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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322

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

Chapter 7

323

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.

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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.

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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 −=

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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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329

[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.

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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.

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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

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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