous solutions.
1H NMR and 13C spectra were obtained in either deuterochloroform (CDCl3), or d6-
dimethylsulfoxide (DMSO-d6) solutions (tetramethylsilane internal standard) using either a
Brucker ACP 300 MHz or a Varian Gemini 200 MHz nuclear magnetic resonance
spectrometer. For studies involving cyclodextrins all 1H (600 MHz) NMR and ROESY
spectra were obtained using a Varian Nova NMR spectrometer. Solutions of BMDBM and
either βCD or HP-βCD were prepared in either D2O or 0.10 mol dm-3 NaOD in D2O and
had a pD ≈ 12. Chemical shifts are quoted as δ (ppm). Multiplicities are abbreviated as: s,
singlet; m, multiplet; br, broad. Ar represents aromatic protons. In determining the keto-
enol equilibrium for β-diketones the vinyl resonance was integrated to determine the
population of the enol form and the methylene resonance was integrated to determine the
population of the keto form. The methylene integrals were divided by a factor of 2 prior to
taking the ratio enol/keto in order to normalize for the number of protons giving rise to
each resonance.
The UVA sunscreen 4-tert-butyl-4′-methoxydibenzoylmethane (BMDBM), obtained as
Parsol® 1789 (tradename), and the UVB sunscreen 2-ethylhexyl-4-methoxycinnamate
(OMC) were kindly donated by Hamilton Laboratories (Adelaide, Australia).
Dibenzoylmethane (Sigma-Aldrich) was recrystallised from ethanol prior to use.
Acetylacetone and benzoylacetone (Aldrich) were used without further purification. The
identity and purity of all compounds was confirmed by 1H and 13C NMR.
The metal salts (Aldrich) Zn(ClO4)2.6(H20), Cu(ClO4)2
.6(H20), Ni(ClO4)2.6(H20),
Co(ClO4)2.6(H20), Cd(ClO4)2
.6(H20) and Al(ClO4)3.9(H20) (Aldrich) were recrystallized
according to literature procedures and dried under vacuum over P4O10. Stock solutions of
the ligands, metal salts and HClO4 were standardized prior to serial dilution to give the
solutions required for spectrophotometric complexation studies.
Chapter 8
326
HEPES (N-2-hydroxyehtylpiperazine-N’-2-ethanesulphonic acid, pKa 7.55) buffer solution
was prepared as described in the literature in a methanol-water (80 : 20 v/v) solvent system
[613]. The pH of the solution was adjusted by the addition of tetraethylammonium
hydroxide (TEAOH) until the desired pH was obtained (5.0 × 10-2 mol dm-3, pH 6.75, I =
0.1 mol dm-3 (NEt4ClO4)).
Tetraethylammonium perchlorate (NEt4ClO4) was prepared by addition of excess HClO4
(1.0 mol dm-3, 1.7 dm3) (Ajax) to NEt4Br (300 g, 1.4 mol) (Aldrich) in H2O. The resulting
NEt4ClO4 was repeatedly recrystallised from aqueous ethanol until free of bromide and
acid. The white crystalline product was then dried under high vacuum over P4O10.
8.2 Synthetic Procedure
1-(2-naphthyl)-3-phenyl-1,3-propanedione (NapPh)
The β-diketone 1-(2-naphthyl)-3-phenyl-1,3-propanedione (NapPh) was readily prepared
by condensation of the acetonaphthone with electron-deficient methylbenzoate according
to the literature [447]. Acetonaphthone (5.11 g, 37.5 mmol) was added to a stirred slurry
of NaNH2 (50% slurry, 4.75 g, 60.9 mmol) in anhydrous ether (50 mL). After stirring for
5 min at room temperature, methylbenzoate (8.17 g, 48.0 mmol) was added neat. The
reaction mixture was allowed to reflux gently in an oil bath for 4 hrs. Upon cooling, the
reaction mixture was poured onto ice and the pH adjusted to pH 7 using conc. HCl and
extracted with ether. Combined ether layers were dried over a bed of anhydrous sodium
sulfate and the organic solvent was evaporated to yield 4.73 g of crude product of NapPh.
Purification of 2.00 g of the crude product was achieved by flash chromatography (50%
dichloromethane, 50% hexane). The resulting orange oil was recrystallised from ethanol to
give NapPh as yellow crystals. m.p. 97-99 °C (lit. m.p. 101 °C [448]. 1H NMR (300
MHz, CDCl3) δ: 7.01 (s, 1H), 7.53-7.61 (m, 5H, Ar), 7.90-8.07 (m, 6H, Ar), 8.56 (s, 1H,
Ar), 16.97 (br s, 1H, -OH); 13C NMR (75.5 MHz, CDCl3) δ: 93.7, 123.5, 127.0, 127.4,
128.0, 128.4, 128.6, 128.7, 128.9, 129.6, 132.7, 133.0, 135.5, 135.8, 185.8, 186.0.
8.3 Potentiometric Titrations
Chapter 8
327
Potentiometric titrations were carried out using either a Metrohm E665 Dosimat
Autoburette equipped with a 5 cm3 burette interfaced to a PC running purpose-written
software or a Metrohm 809 Titrando interfaced to a PC computer running Tiamo
(Metrohm) software. Changes in hydrogen ion concentration were monitored by means of
an Orion Ross Sureflow 81-72 BN combination electrode connected to either to an Orion
720 Digital Voltmeter, with a precision of ± 0.001 pH units or a Metrohm 809 Titrando,
with a precision of ± 0.002 pH units. Prior to and during the course of the titration, a
blanket of nitrogen presaturated with the solvent and ionic strength was maintained over
the solution. The reference compartment of the combination electrode was filled with 0.10
mol dm-3 NaClO4 in methanol-water (80 : 20 v/v) solvent and allowed to attain equilibrium
over 2 days prior to use. The titrations were carried out at 298.2 (± 0.2) K in either a 2 cm3
or a 10 cm3 water-jacketed vessel. All titrations were carried out under an inert
atmosphere by bubbling nitrogen through the cell for 5 minutes prior to proceeding and
also during the titration.
All solutions were prepared in methanol-water (80 : 20 v/v) having a constant ionic
strength ( I = 0.1 mol dm-3) using tetraethyl ammonium perchlorate (NEt4ClO4). The
tetraethyl ammonium hydroxide (NEt4OH, TEAOH) stock solution (0.1 mol dm-3) was
standardised against potassium hydrogen phthalate by potentiometric titration. Electrode
calibration was accomplished by titrating tetraethyl ammonium hydroxide (0.1 mol dm-3)
with perchloric acid (HClO4, 10-3 mol dm-3). Eo and pKw were fitted using the modified
Nernst equation where:
where E is the observed potential (V), Eo is the standard potential (V) of the electrode, R is
the gas constant (8.314 J mol-1 K-1), T is temperature (K), F is Faraday’s constant (9.6487 x
104 Coulombs mol-1) and [H+] is proton concentration (mol dm-3). At 298.2 K the pH of a
solution is given by:
Calibration data were analysed by standard computer treatment provided within the
program MacCalib [614] to obtain the calibration parameters E0 and pKw. The diffusion
]In[HF
T+= +R
EE 0
15.59pH
EE0 −=
Chapter 8
328
correction terms used were E0 = 3.15 and pKw = 1.311 for the autoprotolysis constant of
methanol-water (80 : 20) at 25 C.
The pKas of the β-diketones were determined from titrations of 10 cm3 of ligand with
HClO4 in methanol-water (80 : 20 v/v) against 0.10 mol dm-3 TEAOH. The concentration
of the ligand of interest and HClO4 in solution varied for each ligand. The following
concentrations of ligand and acid were used: [DBM]total = 9.80 × 10-4 mol dm-3, [HClO4]total
= 9.34 × 10-4 mol dm-3; [NapPH]total = 1.01 × 10-3 mol dm-3, [HClO4]total = 9.69 × 10-4 mol
dm-3; [BMDBM] total = 1.08 × 10-3 mol dm-3, [HClO4]total = 1.08 × 10-3 mol dm-3.
Stock solutions of metal perchlorate salts (Aldrich) were standardized in triplicate using
cation exchange chromatography. A Dowex AG 50W-X2 cation exchange column (2 × 20
cm) was washed with HCL (0.1 mol dm-3) to ensure complete protonation and then rinsed
thoroughly with Milli Q water. The column was loaded with 1.0 cm3 of a 0.1 mol dm-3
aqueous solution of the metal salt to be standardized and eluted with water until the eluant
was neutral. The eluant solution was titrated again NaOH (0.1 mol dm-3) that had been
previously standardized against potassium hydrogen phthalate.
The stability constants for complexation of the metal ion with the ligand, BMDBM, were
determined by titration of NEt4OH (0.1 mol dm-3) with a solution of ligand (1 × 10-3 mol
dm-3, 10 cm3) and metal perchlorate solution (either 1 or 2 equivalents) in methanol-water
(80 : 20 v/v) , (I = 0.1, tetraethylammonium perchlorate), at 298.2 (±0.2) K.
The metal stability constants for each ligand were determined from the potentiometric data
obtained by addition of a metal salt solution (varying concentration) to the acidified
titration solution of 10 cm3 of ligand with HClO4 in methanol-water (80 : 20 v/v) against
0.10 mol dm-3 TEAOH. A maximum delay of 300 seconds between each titrant addition
was permitted to allow equilibrium to be established. The following concentrations of
ligand, acid and metal salt were used for titration of a 1 : 1 mole ratio of metal to ligand:
[DBM] total = 9.80 × 10-4 mol dm-3, [HClO4]total = 1 × 10-3 mol dm-3, [Zn2+]total = 1.00 × 10-3
mol dm-3, [Ni2+]total = 9.20 × 10-4 mol dm-3 [Co2+]total = 1.00 × 10-3 mol dm-3, [Cd2+] total =
9.86 × 10-4 mol dm-3; [NapPh]total = 1.01 × 10-3 mol dm-3, [HClO4] total = 1 × 10-3 mol dm-3,
[Zn2+]total = 9.99 × 10-4 mol dm-3, [Ni2+] total = 9.39 × 10-4 mol dm-3 [Co2+]total = 9.90 × 10-4
mol dm-3, [Cd2+] total = 9.96 × 10-4 mol dm-3; [BMDBM] total = 1.00 × 10-3 mol dm-3,
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[HClO4]total = 1.00 × 10-3 mol dm-3, [Zn2+] total = 9.89 × 10-4 mol dm-3, [Ni2+] total = 1.00 × 10-
3 mol dm-3, [Co2+]total = 9.91 × 10-4 mol dm-3, [Cd2+]total = 9.87 × 10-4 mol dm-3.
The following concentrations of ligand, acid and metal salt were used for titration of a 1 : 1
mole ratio of metal to ligand: [DBM]total = 1.02 × 10-3 mol dm-3, [HClO4]total = 9.40 × 10-4
mol dm-3, [Zn2+] total = 4.96 × 10-4 mol dm-3, [Ni2+]total = 4.90 × 10-4 mol dm-3, [Co2+] total =
4.95 × 10-4 mol dm-3, [Cd2+] total = 4.98 × 10-4 mol dm-3; [NapPh]total = 1.01 × 10-3 mol dm-3,
[HClO4]total = 1 × 10-3 mol dm-3, [Zn2+] total = 4.93 × 10-4 mol dm-3, [Ni2+]total = 4.89 × 10-4
mol dm-3 [Co2+]total = 4.99 × 10-4 mol dm-3, [Cd2+]total = 4.97 × 10-4 mol dm-3;
[BMDBM] total = 1.00 × 10-3 mol dm-3, [HClO4] total = 1.00 × 10-3 mol dm-3, [Zn2+]total = 4.90
× 10-4 mol dm-3, [Ni2+]total = 4.96 × 10-4 mol dm-3, [Co2+]total = 4.98 × 10-4 mol dm-3,
[Cd2+] total = 4.97 × 10-4 mol dm-3.
Ligand pKas and metal stability constants were determined from the titration data using the
program Hyperquad2003 [256]. The values given represent an average from at least two
titrations.
8.4 Ultraviolet-Visible Spectroscopy
UV-visible spectra were recorded using a Varian CARY 300 Bio spectrophotometer
equipped with matched 1.0 cm path length quartz cells over the wavelength range 250-500
nm at 0.083 nm intervals with a scan rate of 49.8 nm min-1. The blank used contained all
species present in the solution of interest except the ligand and metal salt. All solutions
were equilibrated at 298.2 (± 0.2) K in a thermostatted block throughout the measurements.
All solutions were prepared directly prior to use unless otherwise stated.
For the UV-visible measurements of BMDBM with Al3+ made over a 7 week period, a
solution was kept in the dark and the appropriate volume for analysis was removed as
needed.
The solutions used for the spectrophotometric titration molar ratio method contained
constant concentration of BMDBM (2 × 10-5 mol dm-3) and variable concentrations of
AlCl 3. pH, constant ionic strength. The solutions were equilibrated for 2 hours at 25°C.
Chapter 8
330
The pH of solutions was kept constant at 2 using HClO4 (X M). All solutions were
prepared by first mixing the appropriate volumes of stock solution of BMDBM and Al3+
then diluting with acid.
For the application of Job’s method of continual variation, the solutions were prepared by
mixing various different volumes of equimolar stock solutions of AlCl3 and BMDBM (1 ×
10-3 mol dm-3). In all solutions the sum of the total concentration of ligand and metal was
kept constant (2 × 10-5 mol dm-3). Solutions containing only BMDBM in the same
concentration as in the mixture were used for corrections of Job’s plot.
8.5 Fluorescence Spectroscopy and Quantum Yields
Fluorescence emission spectra of BMDBM and metal complexes with Zn2+ and Al3+ were
measured using a Perkin-Elmer LS50B fluorimeter with the excitation and emission slit
widths of 5 mm for samples thermostatted at 298 (±0.2) K. Baseline correction
measurements were use for all spectra. Solutions were prepared in a similar manner to
those prepared for the UV-visible studies except at substantially lower ligand
concentrations. Significant fluorescence changes were only observed for BMDBM in the
presence of Al3+ and accordingly the concentration of BMDBM was held constant at 2 ×
10-6 mol dm-3 while the concentration of Al3+ was varied. The fluorescence spectra were
recorded over the range 340-900 nm with excitation at 353 nm.
The relative quantum yield (ΦF) value for [Al(H2O)4L¯ ]2+ was determined by the optically
dilute solution method . The quantum yield of an unknown, x, to that of a reference
standard, r, is related by:
where Φ is the quantum yield, A is the absorbance of the solution at the excitation
wavelength, F is the integrated area under the emission spectrum and n is the refractive
index of the solvents used.
2
2
)(n
)(n
F
F
A
AΦ=Φ
r
x
r
x
x
rrx
Chapter 8
331
The reference standard used was quinine sulphate (Φr = 0.546 in 1.0 N sulphuric acid) .
The refractive index value used was n = 1.33 for water (which is very similar to that for
methanol). Standard solutions were prepared in aqueous sulphuric acid (1.0 N, Convol,
BDH) using analytical reagent grade anhydrous quinine (Fluka). The UV-visible
absorption spectra and fluorescence emission spectra were measured for quinine sulphate
(1.0 × 10-5 mol dm-3 and 5.0 × 10-6 mol dm-3). The excitation wavelength of 365 nm was
used for the unknown and the reference standard. The concentrations used for the
fluorescence measurements corresponded to absorbances of less than 0.04 nm at the
excitation wavelength.
8.6 Laser Flash Photolysis
Extensive details of the experimental design and equipment are given in Chapter 4. The
concentration of BMDBM was 10-5 mol dm-3 unless otherwise stated. All solvents were
purified by normal distillation procedures. Spectral data regarding transient kinetics were
obtained using a quartz cell with a 10 mm path length. The cell was connected to a
reservoir (capacity ~400 cm3) in which solution was pumped through at the rate of 10
mL/s.. The kinetic measurements were carried out at room temperature.
8.7 Photostability Testing
8.7.1 Steady-State Irradiations.
The continuous irradiation experiments were performed using a 150 W Xenon arc lamp (as
used for laser flash photolysis studies). Solutions in matched quartz cuvettes with stoppers
and sealed with parafilm and placed at equivalent distances from the irradiation source.
Spectra were recorded every hour. The absence of evaporation was confirmed by
weighing each cuvette before and after irradiation. Energy of irradiation from the lamp
source was not measured. The temperature of irradiated solutions was not maintained
constant.
Chapter 8
332
Solutions of BMDBM [2 × 10-5 mol dm-3] alone or in the presence of the metal ion, Zn2+
[1 × 10-3 mol dm-3] were prepared in methanol-water (80 : 20 v/v) solvent system which
was buffered to pH 6.75 (HEPES buffer), (I = 0.1 , tetraethyl ammonium perchlorate).
Samples were irradiated in either glass or quartz cells (10 mm). All cells were sealed
airtight to prevent evaporation of solvent. Samples were irradiated for 1 hour, removed
from the light source and UV-visible spectra were recorded before being placed back under
the lamp. Total irradiation time was 8 hours.
The in vitro SPF analysis and UVA evaluation of BMDBM with Al3+ were carried out at
the Australian Photobiology Testing Facility, University of Sydney ) [374]. Sample
formulations were prepared by Hamilton Laboratories. Samples contained 11%
aluminium(III) distearate (stearate d’aluminium), 6.4% 4-tert-butyl-4′-
methoxydibenzoylmethane (Parsol 1789) in C12-15 alkyl benzoate (Finsolv TN).
8.8 Preparation of Cyclodextrin Inclusion Complexes
The following cyclodetrins were used: β-cyclodextrin (βCD) and hydroxypropyl-β-
cyclodextrin (kindly donated by Hamilton Laboratories), degree of substitution (DS) was
listed as 3-8 according to the manufactures specifications (C* Cavitron 82005).
The inclusion complex was prepared at a 1 : 1 molar ratio of BMDBM to β-CD by adding
BMDBM (33 mg, 0.011 mmol) and β-CD (13 mg, 0.011 mmol) to NaOD/D2O (1 ml, 0.1
mol dm-3) with rapid heating until the BMDBM was dissolved and the solution became
clear yellow. The 1 : 2 molar ratio inclusion complex was prepared in a similar manner. 1H NMR and ROESY spectra were recorded.
The inclusion complex was prepared at a 1 : 1 molar ratio of BMDBM to HP-β-CD by
adding BMDBM (31 mg, 0.10 mmol) and randomly substituted HP-β-CD (15 mg, ~ 0.01
mmol) to NaOD/D2O (1 ml, 0.1 mol dm-3) with rapid heating until the BMDBM was
dissolved. A similar preparation involved addition of BMDBM (31 mg, 0.10 mmol) and
randomly substituted HP-β-CD (15 mg, ~ 0.01 mmol) to D2O (1 ml).
Chapter 8
333
8.9 Computational Details
All calculations were performed using the Gaussian 03 [403] suite of programs. All
calculations including the SAC-CI calculations were performed on either a Altix 3700 BX2
(Itanium2 1.6GHz) at APAC (Australian Partnership for Advanced Computing) National
Facility or SGI Altix 3700 (Itanium2) IBM eServer 1350 at SAPAC (South Australian
Partnership for Advanced Computing).
8.9.1 Dibenzoylmethane (III)
Hartree-Fock, MP2 and DFT calculations using the B3LYP functional were used to
optimise the molecular geometry of 1,3-diphenyl-1,3-propanedione (DBM, III ) using the
basis sets as outlined in 6.5.1. The convergence criteria were not met for calculations
performed at the HF and B3LYP levels using Dunning’s correlation consistent basis set
(aug-cc-pVDZ).
8.9.2 β-Diketones.
The ground state geometries of β-diketones I -VI having conformation a-d were optimised
in two steps. In the first step, the geometry was optimised using the restricted Hartree-
Fock methods with 6-311G basis set. The second optimisation setp was performed using
the B3LYP/6-31+G(d,p) level [488:Lee, 1988 #137]. This was determined as an
appropriate model chemistry for reason given in Chapter 6.5.1. Harmonic vibrational
frequences were obtained at the same level of theory to classify the stationary points as
either local minima or TS and to estimate the corresponding zero-point energies. The
reported ZPE energies were used without scaling. The XYZ coordinates of all optimised
structures are given in the Appendix.
The optimisations of the transition state geometries of Ib -VIb were performed with the
initial geometries possessing C2V point group symmetry. The transition state optimisation
method in Gaussian 03 was implemented using the OPT = QST3 keyword where the input
structures were the a and a′ forms in addition to the initial guess of the transition state. No
geometrical constraints were imposed on any of the molecules. The negative frequency
corresponded to motion along the reaction coordinate for intramolecular proton transfer
between oxygen atoms.
Chapter 8
334
NBO analysis: was performed at the B3LYP/6-31+G(d,p) level with the program NBO 5.0
implemented in the Q-Chem 3.0 package [615]. Bond orders were estimated using Wiberg
Bond Indices (WBI) [589]. The NBO analysis was performed using the CHOOSE
keyword. The highly delocalised nature of the systems investigated must be considered.
NBO analysis is based on a single dominant structure with contributions from other
resonance structures being treated as the second-order perturbation corrections. Results of
NBO analysis yield a qualitative description of delocalisation that is suitable in the context
of structurally related systems [535,616].
The wave function files required for Atoms in Molecules (AIM) analysis were generated
using the DENISTY = CURRENT option in G03 at the B3LYP/6-31+G(d,p) level. The
critical points were located and characterised according to Bader’s AIM theory with the
program AIMALL [617]. Partial atomic charges were evaluated in the framework of AIM
theory. The accuracy of the integrations was assessed by ensuring that the integrated
Laplacian in each atomic basis was close to zero.
8.9.3 SAC-CI Calculations:
The threshold for the second-order perturbation energies used in selection of doubles
excitation operators are: Level One (1.0×10−5, 1.0×10−6), Level Two (5.0×10−6, 5.0×10−7)
and Level Three (1.0×10−6, 1.0×10−7) for SAC and SAC-CI respectively.
The solution to the SAC wave function is always solved non-variationally whereas the
SAC-CI equation is solved either variationally or non-variationally as specified by the user
[435]. The variational solution, although implying an upper bound to the exact energy,
leads to complex equations and therefore, increase in computer cost. The non-variational
solution, whilst not giving an upper bound to the energy, reduces the computational cost
without any significant compromise of accuracy [442]. For practical purposes, a non-
variational solution to the SAC-CI equation was specified for all calculations and the
excited-state properties were obtained from the right-hand solution (vector) [217].
Chapter 9
335
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Appendix
364
Appendix A
A.1 Speciation Distribution
FIGURE A1.1: Variation of the concentration of DBM, H1, and its conjugate base, 1-,
containing species with pH at 298.2 K for a solution in which [1]total = 1 × 10-3 mol dm-3,
[Co2+] total = 1 × 10-3 mol dm-3, [Cd2+] total = 1 × 10-3 mol dm-3, [Ni2+] total = 1 × 10-3 mol dm-
3 I = 0.10 mol dm-3 (NEt4ClO4) and for which 100 % = [H1]total.
Appendix
365
FIGURE A.1.2: Variation of the concentration of NapPh, H2, and its conjugate base, 2-,
containing species with pH at 298.2 K for a solution in which [2]total = 1 × 10-3 mol dm-3,
[Co2+] total = 1 × 10-3 mol dm-3, [Cd2+] total = 1 × 10-3 mol dm-3, [Ni2+] total = 1 × 10-3 mol dm-
3 I = 0.10 mol dm-3 (NEt4ClO4) and for which 100 % = [H2]total.
Appendix
366
A.2 APTF Photostability Testing
Sunscreen Formulation containing BMDBM and Al3+ Distearate in Finsolv
TN (Lay-On)
Appendix
367
Appendix
368
Appendix
369
Appendix
370
Appendix
371
Sunscreen Formulation containing BMDBM, and Al3+ Distearate in Finsolv TN (Rub-
In)
Appendix
372
Appendix
373
Appendix
374
Appendix
375
Appendix
376
Sunscreen Formulation containing BMDBM in Finsolv TN (Lay-On)
Appendix
377
Appendix
378
Appendix
379
Appendix
380
Appendix
381
Sunscreen Formulation containing BMDBM in Finsolv TN (Rub-In)
Appendix
382
Appendix
383
Appendix
384
Appendix
385
Appendix
386
Sunscreen Formulation containing Al3+ in Finsolv TN (Lay-On)
Appendix
387
Appendix
388
Appendix
389
Appendix
390
Appendix
391
Sunscreen Formulation containing Al3+ in Finsolv TN (Rub-In)
Appendix
392
Appendix
393
Appendix
394
Appendix
395
Appendix
396
A.3 Patent
HAMILTON HEALTHSCIENCE PTY LTD
AND
THE UNIVERSITY OF ADELAIDE
AUSTRALIA
PATENTS ACT 1990
PROVISIONAL SPECIFICATION FOR AN INVENTION ENTITLED:-
“IMPROVED SUNSCREEN FORMULATIONS”
This invention is described in the following statement:-
Appendix
397
BACKGROUND TO THE INVENTION
The present invention relates to the preparation and application of sunscreening agents being
metal complexes providing enhanced protection from UV radiation. These metal complexes,
between a dibenzoylmethane derivative and aluminium, have enhanced photo-stability, and
stronger and broader absorption in the UVA region, than the uncomplexed
dibenzoylmethane derivatives. This invention also relates to enhanced photostability of
mixtures of a dibenzoylmethane derivative with other sunscreening agents (in particular,
octyl methoxycinnamate) when a metal complex of the former is present.
The sun is the source of all energy in the solar system. It bathes the planets in radiation,
some of which, such as high energy cosmic and gamma radiation and x-rays, is not
compatible with life, while other forms of radiation, such as ultraviolet, visible and infrared
radiation, are essential to life as we know it.
The planet Earth, with its magnetic field, stratospheric oxygen, nitrogen and ozone layer,
protects the surface from all radiation below 290nm, but transmits radiation of wavelengths
longer than this.
Ultraviolet radiation (wavelength 200-400 nm) plays an important role in human biology. It
is essential for the production of Vitamin D, the role of which is to regulate the amount of
calcium and phosphorus in the blood, and is believed to have a role in the regulation of
growth of skin cells. Too much ultraviolet radiation however can lead to sunburn (erythema),
skin aging, suppression of the immune system and skin cancer.
Historically, the ultraviolet (UV) band has been arbitrarily divided into UVC (wavelength
200-290nm), UVB (wavelength 290-320nm) and UVA (wavelength 320-400nm). UVC
radiation is filtered by the ozone layer and never reaches the Earth’s surface. UVB
contributes approximately 0.5% of total solar radiation reaching the earth’s surface, while
UVA contributes approximately 6.3%.
Of the solar radiation reaching the Earth’s surface, UV, visible and infrared radiation have
both acute and long-term biological effects. Radiation is absorbed by chromophores in the
skin. These chromophores absorb specific wavelengths of radiation depending upon their
structure, which causes them to become “excited” and capable of undergoing molecular
Appendix
398
reorganisation or interaction with nearby molecules. The changes cannot occur unless the
chromophore is exposed to precisely the right wavelength of radiation. The major
chromophores in the skin include DNA, proteins and trans urocanic acid, and it is absorption
of radiation by these molecules that can lead to acute and long-term damage.
Dibenzoylmethane derivatives have been widely used to provide protection from the harmful
effects of UV radiation.
SUMMARY OF THE INVENTION
The present invention relates to the preparation and application of a sunscreening agent
being a metal complex providing enhanced protection from UVA radiation. This
sunscreening agent has the structure shown in general formula I:
(Av)x (Al)y (L)z (I)
wherein Av is a moiety of general formula II:
(II)
A is a substituent selected from -H, -OR and –NRR’;
R and R’ are substituents, each of which is selected from -H and straight-chain and branched
alkyl groups having from 1 to 20 carbon atoms;
B is a substituent selected from -H and straight-chain and branched alkyl groups having from
1 to 20 carbon atoms;
Al is aluminium;
Appendix
399
L is a neutral or negatively charged organic or inorganic ligand;
x is the number of Av moieties present in the complex, and is preferably an integer from 1 to
3;
y is the number of aluminium cations (Al) present in the complex, and is preferably an
integer from 1 to 10; and
z is the number of ligands (L) present in the complex, and is preferably an integer from 0 to
10.
Av may, for example, be avobenzone (i.e. 4-tert-butyl-4’-methoxy-dibenzoylmethane).
It should be noted that, as per the conventional depiction of the representative compound,
avobenzone (4-tert-butyl-4’-methoxy-dibenzoylmethane), the Av moiety in the above
general formula II is depicted as the diketo tautomer. However, complexing by the
aluminium cation serves to stabilize the dibenzoylmethane derivative in the form of the more
desirable enol tautomer.
When one or more of the substituents R, R’ and B represents a straight-chain or branched
alkyl group having from 1 to 20 carbon atoms, this alkyl groups preferably has from 1 to 10
carbon atoms, and more preferably has from 1 to 4 carbon atoms.
The ligand L is optionally present in the complex, and may, for example, be the anion of the
salt from which the aluminium cation is derived. Accordingly, the complex may be prepared
by combining the dibenzoylmethane derivative (Av) with an aluminium salt such as
aluminium sulphate, aluminium chloride, aluminium acetate, aluminium citrate or
aluminium stearate.
Solvent molecules may also be incorporated in the complex of general formula I.
The present invention further relates to compositions comprising these complexes and to
methods for providing enhanced protection from the effects of ultraviolet radiation.
Appendix
400
DETAILED DESCRIPTION OF THE INVENTION
Organic sunscreening compounds decrease the total amount of UV radiation penetrating
human skin by absorbing specific wavelengths which cause promotion of electrons from a
low energy molecular orbital to a higher energy molecular orbital. Energy is then released
from the molecule in the form of infrared radiation, fluorescence, phosphorescence,
interaction with other molecules or intra-molecular structural changes.
One such group of organic compounds, dibenzoylmethane derivatives, comprises β-
diketones which absorb UVA radiation with a maximum efficiency near 340 nm.
Dibenzoylmethane derivatives suitable for use as sunscreening agents are, however, photo-
unstable, undergoing a keto-enol tautomerism. The keto form of these compounds has a λmax
of about 260nm, while the enol form has a λmax in excess of 345 nm. The enol form is
desirable for UVA protection but, when exposed to UV, it undergoes a tautomerism to
produce the diketo form, which affords no protection against UVA radiation.
Appendix
401
Further, there is evidence to suggest that sunscreening agents normally considered stable,
typically octylmethoxy cinnamate or Padimate O, undergo photodegradation when
incorporated in sunscreen products comprising dibenzoylmethane derivatives.
The effectiveness of sunscreen preparations in protecting against UVA radiation, which is
the UV band with wavelengths in the range of 320nm-400nm, is further limited by the
inability of current organic sunscreening agents to provide significant protection much
beyond 360 nm, leaving the skin and other surfaces unprotected from around half of the
UVA.
The use and effectiveness of the dibenzoylmethane derivatives is therefore limited by their
photo-instability and less than optimal absorption characteristics.
In International Patent Applications WO 93/10753 and WO 93/11135, Slavtcheff et al reveal
methods for the preparation of sunscreening agents being metal complexes with enhanced
UVA absorption, including aluminium complexes of dibenzoylmethane derivatives.
However, the methods described either require the aluminium-dibenzoylmethane derivative
complex to be isolated as a solid after manufacture by processes not appropriate to large
scale pharmaceutical manufacture, or otherwise require the preparation of the complex in
suitable pharmaceutical carrier oils but (as indicated by the examples) at such dilutions as to
provide poor UVA protection, when added to other components essential for the formation
of an emulsion.
International Patent Applications WO 93/10753 and WO 93/11135 also teach that the λmax of
the complexes, i.e. the wavelength with the largest molar absorptivity, is 366 in a 50:50 (v/v)
chloroform : DMSO solvent. This is not significantly different from the λmax of the
uncomplexed dibenzoylmethane derivative.
The present invention provides improved methods of preparation of dibenzoylmethane
derivative complexes, with significant shift of the wavelength of maximum molar
absorptivity ( λmax = 372nm) resulting in broader protection in the UVA, particularly in the
region designated as UVA1 (340-400 nm), which has previously been poorly protected by
organic sunscreening agents.
Appendix
402
The complexes of the present invention may, for example, comprise one or two molecules of
the dibenzoylmethane derivative combined with a single aluminium cation. It has however
been discovered that, in order to obtain a significant shift in the λmax , thereby increasing
absorption in the UVA1 region, and at the same time increase the molar absorption at the
λmax, it is preferable to utilize a complex having a substantially 1:1 molar ratio, or less, of the
dibenzoylmethane derivative to the aluminium cation. Accordingly, it is preferable to utilize
an equivalent or molar excess of the aluminium cation, with respect to the amount of the
dibenzoylmethane derivative, when preparing the complex.
It has therefore been discovered that this complex is best prepared by using a substantially
1:1 molar ratio of the dibenzoylmethane derivative to the aluminium salt, although such a
complex can also be produced by using molar ratios of the dibenzoylmethane derivative to
the aluminium salt of up to about 1:10 (dibenzoylmethane derivative : aluminium salt).
Accordingly, in the complexes of the present invention, the molar ratio of the
dibenzoylmethane derivative to the aluminium cation generally ranges from about 2:1 to
about 1:10, preferably from about 1:1 to about 1:10, and is most preferably a substantially
1:1 molar ratio.
Preferably, the complex is produced in situ (i.e. without being isolated from the reaction
mixture), although it can be isolated prior to use.
The aluminium salt may, for example, be aluminium sulphate, aluminium chloride,
aluminium acetate, aluminium citrate or aluminium stearate.
It has been discovered that the dibenzoylmethane derivative : aluminium complex is not only
stable in solution or suspension but is also photostable to UV light. The dibenzoylmethane
derivative : aluminium complex does not undergo a tautomerism to the diketo form, thus
providing significant advantages over the uncomplexed dibenzoylmethane derivative.
It has also been discovered that a mixture of the dibenzoylmethane derivative : aluminium
complex and octyl methoxycinnamate inhibits photodegradation of the octyl
methoxycinnamate.
Accordingly, further aspects of the invention include the following:
Appendix
403
A. A method of preparation of a dibenzoylmethane derivative : aluminium complex
having a molar ratio of substantially 1:1, the method comprising combination of the
dibenzoylmethane derivative with an aluminium salt in a molar ratio of from about
10:1 to about 1:10 (dibenzoylmethane derivative : aluminium salt), and preferably in
a molar ratio of around 1:1;
B. A method of increasing the molar absorption at its λmax of a dibenzoylmethane
derivative by complexing the dibenzoylmethane derivative with aluminium;
C. A method of increasing the wavelength of maximum absorption ( λmax ) of a
dibenzoylmethane derivative, so as to provide better protection in the UVA1 region,
by complexing the dibenzoylmethane derivative with aluminium;
D. A method of photostabilising a UVB absorber, such as octylmethoxycinnamate, by
combining same with a dibenzoylmethane derivative : aluminium complex.
EXAMPLES
The following Examples 1 and 2 illustrate methods for preparing the dibenzoylmethane
derivative : aluminium complexes of the present invention.
Example 3 provides an example of a sunscreen formulation comprising a
dibenzoylmethane derivative : aluminium complex.
Please note that these Examples are illustrative, but not restrictive, of the invention.
EXAMPLE 1
In a 250 ml beaker add butyl methoxy dibenzoylmethane (2.0 g, 0.00645 moles) and 50
ml of an ethanol : water mixture (80:20 w/w), stir to disperse, and then add aluminium
chloride hexahydrate (1.56 g, 0.00645 moles). The mixture is stirred for 1 hour to form
the butyl methoxy dibenzoylmethane: aluminium complex, which is then incorporated
directly into an emulsion or gel.
Appendix
404
EXAMPLE 2
In a 250 ml beaker add butyl methoxy dibenzoylmethane (2.0 gms, 0.00645 moles) and
glycerol (2.0 g, 0.022 moles). Add 50 ml of water and stir to disperse the mixture. Add
aluminium chloride hexahydrate (1.56 g, 0.00645 moles). The mixture is heated to 80º C
and stirred for 2 hours to form the butyl methoxy dibenzoylmethane : aluminium
complex, which is then directly incorporated into an emulsion or gel.
EXAMPLE 3
A sunscreen emulsion comprising the aluminium complex with butyl methoxy
dibenzoylmethane.
Ingredient Percentage (w/w)
Phase A
1 water 53.5
2 aluminium chloride hexahydrate 1.56
3 glycerol 2.0
4 butyl methoxy dibenzoylmethane 2.0
5 phenoxy ethanol 0.3
Phase B
6 paraffin light oil 15
7 cetyl phosphate 2.0
8 cetyl stearyl alcohol 2.0
9 carbomer 0.1
10 glycerol mono-stearate 1.5
11 phenoxy ethanol 0.3
12 nipastat 0.3
13 isodecyl neopentanoate 5.0
14 octyl methoxy cinnamate 7.5
15 octyl salicylate 5.0
Appendix
405
16 fragrance 0.44
Phase C
17 potassium hydroxide 0.3
18 water purified 1.2
Method:
Phase A
To a mixer add water (1) and aluminium chloride hexahydrate (2), heat to 80° C and mix
until dissolved. Hold temperature at 80° C. Separately mix butyl methoxy
dibenzoylmethane (4) with glycerol (3) to form a paste, and add to the mixer with
vigorous stirring. Stir at 80° C for 2 hours, and then add phenoxy ethanol (5) and stir
until dissolved. Cool to 70° C.
Phase B
In a mixer add the following ingredients: paraffin light oil (6), cetyl phosphate(7), cetyl
stearyl alcohol (8), carbomer (9), glycerol mono stearate (10), phenoxy ethanol (11),
nipastat (12), isodecyl neopentanoate (13), octyl methoxy cinnamate (14) and octyl
salicylate (15), and heat to 70° C with mixing until a homogeneous solution is obtained.
Phase C
In mixer add potassium hydroxide (17) to water (18) and mix until a clear solution is
obtained.
Add Phase B to Phase A with vigorous stirring, and homogenise until average particle
size is <1 micron. Then add sufficient phase C to bring the pH of the emulsion to 6.0.
Cool to 40° C with stirring, and then add fragrance (16). Mix until the emulsion reaches
room temperature.
Appendix
406
A.3 Molecular Modelling
Triplet States of DBM (IIIa) calculated by the SAC-CI method.
TABLE A.3.1: Basis set dependency on the excited triplet states (A′)′ of dibenzoylmethane
(IIIa) calculated by the SAC-CI method.
State Main Configuration (|C|>0.25) N Eexa f
6-31G
1A′′ 0.82(59-60)-0.32(55-60) π-π* 2.89
2A′′ 0.50(56-60)-0.48(56-61)-0.42(58-63)-0.27(58-60) π-π* 0.88 0.001
3A′′ 0.58(55-60)-0.45(57-62)0.39(59-61)0.27(55-61)-0.27(50-64) π-π* 1.15 0.001 6-31G(d,p)
1A′′ 0.84(59-60)-0.29(55-60) π-π* 2.82
2A′′ 0.50(56-60)-0.47(56-61)-0.41(58-63)-0.29(58-60) π-π* 0.94 0.001
3A′′ -0.61(55-60)0.42(57-62)-0.38(59-61)-0.28(55-61)0.27(59-64) π-π* 1.12 0.001 6-31+G(d,p)
1A′′ 0.84(59-60)0.26(55-60) π-π* 2.78
2A′′ -0.51(56-60)0.41(56-64)-0.34(58-70)0.29(58-60) π-π* 0.88 0.001
3A′′ -0.61(55-60)0.36(57-69)0.29(59-64) π-π* 1.20 0.002 6-311G
1A′′ -0.84(59-60)0.29(55-60) π-π* 2.93
2A′′ 0.50(56-60)-0.50(56-61)-0.42(58-63)-0.28(58-60) π-π* 0.84 0.001
3A′′ -0.59(55-60)0.44(57-62)-0.38(59-61)-0.27(55-61)-0.26(59-67) π-π* 1.15 0.001 a Calculated excitation energy is the relative energy in eV from the lowest triplet state, 1A′′
Appendix
407
TABLE A.3.2: Excited triplet states of dibenzoylmethane (IIIa) calculated by the SAC-CI
method with configuration selections thresholds corresponding to Level One and Level Two
employing the 6-31+G(d,p) basis set.
State Main Configuration (|C|>0.25) N Eexa f
Level One
1A′′ 0.84(59-60)0.26(55-60) π-π* 2.78
2A′′ -0.51(56-60)0.41(56-64)-0.34(58-70)0.29(58-60) π-π* 0.88 0.001
3A′′ -0.61(55-60)0.36(57-69)0.29(59-64) π-π* 1.20 0.002 Level Two
1A′′ 0.85(59-60)0.28(55-60) π-π* 2.81
2A′′ 0.53(56-60)-0.41(56-64)0.31(58-70)-0.30(58-60) π-π* 0.97 0.001
3A′′ -0.65(55-60)0.32(57-69)0.31(59-64) π-π* 1.29 0.002 a Calculated excitation energy is the relative energy in eV from the lowest triplet state, 1A′′
TABLE A.3.3: Excited triplet states of chelated enol of dibenzoylmethane (IIIa) calculated
by SAC-CI/6-31+G(d,p) with varying active space size.
State Main Configuration (|C|>0.25) N Eexa f
1 (MO18-MO279)
1A′′ 0.84(59-60)0.26(55-60) π-π* 2.77
2A′′ -0.51(56-60)0.41(56-64)-0.33(58-70)0.29(58-60) π-π* 0.89 0.001
3A′′ -0.61(55-60)0.36(57-69)0.29(59-64) π-π* 1.19 0.002
FC MO18-MO381
1A′′ -0.84(59-60)-0.26(55-60) π-π* 2.77
2A′′ 0.51(56-60)-0.41(56-64)0.34(58-70)-0.29(58-60) π-π* 0.88 0.001
3A′′ -0.61(55-60)0.36(57-69)0.29(59-64) π-π* 1.19 0.002 a Calculated excitation energy is the relative energy in eV from the lowest triplet state, 1A′′
Appendix
408
TABLE A.3.4: Excited triplet states of three different conformations of the chelated enol
form of dibenzoylmethane IIIa calculated by the SAC-CI / 6-31+G(d,p) method.
State Main Configuration (|C|>0.25) N Eexa f
DBMenol-saCone
1A′′ -0.84(59-60)-0.26(55-60) π-π* 2.75
2A′′ -0.50(56-60)-0.38(58-70)0.38(56-64)-0.29(58-60) π-π* 3.64 0.001
3A′′ 0.61(55-60)0.35(57-69)-0.26(59-64) π-π* 3.89 0.001 a Calculated excitation energy is the relative energy in eV from the lowest triplet state, 1A′′
Cartesian Cordinates of a-d forms of I-VI.
TABLE A.3.5: DFT-optimised geometries (Cartesian coordinates in Å) and absolute
energies (Hartrees) of chelated enol forms a and a′ and keto form d of acetylacetone (I),
benzoylacetone (II), dibenzoylmethane (III), butyl methoxydibenzoylmethane (IV),NapPh (V)
and IndolePh (VI) . All calculations performed at the B3LYP/6-31+G(d,p) level of theory.
Ia
Energy = -345.832441 a.u.
Atom X Y Z
C 0.015021 0.051525 -0.009956
C -0.002156 -0.006947 1.484997
O 1.198491 -0.107200 2.037909
C -1.146237 0.038805 2.250803
C -1.062339 -0.027505 3.688138
O 0.045592 -0.120105 4.272723
C -2.327888 -0.014189 4.515228
H 1.038738 -0.136324 3.040003
H -0.993304 0.133470 -0.419434
H -3.172308 0.424714 3.977509
H 0.610315 0.910070 -0.339688
H 0.495823 -0.848059 -0.409687
H -2.588675 -1.046334 4.779669
H -2.150554 0.530606 5.445651
H -2.110381 0.123319 1.765232
Appendix
409
Ib
Energy = -345.829742 a.u.
Atom X Y Z
H 0.589511 -0.081267 -0.261678
H -0.293915 0.085039 1.280043
H 1.485309 -0.052029 1.255922
C 0.555670 -0.392754 0.787763
C 0.479928 -1.890666 0.861330
O 1.437227 -2.555760 0.309094
H 1.115575 -3.699208 0.520978
O 0.435741 -4.603827 0.939679
C -0.541321 -3.979148 1.504359
C -0.574817 -2.572103 1.497026
H -1.386127 -2.031145 1.965482
C -1.607562 -4.816626 2.149846
H -2.051103 -5.481467 1.401011
H -2.391751 -4.205067 2.600915
H -1.155341 -5.452204 2.918631
Ic
Energy = -345.806281 a.u. Atom X Y Z
C 0.063302 0.084756 0.015254
C -0.068617 -0.008091 1.510613
C 0.995761 0.035343 2.349935
C 0.964872 -0.047622 3.821031
C 2.325398 0.029710 4.504963
O -1.330081 -0.139829 1.982373
O -0.062195 -0.170270 4.480009
H 1.106308 0.189031 -0.287602
H 2.975865 -0.784324 4.162383
H -0.344921 -0.814525 -0.464378
H -0.493310 0.950072 -0.367913
H 2.828723 0.972152 4.256822
H 2.193657 -0.039483 5.585730
H 1.970053 0.142628 1.883927
H -1.960248 -0.152260 1.249282
Appendix
410
Id
Energy = -345.822837 a.u.
Atom X Y Z
C -0.228879 -0.035264 0.622460
C 0.814612 0.693518 1.435948
C 1.986968 -0.148904 1.963152
C 1.606964 -0.706749 3.343614
O 1.032045 -1.776139 3.440578
O 0.738258 1.879769 1.701519
C 1.949069 0.153550 4.537353
H -0.548099 -0.943904 1.145670
H -1.081603 0.617718 0.431023
H 0.209188 -0.355428 -0.331109
H 1.607391 1.181706 4.372191
H 1.500168 -0.260270 5.441496
H 3.038956 0.196192 4.656102
H 2.184957 -0.994922 1.300601
H 2.862529 0.500718 2.035752
IIa
Energy = -537.581410 a.u.
Atom X Y Z
C 0.006943 0.150319 0.000457
C -0.001959 0.080540 1.403777
C 1.220384 -0.055248 2.084081
C 2.421353 -0.113150 1.379896
C 2.419638 -0.042522 -0.017184
C 1.209690 0.086827 -0.704514
C -1.257209 0.135711 2.215393
O -1.179404 -0.073036 3.456924
C -2.531438 0.428230 1.606566
C -3.674301 0.470329 2.374733
C -5.037381 0.768602 1.833313
O -3.648374 0.245840 3.680443
H -5.710247 -0.069839 2.044267
H -5.450481 1.649317 2.337135
H -5.012420 0.947961 0.757028
H -2.615588 0.631087 0.548680
H 1.203319 -0.112964 3.166853
H 3.359027 -0.214247 1.918573
Appendix
411
H 3.355276 -0.089798 -0.566994
H 1.201495 0.136631 -1.789355
H -0.920274 0.242380 -0.554171
H -2.672701 0.067915 3.904107
IIa′
Energy = -537.580601 a.u.
Atom X Y Z
C 0.005430 0.087492 -0.008628
C 0.001664 0.109128 1.384577
C 1.208526 0.040295 2.103643
C 2.418330 -0.043797 1.391726
C 2.418428 -0.068615 -0.002605
C 1.213624 -0.003781 -0.707539
C 1.239888 0.057192 3.582110
C 0.130167 -0.066201 4.401326
C 0.280364 -0.039978 5.829423
O 1.410932 0.089699 6.369624
O 2.448073 0.191264 4.112355
C -0.933962 -0.170159 6.720291
H 2.308456 0.176640 5.125363
H -0.788424 -1.012195 7.404560
H -1.025537 0.732414 7.333941
H -1.857939 -0.316140 6.155993
H -0.853972 -0.200078 3.975590
H 3.350229 -0.092192 1.942897
H 3.360263 -0.138023 -0.538749
H 1.214555 -0.020627 -1.793499
H -0.934231 0.146620 -0.549669
H -0.944246 0.194834 1.908178
IIb
Energy = -537.578511 a.u.
Atom X Y Z
H -0.175890 0.099348 -0.038853
H -0.329876 0.132742 1.716577
H 1.275915 -0.109866 0.977149
C 0.322839 0.415008 0.883689
C 0.497170 1.907192 0.870455
C 1.758333 2.523046 0.968198
Appendix
412
C 1.814134 3.932241 0.946558
O 0.711312 4.603064 0.841120
H -0.122080 3.748889 0.784696
O -0.571180 2.621396 0.765007
H 2.646747 1.916217 1.061358
C 3.072851 4.713310 1.041421
C 4.335924 4.099185 1.101461
H 4.423800 3.018652 1.075572
C 5.494103 4.870279 1.189780
H 6.463416 4.382700 1.233819
C 5.408015 6.265656 1.219962
H 6.311229 6.864994 1.289089
C 4.156380 6.885827 1.159891
H 4.083966 7.969185 1.182662
C 2.997204 6.116725 1.070219
H 2.021216 6.586160 1.022118
IIc
Energy = -537.554387 a.u.
Atom X Y Z
C -0.036954 -0.158038 0.092088
C 0.046034 -0.161738 1.486773
C 1.286879 -0.020425 2.128653
C 2.442739 0.120659 1.343013
C 2.359360 0.138419 -0.047889
C 1.117776 -0.001042 -0.678286
C 1.457800 -0.044645 3.629568
C 0.271462 0.224641 4.457340
C 0.193606 0.104617 5.806668
O 1.244456 -0.329556 6.539579
O 2.571068 -0.264481 4.106380
C -1.051825 0.431550 6.584056
H -1.408093 -0.450590 7.132117
H -0.849886 1.222367 7.318366
H -1.854387 0.772781 5.928400
H -0.625882 0.577286 3.965009
H 3.398015 0.212997 1.849062
H 3.260680 0.258053 -0.642394
H 1.051938 0.008275 -1.762630
H -1.002093 -0.280579 -0.391190
Appendix
413
H -0.860096 -0.303266 2.066583
H 1.004466 -0.365089 7.475468
IIc ′
Energy = -537.554141 a.u.
Atom X Y Z
O -0.067146 0.390285 -0.156134
C -0.026287 0.136814 1.173271
C 1.155281 -0.073651 1.811715
C 2.504153 0.018084 1.225277
O 2.726236 0.294299 0.051107
C -1.336098 0.063741 1.871708
C -1.505195 0.606914 3.156716
C -2.742037 0.536742 3.797738
C -3.830030 -0.073603 3.166039
C -3.673953 -0.614655 1.887342
C -2.437993 -0.544462 1.242484
C 3.650915 -0.256081 2.191966
H 4.601544 -0.154559 1.666520
H 3.622223 0.443754 3.036069
H 3.568617 -1.267713 2.607898
H 1.093388 -0.347018 2.859626
H -2.319480 -1.002078 0.263657
H -4.510767 -1.100858 1.394734
H -4.792506 -0.125192 3.666159
H -2.859893 0.969785 4.786664
H -0.670035 1.104505 3.639197
H -0.957320 0.678122 -0.403475
IId
Energy = -537.570066 a.u.
Atom X Y Z
C -0.747934 0.356977 -0.062371
C -0.718124 0.585305 1.450332
C 0.639323 0.181933 -0.689324
O -1.010709 1.677691 1.902655
O 1.641464 0.123213 0.009662
C -0.346142 -0.583672 2.332392
H 0.683311 -0.885104 2.111915
H -0.435637 -0.299035 3.381876
Appendix
414
H -0.993624 -1.444122 2.123788
C 0.736140 0.084124 -2.181555
H -1.249711 1.215985 -0.518929
C 2.012942 -0.056137 -2.753024
C 2.160433 -0.158469 -4.133956
C 1.033726 -0.123374 -4.963623
C -0.239911 0.015534 -4.406011
C -0.389025 0.120410 -3.021951
H 2.873878 -0.081550 -2.093545
H 3.151034 -0.265052 -4.565978
H 1.148774 -0.202871 -6.040772
H -1.115830 0.044568 -5.047074
H -1.385226 0.230764 -2.606780
H -1.343847 -0.537119 -0.293113
IIIa
Energy = -729.329315 a.u.
Atom X Y Z
C 0.058940 0.031295 -0.159121
C -0.048278 0.261333 1.215262
C 1.094064 0.261436 2.016871
C 2.361430 0.038230 1.452646
C 2.458151 -0.182816 0.068110
C 1.316215 -0.191076 -0.730484
H -0.831520 0.028236 -0.781210
H -1.020674 0.443447 1.663309
H 0.988474 0.455452 3.078667
H 3.440957 -0.346180 -0.360095
H 1.405116 -0.369117 -1.798187
C 3.623496 0.035502 2.255055
O 4.725983 0.041481 1.637471
C 3.591186 0.014700 3.692827
H 2.648734 0.004378 4.217229
C 4.770405 0.009577 4.416709
O 5.943621 0.039928 3.797957
C 4.849907 -0.012189 5.893902
C 3.736438 -0.321384 6.695531
C 3.844396 -0.328841 8.084878
C 5.064877 -0.026489 8.697504
C 6.178575 0.276976 7.909853
Appendix
415
C 6.074995 0.280326 6.519122
H 2.786741 -0.578235 6.238736
H 2.977519 -0.577134 8.689968
H 5.146775 -0.032414 9.780490
H 7.130006 0.510559 8.378421
H 6.936702 0.511904 5.903938
H 5.723273 0.051498 2.800223
IIIb
Energy = -729.327133 a.u.
Atom X Y Z
C -0.065933 -0.056463 0.168295
C -0.217955 -0.232955 1.554584
H 0.647202 -0.405968 2.185358
C -1.484760 -0.207604 2.136591
H -1.587922 -0.351285 3.208049
C -2.618015 -0.002047 1.343656
H -3.603947 0.019159 1.798918
C -2.477389 0.172426 -0.036411
H -3.354150 0.331135 -0.657317
C -1.212149 0.142173 -0.620831
H -1.090762 0.271894 -1.690280
C 1.261743 -0.077549 -0.496997
O 1.270831 -0.084671 -1.791515
H 2.445406 -0.105410 -2.044819
O 3.628094 -0.121109 -1.832161
C 3.682236 -0.100234 -0.538892
C 2.484567 -0.081074 0.204470
H 2.503330 -0.069414 1.282222
C 5.032271 -0.107426 0.080085
C 5.232385 0.098938 1.456104
H 4.389641 0.285867 2.112721
C 6.518690 0.085704 1.994077
H 6.659028 0.252476 3.057939
C 7.623737 -0.137366 1.166807
H 8.624926 -0.149092 1.587829
C 7.435228 -0.341580 -0.203435
H 8.289907 -0.514000 -0.850904
C 6.150402 -0.323499 -0.743979
H 5.991915 -0.476264 -1.805501
Appendix
416
IIIc
Energy = -729.302406 a.u.
Atom X Y Z
C 1.323636 -0.719847 -3.373463
C 1.150818 0.059994 -2.215091
C 2.234215 0.820234 -1.742549
C 3.459602 0.795584 -2.408542
C 3.622790 0.014424 -3.556771
C 2.551800 -0.743986 -4.036354
C -0.163101 0.084679 -1.521104
O -1.260565 0.088304 -2.312784
C -0.269343 0.058472 -0.165359
C -1.515761 0.154641 0.610341
O -2.606651 0.410679 0.100709
C -1.423882 -0.040338 2.105517
C -0.360725 -0.706923 2.735826
C -0.353627 -0.881173 4.122067
C -1.402823 -0.380610 4.896700
C -2.467638 0.283687 4.277516
C -2.480817 0.444763 2.893366
H -1.393738 -0.510726 5.975213
H 0.469119 -1.409924 4.594873
H 0.454378 -1.119910 2.150508
H -3.305679 0.942574 2.394347
H -3.287500 0.672029 4.875122
H 0.662987 -0.025009 0.377047
H 2.103604 1.448100 -0.866917
H 4.284747 1.396169 -2.037311
H 4.577260 -0.001694 -4.074354
H 2.673812 -1.362840 -4.920324
H 0.509524 -1.343046 -3.734804
H -0.999229 0.261233 -3.228288
IIId
Energy = -729.321024 a.u.
Atom X Y Z
C -0.357633 -0.400128 0.546211
C -0.026143 0.959595 0.677251
C 1.162644 1.445966 0.129209
C 2.030953 0.583143 -0.543722
Appendix
417
C 1.707178 -0.772787 -0.677350
C 0.520007 -1.260583 -0.139201
H -0.699008 1.645682 1.179815
H 1.407765 2.499192 0.227451
H 2.957010 0.964373 -0.964747
H 2.380935 -1.444450 -1.201167
H 0.249223 -2.306634 -0.235451
C -1.616080 -0.981384 1.103079
C -2.547407 -0.102034 1.955190
C -3.423478 0.875145 1.152482
O -1.912234 -2.154042 0.909864
O -3.119796 2.061236 1.118837
C -4.639774 0.368411 0.448570
C -5.473258 1.306993 -0.187663
C -6.620055 0.890583 -0.857279
C -6.946644 -0.470372 -0.906016
C -6.121632 -1.409797 -0.283042
C -4.973874 -0.995975 0.396313
H -5.200805 2.356032 -0.141890
H -7.260115 1.621866 -1.342059
H -7.841121 -0.795766 -1.429666
H -6.368584 -2.466297 -0.325976
H -4.333236 -1.739071 0.858291
H -1.963562 0.508768 2.646650
H -3.173523 -0.787663 2.529617
IVa
Energy = -1001.129324 a.u.
Atom X Y Z
C 0.005795 0.039081 -0.012710
C 0.010555 -0.038438 1.388694
C 1.258699 -0.104947 2.042497
C 2.444230 -0.099283 1.326028
C 2.421202 -0.025019 -0.077943
C 1.191775 0.045609 -0.747290
C -1.268744 -0.047842 2.119918
O -2.347358 0.100816 1.359879
O 3.636990 -0.026240 -0.689213
C 3.690606 0.053102 -2.110978
C -1.398247 -0.202136 3.491408
Appendix
418
C -2.698610 -0.202227 4.101045
O -3.742044 -0.077268 3.394735
C -2.857807 -0.367096 5.576258
C -1.788638 -0.292093 6.484943
C -2.002985 -0.448783 7.851180
C -3.285350 -0.694586 8.376783
C -4.346912 -0.764613 7.460332
C -4.140569 -0.599950 6.090822
C -3.474373 -0.868875 9.894381
C -3.018808 0.421240 10.620039
C -4.942110 -1.142501 10.276498
C -2.618306 -2.062643 10.385106
H -1.149434 -0.375061 8.518263
H -0.780600 -0.092115 6.137404
H -4.973734 -0.651086 5.398201
H -5.356607 -0.949645 7.807844
H -0.517009 -0.349312 4.095635
H 1.310118 -0.156234 3.124445
H 3.404478 -0.148810 1.828525
H 1.144499 0.104675 -1.827972
H -0.944494 0.093084 -0.531052
H -3.141064 0.058213 2.006908
H 4.750138 0.038230 -2.367676
H 3.189972 -0.804569 -2.576057
H 3.239617 0.984355 -2.474135
H -5.020701 -1.260377 11.362378
H -5.600586 -0.316942 9.986371
H -5.319405 -2.062236 9.816865
H -3.141219 0.309111 11.703540
H -1.966516 0.648906 10.424772
H -3.613534 1.282672 10.297674
H -2.743725 -2.199205 11.465473
H -2.919063 -2.990981 9.887607
H -1.552705 -1.908472 10.190519
IVa′
Energy = -1001.129509 a.u.
Atom X Y Z
C -3.270101 -0.184591 -4.780826
C -3.408154 -0.233841 -3.383577
Appendix
419
C -2.287963 -0.145659 -2.570081
C -0.997600 -0.006857 -3.119427
C -0.879390 0.041423 -4.516603
C -1.994432 -0.045119 -5.348224
H -4.402320 -0.341284 -2.962551
H -2.430835 -0.186516 -1.496049
H 0.111586 0.148654 -4.944021
H -1.860857 -0.003951 -6.422621
C 0.242246 0.091012 -2.301298
O 1.351110 0.219033 -2.899225
C 0.195657 0.039220 -0.863650
H -0.743349 -0.097612 -0.350796
C 1.359935 0.134946 -0.122492
O 2.536513 0.263853 -0.724183
C 1.420506 0.086191 1.352665
C 0.277177 0.227650 2.159263
C 0.372360 0.168335 3.544676
C 1.604087 -0.036308 4.196735
C 2.739033 -0.168997 3.383107
C 2.654141 -0.105391 1.991354
H -0.693465 0.406095 1.708508
H -0.534968 0.290604 4.128195
H 3.714567 -0.325607 3.828165
H 3.548923 -0.209361 1.388202
H 2.325739 0.268718 -1.725433
O -4.426484 -0.279575 -5.492688
C -4.362624 -0.238578 -6.915456
H -5.392822 -0.332650 -7.259969
H -3.945141 0.712371 -7.267553
H -3.767806 -1.070624 -7.310970
C 1.660446 -0.098311 5.733335
C 3.089017 -0.337675 6.259540
C 1.147036 1.239512 6.320889
C 0.762350 -1.256384 6.234238
H 3.072909 -0.378399 7.353698
H 3.503172 -1.285999 5.900752
H 3.771964 0.468144 5.970257
H 0.792613 -1.312028 7.328515
H -0.282004 -1.121985 5.936737
H 1.103684 -2.217603 5.835121
H 1.176399 1.207096 7.416109
Appendix
420
H 1.768806 2.077712 5.988495
H 0.115548 1.448185 6.020991
IVb
Energy = -1001.100937 a.u.
Atom X Y Z
C -0.065899 -0.076395 -0.117194
C -0.179993 -0.112949 1.278858
C 1.003956 -0.064371 2.032626
C 2.246517 0.019774 1.407120
C 2.368902 0.069749 0.006991
C 1.179195 0.019163 -0.738015
C -1.563100 -0.229318 1.872228
O -2.506526 -0.543764 1.144608
C 3.761326 0.173314 -0.641283
C 4.459877 1.467466 -0.156600
C -1.719937 0.061773 3.304271
C -2.854828 -0.099686 4.038274
O -4.009173 -0.518057 3.464952
C -2.914152 0.199778 5.489272
C -4.047894 0.812916 6.044402
C -4.124959 1.110504 7.407547
C -3.051796 0.785729 8.247663
C -1.911901 0.165363 7.708248
C -1.847616 -0.121343 6.352767
O -3.018034 1.024833 9.587747
C -4.140081 1.653316 10.200631
C 4.613704 -1.052815 -0.230990
C 3.690874 0.214586 -2.180519
H 3.136219 0.044629 2.029470
H 0.973321 -0.114361 3.116098
H -0.975242 -0.125978 -0.707187
H 1.210992 0.052616 -1.820996
H -0.875295 0.479825 3.835627
H -0.971779 -0.623671 5.954899
H -1.096362 -0.093159 8.375603
H -5.010526 1.601246 7.792734
H -4.873662 1.108653 5.402300
H -3.889553 1.738872 11.258234
H -4.311873 2.653320 9.784325
Appendix
421
H -5.046880 1.046534 10.088543
H 4.703424 0.288144 -2.591425
H 3.232623 -0.690464 -2.593530
H 3.125370 1.080767 -2.540405
H 5.610038 -0.990589 -0.684098
H 4.744029 -1.113844 0.853752
H 4.145058 -1.984752 -0.564935
H 5.453619 1.554844 -0.611282
H 3.879035 2.353411 -0.434921
H 4.588068 1.479223 0.930180
H -4.638872 -0.759915 4.158871
IVc
Energy = -1001.100937 a.u.
Atom X Y Z
C -0.065899 -0.076395 -0.117194
C -0.179993 -0.112949 1.278858
C 1.003956 -0.064371 2.032626
C 2.246517 0.019774 1.407120
C 2.368902 0.069749 0.006991
C 1.179195 0.019163 -0.738015
C -1.563100 -0.229318 1.872228
O -2.506526 -0.543764 1.144608
C 3.761326 0.173314 -0.641283
C 4.459877 1.467466 -0.156600
C -1.719937 0.061773 3.304271
C -2.854828 -0.099686 4.038274
O -4.009173 -0.518057 3.464952
C -2.914152 0.199778 5.489272
C -4.047894 0.812916 6.044402
C -4.124959 1.110504 7.407547
C -3.051796 0.785729 8.247663
C -1.911901 0.165363 7.708248
C -1.847616 -0.121343 6.352767
O -3.018034 1.024833 9.587747
C -4.140081 1.653316 10.200631
C 4.613704 -1.052815 -0.230990
C 3.690874 0.214586 -2.180519
H 3.136219 0.044629 2.029470
H 0.973321 -0.114361 3.116098
Appendix
422
H -0.975242 -0.125978 -0.707187
H 1.210992 0.052616 -1.820996
H -0.875295 0.479825 3.835627
H -0.971779 -0.623671 5.954899
H -1.096362 -0.093159 8.375603
H -5.010526 1.601246 7.792734
H -4.873662 1.108653 5.402300
H -3.889553 1.738872 11.258234
H -4.311873 2.653320 9.784325
H -5.046880 1.046534 10.088543
H 4.703424 0.288144 -2.591425
H 3.232623 -0.690464 -2.593530
H 3.125370 1.080767 -2.540405
H 5.610038 -0.990589 -0.684098
H 4.744029 -1.113844 0.853752
H 4.145058 -1.984752 -0.564935
H 5.453619 1.554844 -0.611282
H 3.879035 2.353411 -0.434921
H 4.588068 1.479223 0.930180
H -4.638872 -0.759915 4.158871
IVc ′
Energy = -1001.101986 a.u.
Atom X Y Z
C -0.037455 -0.287821 -0.016140
C -0.162813 0.181981 1.300135
C 1.009076 0.566780 1.973614
C 2.249498 0.476156 1.350437
C 2.388108 0.003492 0.031343
C 1.213228 -0.376963 -0.633002
C -1.495392 0.279187 1.947277
O -2.521023 0.670594 1.154101
C 3.782506 -0.074669 -0.615874
C 4.683153 -1.020014 0.216747
C -1.694907 -0.046601 3.252740
C -2.952374 0.091444 4.004965
O -3.946004 0.660729 3.548469
C -2.991135 -0.462635 5.403539
C -2.067179 -1.396248 5.910804
C -2.177744 -1.885772 7.206495
Appendix
423
C -3.217702 -1.443942 8.039123
C -4.150429 -0.515583 7.552401
C -4.030871 -0.044257 6.245713
O -3.238029 -1.975027 9.295300
C -4.276567 -1.583903 10.187145
C 3.729890 -0.609706 -2.060230
C 4.414678 1.338841 -0.647819
H -1.473712 -2.614489 7.595007
H -1.263572 -1.772584 5.286562
H -4.752895 0.663614 5.851910
H -4.963647 -0.160055 8.174036
H -0.827293 -0.426459 3.775517
H 0.940779 0.962378 2.982193
H 3.126980 0.793697 1.905247
H 1.257408 -0.761337 -1.645260
H -0.915573 -0.631113 -0.557781
H -4.094412 -2.132393 11.111973
H -4.243905 -0.506461 10.390208
H -5.263899 -1.852768 9.792194
H 4.742877 -0.642879 -2.474456
H 3.323276 -1.625740 -2.106063
H 3.128911 0.032393 -2.713205
H 5.681716 -1.080950 -0.230843
H 4.801126 -0.669791 1.246645
H 4.263318 -2.030959 0.252140
H 5.408992 1.296891 -1.106809
H 3.799059 2.031126 -1.232131
H 4.529729 1.758374 0.356197
H -2.170005 1.006076 0.317184
IVd
Energy = -1001.122250 a.u.
Atom X Y Z
C -3.269281 -0.429275 -0.674863
C -2.709155 0.835948 -0.439854
C -3.361439 1.703577 0.463317
C -4.528717 1.322650 1.099881
C -5.080165 0.050165 0.854542
C -4.443807 -0.827881 -0.034138
H -2.781617 -1.131487 -1.342261
Appendix
424
H -2.925760 2.679773 0.647878
H -5.037948 1.984330 1.792888
H -4.845364 -1.814146 -0.232092
C -1.460018 1.303663 -1.091987
O -0.971043 2.397778 -0.827580
C -0.773330 0.410873 -2.142102
H -1.516000 -0.015953 -2.819351
H -0.109739 1.064825 -2.711608
C 0.013876 -0.775770 -1.562926
O -0.464426 -1.902854 -1.632121
C 1.350051 -0.539557 -0.946105
C 1.904117 0.741936 -0.780554
C 3.158641 0.894883 -0.195751
C 3.915092 -0.208429 0.240102
C 3.348194 -1.483840 0.068988
C 2.091675 -1.648051 -0.508500
H 1.352254 1.625673 -1.082131
H 3.550044 1.900436 -0.076968
H 3.886922 -2.368300 0.387922
H 1.666145 -2.638608 -0.631367
C 5.298726 0.011925 0.876617
C 5.980642 -1.310779 1.277516
H 6.956877 -1.096430 1.724887
H 5.395028 -1.865950 2.018075
H 6.149957 -1.962015 0.413321
C 6.218569 0.742001 -0.133207
H 6.348132 0.149120 -1.045000
H 5.816123 1.717569 -0.421761
H 7.207807 0.906729 0.309079
C 5.143265 0.880575 2.149506
H 4.715780 1.862051 1.923925
H 4.491482 0.391060 2.881063
H 6.121197 1.041243 2.617856
O -6.227555 -0.232479 1.526000
C -6.843206 -1.503932 1.333938
H -7.732341 -1.499055 1.964832
H -7.137854 -1.648000 0.287657
H -6.177919 -2.317954 1.645227
Appendix
425
Va
Energy = -882.981004 a.u.
Atom X Y Z
C 0.001486 -0.073259 0.003604
C -0.000610 -0.017568 1.425569
C 1.252047 0.030196 2.120051
C 2.456724 0.022052 1.368339
C 2.425876 -0.032349 -0.009749
C 1.187455 -0.080485 -0.698526
C 1.236190 0.087208 3.542311
C 0.053665 0.092532 4.241153
C -1.199056 0.043605 3.558889
C -1.205629 -0.006590 2.172771
C -2.484470 0.043737 4.286808
O -3.562495 0.135450 3.517480
C -2.610522 -0.051382 5.662273
C -3.912003 -0.042874 6.274617
O -4.954758 0.066559 5.569371
C -4.067737 -0.147155 7.758410
C -5.328078 0.135429 8.312198
C -5.532291 0.054943 9.688302
C -4.482033 -0.320191 10.532654
C -3.227152 -0.613701 9.991795
C -3.019517 -0.524411 8.614664
H -2.041956 -0.770882 8.214738
H -2.410565 -0.915199 10.641228
H -4.641132 -0.386620 11.605132
H -6.509701 0.282671 10.103536
H -6.133615 0.417032 7.643018
H 0.082423 0.148449 5.323314
H 2.181979 0.130642 4.075874
H -2.154667 -0.040283 1.648792
H -0.949965 -0.109063 -0.520263
H 1.177854 -0.122882 -1.783598
H 3.353913 -0.038564 -0.573938
H 3.406287 0.058878 1.895962
H -1.725231 -0.123012 6.273600
H -4.356346 0.127807 4.159719
Appendix
426
Va′
Energy = -882.980589 a.u.
Atom X Y Z
C -0.025961 -0.113563 -0.013855
C -0.013145 -0.167556 1.362797
C 1.210810 -0.067614 2.082989
C 2.435314 0.089653 1.353356
C 2.388207 0.142293 -0.065756
C 1.186125 0.042807 -0.734091
C 1.254599 -0.116768 3.498208
C 2.451267 -0.025189 4.191502
C 3.663670 0.130857 3.457635
C 3.652013 0.189471 2.083409
C 2.405875 -0.091425 5.683333
C 3.611882 -0.199982 6.459326
C 3.547736 -0.266920 7.840459
C 4.723363 -0.380797 8.731384
C 5.994040 -0.738370 8.246201
C 7.081870 -0.831711 9.112253
C 6.919949 -0.568464 10.476357
C 5.660134 -0.218019 10.969314
C 4.568475 -0.129134 10.106127
O 1.277808 -0.059561 6.254580
O 2.379422 -0.214138 8.465584
H 1.679699 -0.136148 7.722210
H 6.134495 -0.966566 7.195098
H 8.055103 -1.116790 8.723896
H 7.769188 -0.641260 11.149494
H 5.526472 -0.014547 12.027655
H 3.588710 0.139124 10.483984
H 4.610443 0.222792 3.977577
H 4.582667 0.316751 1.536615
H 0.334760 -0.228988 4.063415
H -0.938888 -0.286284 1.919431
H -0.965079 -0.190288 -0.553750
H 1.163203 0.084015 -1.819220
H 3.316302 0.262063 -0.618714
H 4.574644 -0.224808 5.974028
Appendix
427
Vb
Energy = -882.978639 a.u.
Atom X Y Z
C -0.016685 -0.013335 0.017456
C -0.001872 0.091035 1.419208
H 0.952610 0.194500 1.922724
C -1.192289 0.059956 2.143981
H -1.166009 0.136765 3.226957
C -2.415869 -0.068339 1.479770
H -3.343699 -0.090228 2.044071
C -2.442040 -0.164918 0.085020
H -3.389680 -0.256868 -0.437318
C -1.252091 -0.139409 -0.641278
H -1.294525 -0.202660 -1.723179
C 1.275806 0.019675 -0.713010
O 2.330694 0.326913 -0.026964
H 3.198775 0.274345 -0.847303
O 3.701550 0.109643 -1.932853
C 2.686346 -0.213587 -2.668094
C 1.402726 -0.274100 -2.085343
H 0.540708 -0.549365 -2.670781
C 2.948252 -0.500500 -4.099814
C 1.922644 -0.931158 -4.992631
H 0.908847 -1.067829 -4.633990
C 2.202300 -1.187227 -6.313751
H 1.411884 -1.517665 -6.982496
C 3.518348 -1.029206 -6.831679
C 3.840699 -1.284500 -8.191249
H 3.053950 -1.612708 -8.865582
C 5.130290 -1.119170 -8.651654
H 5.364444 -1.317313 -9.693566
C 6.157511 -0.690706 -7.772684
H 7.168310 -0.564844 -8.149163
C 5.876064 -0.435343 -6.448136
H 6.659771 -0.107430 -5.770495
C 4.555699 -0.596520 -5.941633
C 4.237776 -0.342791 -4.584083
H 5.016678 -0.017171 -3.902439
Appendix
428
Vc
Energy = -882.953814 a.u.
Atom X Y Z
C -0.288495 -0.479416 0.175421
C -0.048413 0.013593 1.468162
C 1.275512 0.275311 1.857841
C 2.331373 0.067670 0.972530
C 2.082002 -0.422297 -0.314452
C 0.771031 -0.701853 -0.707833
C -1.138452 0.248334 2.487538
O -0.842812 0.323922 3.680225
C -2.511921 0.412160 1.987553
C -3.636511 0.519838 2.746298
O -3.592208 0.364754 4.089473
C -4.975377 0.759045 2.149977
C -5.128964 1.635066 1.035003
C -6.368755 1.863022 0.486550
C -7.533691 1.234548 1.008718
C -7.391333 0.351011 2.127923
C -6.099074 0.138470 2.676507
C -8.827361 1.452140 0.463326
C -9.931411 0.820741 0.995957
C -9.790466 -0.058787 2.099124
C -8.548965 -0.288819 2.651677
H -1.297503 -0.720621 -0.143042
H 0.571871 -1.095946 -1.700344
H 2.904773 -0.589078 -1.003976
H 3.349295 0.283859 1.284339
H 1.450959 0.639258 2.864794
H -4.256866 2.145525 0.640099
H -6.473107 2.544548 -0.353605
H -6.001734 -0.565718 3.500008
H -8.439702 -0.963056 3.497202
H -10.667408 -0.551581 2.508225
H -10.915247 0.994005 0.570139
H -8.933482 2.124952 -0.383592
H -2.658716 0.472315 0.917368
H -4.436260 0.641451 4.473540
Appendix
429
Vc′
Energy = -882.953326 a.u.
Atom X Y Z
C 0.185772 -0.539740 0.164647
C -0.070276 0.044823 1.418752
C 0.995335 0.630926 2.123073
C 2.283814 0.626499 1.588805
C 2.529108 0.039579 0.343537
C 1.476706 -0.544491 -0.366088
C -1.449979 0.051823 1.971136
O -2.449892 0.272823 1.086725
C -1.707995 -0.193743 3.284055
C -3.024529 -0.132370 3.937447
O -4.038289 0.272762 3.368016
C -3.102273 -0.554460 5.385644
C -4.195084 -0.128350 6.121711
C -4.354892 -0.477530 7.485728
C -3.366156 -1.306112 8.112965
C -2.260404 -1.747975 7.336337
C -2.126980 -1.380115 6.016039
C -3.530152 -1.657420 9.480649
C -4.620128 -1.210620 10.196827
C -5.599118 -0.391110 9.577700
C -5.468506 -0.033299 8.253699
H 0.803843 1.110672 3.077630
H 3.095275 1.092261 2.140139
H 3.532800 0.038948 -0.070903
H 1.660981 -1.013288 -1.328149
H -0.616977 -1.030245 -0.380079
H -1.280853 -1.753752 5.449216
H -1.516251 -2.390041 7.800901
H -4.942327 0.486642 5.628996
H -6.216220 0.593359 7.774808
H -6.453342 -0.047268 10.153586
H -4.734031 -1.485937 11.241395
H -2.780631 -2.285936 9.954875
H -0.847448 -0.437064 3.892818
H -2.077985 0.577747 0.247031
Appendix
430
Vd
Energy = -882.968728 a.u.
Atom X Y Z
O 0.509726 0.183302 -1.538401
C 0.240336 0.600010 -0.421186
C 1.296967 1.326657 0.417094
C 2.632048 1.493141 -0.307988
O 2.904781 2.579372 -0.799502
C -1.126435 0.422039 0.166574
C 3.593845 0.349895 -0.373952
C 3.310580 -0.914080 0.167470
C 4.246929 -1.945826 0.083626
C 5.476422 -1.724438 -0.541930
C 5.767068 -0.468153 -1.086615
C 4.832565 0.560850 -1.003737
H 2.356834 -1.108547 0.646295
H 4.015324 -2.920700 0.502196
H 6.204928 -2.527612 -0.607028
H 6.721103 -0.295119 -1.575929
H 5.037427 1.540230 -1.422863
C -1.479643 0.908430 1.458826
C -2.748078 0.717417 1.957202
C -3.738034 0.031542 1.200837
C -3.390278 -0.460238 -0.101564
C -2.077694 -0.247291 -0.587791
H -0.750783 1.439309 2.061569
H -3.008796 1.093967 2.942717
H -1.797987 -0.611465 -1.571875
C -4.375212 -1.147525 -0.866414
C -5.056211 -0.183304 1.686345
C -5.986938 -0.853173 0.921009
C -5.644348 -1.339921 -0.366982
H -4.106937 -1.517378 -1.852288
H -6.388941 -1.865090 -0.957662
H -6.991261 -1.010884 1.303222
H -5.320813 0.189591 2.672306
H 1.423199 0.803656 1.372920
H 0.935212 2.335008 0.644732
Appendix
431
VIa
Energy = -860.908644 a.u.
Atom X Y Z
C -6.035352 1.173489 0.112689
C -4.886092 1.927504 -0.140511
C -3.636196 1.307971 -0.180342
C -3.518795 -0.076716 0.026800
C -4.682138 -0.826250 0.270848
C -5.929310 -0.205993 0.318050
H -7.007280 1.657405 0.146677
H -4.962418 2.997618 -0.309580
H -2.759232 1.909730 -0.392229
H -4.583369 -1.895713 0.420561
H -6.819351 -0.797077 0.513422
C -2.209342 -0.799813 -0.011244
O -2.227509 -2.065502 -0.031334
C -0.966313 -0.083257 -0.007720
H -0.961272 0.992860 0.058962
C 0.238640 -0.769559 -0.046442
O 0.246544 -2.097565 -0.083858
C 1.571095 -0.139521 -0.037074
C 1.734419 1.270268 -0.135521
C 2.986236 1.861578 -0.121458
C 4.132597 1.049726 -0.006281
C 3.953953 -0.360330 0.086941
C 2.698704 -0.964279 0.071447
H 0.862041 1.905123 -0.237156
H 3.081199 2.940393 -0.202496
H 2.576286 -2.039075 0.142619
H -0.738868 -2.375428 -0.065902
N 5.212308 -0.924560 0.187034
C 6.162129 0.076021 0.158555
H 7.213743 -0.164166 0.224853
C 5.543349 1.298297 0.041527
H 6.040056 2.256927 -0.004281
H 5.405829 -1.910362 0.264492
Appendix
432
VIa′
Energy = -860.908576 a.u.
Atom X Y Z
C -6.044470 1.165384 0.039620
C -4.903063 1.911452 -0.271715
C -3.648818 1.303923 -0.280600
C -3.514186 -0.062949 0.021620
C -4.668905 -0.806587 0.322775
C -5.922295 -0.194891 0.335331
H -7.021016 1.640779 0.046404
H -4.990831 2.966403 -0.514147
H -2.778008 1.894449 -0.544210
H -4.569345 -1.861999 0.548264
H -6.804168 -0.781532 0.575464
C -2.197680 -0.739610 0.027430
O -2.255526 -2.065830 0.050127
C -0.979722 -0.085498 0.027353
H -0.961736 0.992521 0.039333
C 0.249505 -0.836500 0.038931
O 0.217976 -2.102902 0.052705
C 1.575431 -0.157695 0.036531
C 1.721705 1.256260 0.043292
C 2.969582 1.860275 0.041343
C 4.125156 1.054894 0.031079
C 3.962383 -0.361241 0.024163
C 2.712901 -0.974312 0.027323
H 0.843422 1.890773 0.052786
H 3.053073 2.943156 0.047751
H 2.589140 -2.052088 0.023551
N 5.229288 -0.916504 0.014954
C 6.168046 0.094608 0.016063
H 7.223649 -0.137385 0.009746
C 5.534971 1.315110 0.025842
H 6.021521 2.280060 0.029079
H 5.433861 -1.903087 0.008212
H -1.278976 -2.373926 0.061565
Appendix
433
VIb
Energy = -860.906593 a.u.
Atom X Y Z
C 0.007899 0.000000 0.049859
C -0.057960 0.000000 1.454130
H 0.849313 0.000000 2.048051
C -1.290391 0.000000 2.106186
H -1.324798 0.000000 3.191659
C -2.476898 0.000000 1.366362
H -3.436208 0.000000 1.875867
C -2.422590 0.000000 -0.030611
H -3.340556 0.000000 -0.611093
C -1.191004 0.000000 -0.684044
H -1.136156 0.000000 -1.766670
C 1.296720 0.000000 -0.691192
O 1.228048 0.000000 -1.985881
H 2.384720 0.000000 -2.304386
O 3.579374 0.000000 -2.162559
C 3.713795 0.000000 -0.872785
C 2.555863 0.000000 -0.063159
H 2.636081 0.000000 1.011375
C 5.091862 0.000000 -0.334861
C 5.362283 0.000000 1.061134
H 4.540996 0.000000 1.768190
C 6.657655 0.000000 1.552042
H 6.836225 0.000000 2.623295
C 7.738049 0.000000 0.647299
C 9.164908 0.000000 0.782290
H 9.734876 0.000000 1.700392
C 9.688187 0.000000 -0.489344
H 10.719164 0.000000 -0.813722
N 8.663813 0.000000 -1.413505
H 8.780964 0.000000 -2.414293
C 7.450976 0.000000 -0.748581
C 6.152219 0.000000 -1.250178
H 5.939376 0.000000 -2.313558
Appendix
434
VIc
Energy = -860.880469 a.u.
Atom X Y Z
C -0.174889 0.071143 0.141139
C -0.053628 -0.125498 1.557814
C 1.283379 0.214509 1.912068
N 1.926184 0.602874 0.753379
C 1.044442 0.513696 -0.308294
C 1.753245 0.142827 3.225175
C 0.860547 -0.270797 4.224162
C -0.473994 -0.614992 3.882998
C -0.930419 -0.547156 2.575119
C 1.329154 -0.350640 5.629657
O 2.592818 -0.803433 5.814260
C 0.558466 0.037506 6.682883
C 0.935376 -0.022550 8.100836
O 2.067112 -0.321738 8.484834
C -0.122469 0.322530 9.125689
C -1.498581 0.356074 8.847604
C -2.420658 0.661058 9.852034
C -1.979069 0.945766 11.146297
C -0.610116 0.913054 11.434646
C 0.307605 0.598006 10.434393
H -2.696021 1.188130 11.925736
H -3.482525 0.673756 9.623074
H -1.866083 0.123388 7.853829
H 1.371671 0.555742 10.641893
H -0.260768 1.131534 12.439866
H -0.403393 0.460895 6.426494
H -1.137147 -0.966348 4.666148
H -1.952670 -0.827932 2.338791
H 2.764750 0.453292 3.474437
H 1.362472 0.776837 -1.306966
H -1.053364 -0.090911 -0.466918
H 2.884274 0.908019 0.688413
H 2.901589 -1.215026 4.994334
Appendix
435
VIc ′
Energy = -860.880784
Atom X Y Z
C -0.182960 0.274873 0.135626
C -0.046893 0.293337 1.564083
C 1.270833 -0.160329 1.862914
N 1.889153 -0.437583 0.656645
C 1.011620 -0.172837 -0.375681
C 1.751527 -0.267429 3.165392
C 0.895714 0.074332 4.217640
C -0.419434 0.531341 3.935781
C -0.889714 0.647093 2.634730
C 1.455352 -0.046484 5.611034
O 2.670388 -0.183392 5.770639
C 0.505359 -0.031908 6.736227
C 0.823330 -0.025545 8.057924
O 2.106838 0.084774 8.477053
C -0.212480 -0.087499 9.122431
C -1.319319 -0.946089 9.008465
C -2.279884 -1.000753 10.018441
C -2.150561 -0.202638 11.159344
C -1.053038 0.652879 11.284432
C -0.089236 0.708516 10.276214
H -2.898826 -0.248498 11.944985
H -3.124601 -1.676219 9.919962
H -1.409762 -1.586260 8.136666
H 0.739641 1.405806 10.368467
H -0.951090 1.285298 12.161388
H -0.552454 -0.042857 6.511641
H -1.073026 0.829009 4.748003
H -1.895764 1.011430 2.446848
H 2.759066 -0.599525 3.395034
H 1.311332 -0.325839 -1.402803
H -1.052083 0.556620 -0.441721
H 2.833786 -0.770942 0.549180
H 2.150440 -0.084394 9.428687
Appendix
436
VId
Energy = -860.900385 a.u.
Atom X Y Z
C 2.343506 -0.378669 -0.373862
C 2.250008 -1.372115 0.603597
C 2.088391 -1.024036 1.946529
C 2.025484 0.329335 2.320677
C 2.126558 1.323332 1.329852
C 2.281744 0.971687 -0.007900
H 2.465564 -0.653483 -1.417852
H 2.304571 -2.419848 0.323452
H 2.038702 -1.805851 2.696384
H 2.079892 2.363558 1.634141
H 2.355490 1.745330 -0.766608
C 1.855228 0.768592 3.739909
O 1.855078 1.956829 4.036887
C 1.649345 -0.283241 4.841490
C 2.920925 -1.044799 5.259462
O 3.083649 -2.193161 4.856152
C 3.907731 -0.389878 6.158335
C 3.776142 0.959661 6.585602
C 4.712811 1.544290 7.424812
C 5.812777 0.784528 7.867767
C 5.928584 -0.568300 7.427790
C 4.999376 -1.162161 6.582059
H 2.944454 1.557735 6.231767
H 4.598256 2.579163 7.733314
H 5.086472 -2.189285 6.242570
N 7.080067 -1.084324 7.996456
C 7.680194 -0.110458 8.766815
H 8.598987 -0.319697 9.296293
C 6.938146 1.046061 8.715832
H 7.172323 1.970803 9.223556
H 7.426174 -2.021688 7.867060
H 1.227116 0.248098 5.696531
H 0.937041 -1.041276 4.508631
Appendix
437
TABLE A.3.5: Summary of structural parameters for transition state b and open structures
c and c enols of I-VI.
d(O6--O7) q1 q2 |Q| λ
Ib 2.365 0.000 0.000 0.000 1.000 Ic 2.801 -0.127 0.174 0.047 0.853 IIb 2.362 -0.006 0.003 0.003 0.991 IIc 2.772 0.122 0.114 0.236 0.263 IIc ′ 2.803 0.128 0.115 0.243 0.241 IIIb 2.358 0.000 0.000 0.000 1.000 IIIc 2.782 0.122 0.111 0.233 0.272 IVb 2.359 0.001 -0.002 0.001 0.997 IVc 2.765 0.123 0.109 0.232 0.275 IVc′ 2.786 0.121 0.112 0.233 0.272 Vb 2.358 -0.001 -0.002 0.003 0.991 Vc 2.780 0.122 0.110 0.232 0.275 Vc′ 2.780 0.122 0.110 0.232 0.275 VIb 2.358 0.000 0.006 0.006 0.981 VIc 2.764 0.123 0.106 0.229 0.284 VIc′ 2.777 0.122 0.114 0.236 0.263