PHOTOLYSIS OF1-METHYL-9,10-ANTHRAQUINONE DERIVATIVES

AND THEIR POTENTIAL REACTIVITY IN THE

PHOTOENOL DIELS-ALDER REACTION

BY

GINA MARIE HILTON

A Thesis Submitted to the Graduate Faculty of

WAKE FOREST UNIVERSITY SCHOOL OF ARTS AND SCIENCES

in Partial Fulfillment of the Requirements

for the Degree of

MASTER OF SCIENCE

Chemistry

December 2013

Winston-Salem, North Carolina

Approved By:

Paul B. Jones, Ph.D., Advisor

S. Bruce King, Ph.D., Chair

Christa Colyer, Ph.D.

ii

TABLE OF CONTENTS

LIST OF TABLES iv

LIST OF FIGURES v

LIST OF ABBREVIATIONS vii

ABSTRACT x

INTRODUCTION 1

Photochemistry 1

Carbonyl Photochemistry 2

Type II Photoelimination 5

Photoinduced Diels-Alder Reaction 9

Click Chemistry 11

Protein Labeling 12

Quinone derivatives in photochemistry 14

Summary 16

RESULTS AND DISCUSSION 17

Background 17

Synthesis of Functionalized Anthraquinones 19

iii

Photoreactions 26

CONCLUSION 34

EXPERIMENTAL 36

APPENDIX A 48

REFERENCES 55

SCHOLASTIC VITA 58

iv

LIST OF TABLES

TABLE PAGE

Table 1 Substituent effects on the product yield in the PEDA reaction 17

Table 2 Synthesized AQs for photolysis in the PEDA reaction 18

Table 3 Summary of photoreactions. All reactions were conducted 35

using the general photolysis setup

v

LIST OF FIGURES

FIGURE PAGE

Figure 1 Jablonski diagram showing potential photochemical 1

excited state outcomes

Figure 2 Electron spin flip from a singlet to a triplet excited state 2

Figure 3 Energy gap differences in n,π* and π,π*: (a) dialkyl (acetone) 4

no mixing, (b) diaryl (benzophenone) spin-orbit mixing between

n,π* and π,π*

Figure 4 Basic Norrish Type II reaction Mechanism 6

Figure 5 1,4-biradical potential conformations and products 6

Figure 6 Potential intramolecular hydrogen bonding in 1,4-biradical 7

intermediate

Figure 7 Example of conformation effects and intramolecular hydrogen 8

binding on the Type II photochemical outcome

Figure 8 General PEDA reaction between a diene and dienophile 10

Figure 9 PEDA reaction of the photoenol precursor 11

Figure 10 Suggested catalytic cycle for the copper(I) 1,3-dipolar cycloaddition 12

Figure 11 Photochemical 1,3-dipolar cycloaddition protein label 13

Figure 12 Proposed PEDA reaction with a dienophile tagged protein 14

Figure 13 Proposed photoreduction mechanism of AQ with polyethylene 14

Figure 14 Potential 1-methyl-9,10-AQ methoxy functionalized derivatives 15

Figure 15 Potential hydrogen bonding for intermediates 10 and 19 19

Figure 16 Friedel-Crafts reaction condition control 20

vi

Figure 17 Synthesis of compound 4 20

Figure 18 Synthesis of compound 6 and 8 21

Figure 19 Synthesis of compound 10, 14, 15/16 22

Figure 20 Synthesis of compound 19, 20, 23/24 23

Figure 21 Crystal structure of the intermediate, 31, for the major 24

product from the Friedel-Crafts reaction between

4-methylanisole and 3-methyl phthalic anhydride

Figure 22 Predicted major Friedel-Crafts product: 20 25

Figure 23 Isomer formation prediction 25

Figure 24 Control PEDA reaction 27

Figure 25 1H-NMR of control PEDA product superimposed with the 27

tolualdehyde starting material

Figure 26 Photolysis of compound 4 28

Figure 27 Photolysis of compound 6 and 8 29

Figure 28 Photolysis of compounds 10, 14, and 15/16 29

Figure 29 Proposed PEDA mechanism to produce compound 29 30

Figure 30 1H-NMR of compound 29 31

Figure 31 Hydrogen bonding of intermediate 27 32

Figure 32 Predicted photo reaction of 14 32

Figure 33 Photolysis of compounds 20, and 23/24 33

Figure 34 1H-NMR of compound 30 33

Figure 35 Labeled positions on 9,10-anthraquinone 34

vii

LIST OF ABBREVIATIONS

APCI Atmospheric-Pressure Chemical Ionization

Ar Argon

AQ Anthraquinone

au Arbitrary Units

BR Biradical

BSA Bovine Serum Albumin

C Celsius

CID Collision-induced Dissociation

d Doublet

DCM Dichloromethane

dd Doublet of doublet

DMAD Dimethyl Acetylenedicarboxylate

DMF Dimethylformamide

EDG Electron Donating Group

eq Equivalent

EWG Electron Withdrawing Group

viii

HRMS High Resolution Mass Spectrometry

hν Photons

ISC Intersystem Crossing

J Coupling Constant

LC Liquid Chromatography

m Multiplet

Me Methyl

MS Mass spectrometry

MW Molecular weight

m/z Mass-to-charge ratio

NBS N-Bromosuccinimide

NHS N-hydroxysuccinimide

NMR Nuclear Magnetic Resonance

NR No Reaction

PAGE Polyacrylamide Gel Electrophoresis

PEDA Photoenolization Diels Alder

Ph Phenyl

ix

rt Room Temperature

s Singlet

t Triplet

TBAF Tetrabutyl Ammonium Fluoride

THF Tetrahydrofuran

TLC Thin-Layer Chromatography

UV Ultraviolet

µ Micro

V Volts

x

ABSTRACT

PHOTOLYSIS OF1-METHYL-9,10-ANTHRAQUINONE DERIVATIVES

AND THEIR POTENTIAL REACTIVITY IN THE

PHOTOENOL DIELS-ALDER REACTION

Functionalized 9,10-anthraquinones (AQ) have proven to undergo a Photoenol

Diels-Alder (PEDA) reaction. The PEDA reaction has been enhanced by the following

factors: increased AQ electron density and the geometry of the intermediate 1,4-biradical

(BR). Hydrogen bonding of the intermediate BR aids the intermolecular Diels-Alder

reaction upon the formation of the photo induced diene by preventing conversion back to

starting material. A series of hydroxy, methyl, and methoxy substituted AQs were

synthesized and photolyzed under 366 nm light. 1-Methyl-9,10-anthraquinone was

photolyzed as a negative control due to a lack of electron density and inability to form an

intramolecular hydrogen bond. Both 1,8-dimethyl-4-methoxy-9,10-anthraquinone, and

1,4-dimethoxy-8-methyl-9,10-anthraquinone produced the PEDA product when

irradiated with dimethyl acetylenedicarboxylate in benzene. The hydroxy analogs of

these compounds did not undergo the PEDA reaction and only produced starting material

after irradiation. Characterization of the compounds was achieved by NMR, high-

resolution Mass Spectrometry, and X-ray crystallography.

1

INTRODUCTION

Photochemistry

Photochemistry is the study of chemical reactions of compounds that have

absorbed a photon of light.1 There are numerous pathways that reactions can undergo

once light absorption has occurred. The pathways followed are highly dependent on the

nature of the compound and its environment. Some of the most common outcomes from

light absorption are concisely illustrated in the Jablonski diagram (Figure 1).2,3

Figure 1: Jablonski diagram showing potential photochemical excited state

outcomes.2

2

An energy jump from the ground singlet state (S0) to an excited singlet state (Sn) requires

an electron be promoted to a higher energy level. More specifically, an electron is

promoted from the highest occupied molecular orbital (HOMO) to the lowest unoccupied

molecular orbital (LUMO), while maintaining the original paired electronic spin state.1

Once a molecule is excited into the S1 state it can potentially undergo a spin flip and

intersystem cross (ISC) to a triplet excited state (Tn) (Figure 2), vibrationaly relax to the

S0 state, or fluoresce to the S0 state by emitting a photon. If the electron undergoes ISC

to the T1, it can ISC back to a Sn state, transfer energy via molecular collisions, undergo

quenching, or it can emit a photon by phosphorescence in order to relax to the S0 state.1

These photoreactions are commonly explored for their ability to ISC to the triplet excited

state, and thus achieve products that would not be easily achieved by other means of

energy input.

Figure 2: Electron spin flip from a singlet to a triplet excited state.1, 4

Carbonyl Photochemistry

The carbonyl functional group is one of the most commonly studied functional groups in

photochemistry due to the electronic interaction between the carbon and oxygen.

3

Carbonyl compounds can potentially have the following energy orbital-configurations:

n,π* and π,π*.1

In carbonyl photochemistry, the HOMO can consist of the non-bonding

electrons (n) on the oxygen, and the LUMO can consist of the antibonding π orbital (π*)

from the carbon-oxygen π bond (eq.1).

R* (HOMO, LUMO) = R* (n,π*) eq.1

The π bonded electrons between the oxygen and carbon can also undergo excitation to the

LUMO which contains the π* orbital. The most commonly observed orbital-

configuration in alkyl aryl ketones is n,π* because it is most often the lowest energy

reactive state. The pure π,π* configuration is must less common in alkyl aryl ketones,

but can be observed as the reactive state if the carbonyl group is highly conjugated with

an extended π system.4 Mixing between n,π* and π,π* configurations can be observed

within an excited molecule depending on the size of the energy gap between the energy

states (Figure 3).1 According to Figure 3, acetone possesses a large energy gap between

T1 (n,π*) and T2 (π,π*); thus, mixing does not occur and the excited state is considered

purely n,π*. However, diaryl compounds, like benzophenone, have considerable orbit-

mixing between T1 (n,π*) and T2 (π,π*), which in turn leads to faster ISC.1 Therefore,

the smaller the energy gap between the n,π* and the π,π* configurations, the greater the

potential of spin-orbit mixing.

Another interesting feature of the carbonyl group in photochemistry is that the

reactive species can occur from the S1 or T1 excited state. The primary photophysical

reaction will occur in the lowest energy state, which is the S1 or T1 compared to S2 or T2,

according to Kasha‘s rule.5

When possible, ISC to the T1 state occurs rapidly because it is

4

always the lower energy excited state according to Hund‘s rule (Figure 3).5 Once the

compound has intersystem crossed to the T1 state, the excited electron has undergone a

spin flip and is thus unpaired with the other excited electron. This unpairing of the

electrons leads to a biradical-like character.

Figure 3: Energy gap differences in n,π* and π,π*: (a) dialkyl (acetone) no mixing,

(b) diaryl (benzophenone) spin-orbit mixing between n,π* and π,π*.1

5

If the compound contains biradical character it can potentially undergo the following

pathways: (i) spin flip back to the S1 state without reacting; (ii) react as an intermolecular

reaction; (iii) react as a Norrish type I reaction; or (iv) react as a Norrish type II reaction.

The outcome of excited T1 state is highly dependent on the compound and the

environment.1,6

Type II Photoelimination

The Norrish Type II (Type II) photoreaction is one of the most well understood

photochemical processes. An interesting feature of the Type II reaction is that it can

occur from either the singlet or triplet excited state for aliphatic ketones, but occurs

exclusively through the triplet excited state for alkyl aryl ketones.1,6

The focus of this

project will be photolysis of aryl ketones. In its most basic form, the Type II reaction

proceeds by an intramolecular γ-Hydrogen abstraction from the non-bonded electrons of

the carbonyl oxygen in the 3n, π* (triplet) state (Figure 4). A 1,4-biradical species is

formed as an intermediate and various products can be formed depending on the

molecular conformation and the solvent.1,4,6,7

A chair conformation is adopted by the 1,4-

biradical and can thus yield a syn or anti radical position (Figure 5). The anti-position

will yield the enol and the syn-position, the cyclobutanol.4

The biradical (BR)

intermediate is confirmed by the potential production of both alkene/ketone, and

cyclobutanol products.6

6

Figure 4: Basic Norrish Type II reaction Mechanism.4,8

Figure 5: 1,4-biradical potential conformations and products.4

7

The major limitation of the Type II reaction is the low quantum yield of the cyclobutanol

and enol products due to the conversion of the BR intermediate back to the starting

ketone, also known as disproportionation.6 The principle that the BR intermediate can

undergo conversion back to the starting ketone leaves the possibility for investigation of

the potential outcomes from enhancing the lifetime of the triplet 1,4-biradical (1,4-BR)

intermediate. Various factors have been proven to influence the lifetime of the triplet

1,4-BR intermediate, including: solvent effects, conformation of the BR (Figure 5), and

intramolecular hydrogen bonding to neighboring substituents.9

A good example of the solvent effect on the intermediate was reported by

Wagner in which a more polar solvent, tert-butanol, dramatically increases the quantum

yield of the eliminated product by 3-fold and the cyclobutanol product by 2-fold for the

photolysis of 4-methyl-1-phenyl-1-hexanone compared to benzene. Benzene gave a

quantum yield of 0.23, whereas tert-butanol produced a quantum yield of 0.94 for the

eliminated product.10

Intramolecular hydrogen bonding to the OH in the 1,4-BR can be

achieved by placing a group in the γ position that is capable of hydrogen bonding (Figure

6).9

Figure 6: Potential intramolecular hydrogen bonding in 1,4-biradical intermediate.

The effects of intramolecular hydrogen bonding have been recently reported to have

significant control over the Type II photolysis product distribution for both the syn and

8

anti conformation of the 1,4-BR. If the 1,4-BR is in the anti conformation with the OH

hydrogen bonded to a methoxy group, then >90% of the cyclization butanol product is

formed. In the syn conformation under the same hydrogen bonding conditions, >75% of

the enol is formed (Figure 7).9

Figure 7: Example of conformation effects and intramolecular hydrogen binding on

the Type II photochemical outcome.9

9

Sterics exhibit strong control in the anti conformation example presented in Figure 7 by

minimizing unwanted 1,3 ―flagpole‖ interactions in the chair conformation.9 This is

clearly illustrated by the fact that intermediate b undergoes twisting to c in order to

alleviate the steric strain and thus produce a greater amount of the cyclized product.

However, the syn conformation will maintain the more energetically favorable chair-like

conformation because it does not have the steric interactions seen in the anti

conformation. Ultimately, the Norrish Type II reaction is a very interesting photoreaction

because there are many variables that can be manipulated in order to produce a desired

outcome.

Photoinduced Diels-Alder Reaction

In 1950, the Nobel Prize in Chemistry was awarded to Otto Diels and Kurt Alder

for describing the formation of carbon-carbon sigma bonds from carbon-carbon π bonds

in order to create a six membered ring.4 Traditional Diels-Alder reactions are among the

most well-known and commonly used cycloaddition reactions due to their efficiency and

versatility in organic synthesis.10

The reaction is best described as a concerted

cycloaddition reaction between a diene and a dienophile (alkene/alkyne) to produce a

cyclohexene.4 Photoenolization Diels-Alder (PEDA) reactions have been utilized for

photochemical cycloadditions after first being reported by Yang.8 The report included

the photoenolization of O-methyl and benzyl benzophenone to produce a quantum yield

of > 0.5 of the Diels-Alder adduct.8,11

The PEDA reaction can occur by first making a

diene through the Norrish Type II photoreaction. Once the diene is produced it can react

10

with a dienophile.4,8,12

As illustrated in Figure 5, the excited state intermediate, A, can

ISC back to the S0 to produce an enol.4,7

The diene is then able to react with a dienophile

depending on the lifetime of the diene species (Figure 8).

Figure 8: General PEDA reaction between a diene and dienophile.

A significant application of the PEDA reaction has been recently employed in polymer

chemistry (Figure 9).12

It was demonstrated that polymerization can be achieved using a

photoinduced [4+2] cycloaddition with highly reactive dienophiles to yield an

irreversible, thermally stable, and functionalized product. The PEDA reaction is ideal

because it does not require a catalyst and can be performed under ambient temperatures.

In addition, the use of photoenols in polymer chemistry has proved to be highly

orthogonal to electrophiles, thus minimizing unwanted side reactions. Bioconjugation

can also be considered an ideal target for photoenolization because of its ability to react

orthogonally and thus not cause harm to the biological system. The most significant and

unique attribute of the PEDA reaction in polymer chemistry is the functionality of the end

group since it cannot be easily achieved by other reactions.12

11

Figure 9: PEDA reaction of the photoenol precursor.12

Click Chemistry

In the early 2000‘s, Sharpless, Kolb, and Finn generated the idea of ―click‖ chemistry and

the stringent criteria that governs what qualifies as a click reaction. To be considered a

click type reaction the reaction must: produce high yields, inoffensive byproducts, be

isolated by nonchromatographic methods, be modular and wide in scope, be

stereospecific, be made from readily available starting materials and benign solvents, and

be stable under physiological conditions.13,14

For a reaction to meet the click reaction

criteria, they usually have a strong thermodynamic driving force that is >20 kcal/mol, and

thus the reaction is more selective for a single product.14

Therefore, the 1,3-dipolar cycloaddition and the Diels-Alder reactions can be

considered click reactions because they meet many of the criteria and are under a strong

thermodynamic driving force.14

One of the original, and most well-known click reactions

was that of the copper(I) catalyzed Huisgen 1,3-dipolar cycloaddition reported by

Sharpless (Figure 10).15

Obviously, click chemistry is an ideal target for organic

synthetic chemists due to the high product yield and less hazardous reaction conditions.

In addition, the selectivity of the photoinduced Diels-Alder reaction can be considered a

click chemistry type reaction.12,13,15

Thus, the aspiration of achieving click chemistry

12

criteria is the goal of PEDA reactions explored in this thesis such that the reaction might

be used as a technique for small molecule biological labeling.

Figure 10: Suggested catalytic cycle for the copper(I) 1,3-dipolar cycloaddition.15

Protein Labeling

In the last decade, there has been a large effort to explore means of labeling small

biological molecules, including proteins. Labeling proteins serves to enhance selective

detection of proteins, as well as monitor their activity. With the emergence of click

chemistry came the hope for improved of protein labeling; however, there have been

limitations to using the traditional copper-catalyzed azide-alkyne coupling due to the

potential cytotoxicity from the metal.13,16

Thus, a significant push has been made to

establish metal-free reaction conditions that meet the click chemistry criteria and can also

be used in biological systems. A click reaction has been demonstrated using proteins

13

tagged with the appropriate alkene, which will undergo a photoactivated 1,3-dipolar

cycloaddition with an azide functional group when irradiated with 302 nm light (Figure

11).16

Figure 11: Photochemical 1,3-dipolar cycloaddition protein label.

Considering the success of the 1,3-dipolar cycloaddition reaction, the

photoinduced Diels-Alder cyclization should be considered as a potential click reaction

due to the fact that they are both similar cycloaddition reactions (Figure 12). Figure 12

demonstrates the potential to generate a diene by the PEDA reaction mechanism in order

to react with a dienophile that has already been attached to a protein. The diene is likely

to be produced due to enhanced electron density from the methoxy groups.8,17

Overall,

click chemistry is an ideal type of synthetic application available for chemists to exploit

in small biological labeling; thus, the PEDA reaction under study will be optimized for

click conditions with the hope to use the reaction in protein labeling experimentation.

14

Figure 12: Proposed PEDA reaction with a dienophile tagged protein.

Quinone derivatives in photochemistry

Within the quinone class of molecules, 9,10-anthraquinones (AQ) have been

studied in photochemical reactions due to their interesting electronic properties and their

ability to absorb light in the long-wavelength UV region.1,8,18

AQ are known to actively

undergo photoreduction by abstracting a hydrogen atom in the triplet excited state in non-

polar solvents to yield a semi-quinone radical (Figure 13).19

Figure 13: Proposed photoreduction mechanism of AQ with polyethylene.19

In addition to the ability of hydrogen abstraction via an intermolecular mechanism, AQ

can also undergo intramolecular 1-alkoxy γ-hydrogen abstraction in the triplet excited

15

state to give a 1,5-diradical.18

Unlike the 1-alkoxy-9,10-AQ molecule, the 1-methyl-9,10-

AQ derivative has not been reported to readily undergo the intramolecular γ-hydrogen

abstraction at room temperature.23

The lack of a photoenol to produce a biradical as

reported by Yang, may be due to deficiency in electron donating groups on the AQ

rings.8 Thus, a series of 1-methyl-9,10-AQ compounds that have been functionalized

with various electron donating groups will be explored for the potential to undergo the

PEDA reaction to generate a diene (Figure 14).

Figure 14: Potential 1-methyl-9,10-AQ methoxy functionalized derivatives.

Benzophenones have also been widely studied in photochemical reactions, especially for

their properties of the intramolecular γ-hydrogen abstraction that led Yang to the

discovery of the PEDA reaction.1,8

Quinones are an ideal candidate for investigating

potential PEDA generated dienes due to their long UV wavelength absorption.

Excitation using longer wavelength is critical for the photo-labeling of biological

molecules in order to prevent unwanted decomposition or fragmentation that might

otherwise occur if using shorter wavelength light.13,20

16

Summary

Functionalized anthraquinone compounds will be explored for the potential to

undergo PEDA reactions with the hope of, ultimately, using the photochemicially

generated dienes to label biological molecules. A long wavelength photoinduced diene is

of great interest because the diene could potentially be generated in vivo under minimally

invasive conditions. Thus, a Diels-Alder reaction could be used in vivo to label small

biological molecules under the control of light. In order to find a compound that could

theoretically undergo a PEDA reaction under long wavelength irradiation, AQs were

tested and functionalized to try and produce a PEDA product upon photolysis. The AQs

used in the photoreactions will be photolyzed with various controls and optimized to find

the best conditions for higher yields in order to try to achieve a ‗click‘ type reaction.

Both electron density and molecular geometry effects will be investigated in the PEDA

reaction in order to better control and predict photo reactions and products.

17

RESULTS AND DISCUSSION

Background

The scope of this project was to investigate the extent to which the PEDA reaction

is controlled by substituent effects, as well as the geometry of the intermediate BR

(Figure 7). More specifically, is the likelihood of occurrence of the PEDA reaction

enhanced by electron donating groups and by the assistance of hydrogen bonding to

allow the intermediate to stay in a more reactive geometry? While these principles have

been shown to enhance photoreactivity in some compounds, they have not been displayed

in an anthraquinone model at temperatures ≥ 25 °C.8,9,21,22,23

Since Yang‘s discovery of

the PEDA reaction, there have been few successful cases reported to produce the PEDA

product.8,21

Nicolaou demonstrated the importance of substituent effects for the PEDA

reaction in the total synthesis of Hamigerans (Table 1).21,22

Table 1: Substituent effects on the product yield in the PEDA reaction.21

18

The examples given in Table 1 clearly demonstrate that the greater the electron density

on the photoinduced diene, the higher the percent yield of the PEDA product.

Once a compound forms the BR intermediate, orientation of the newly formed

hydroxy group will dictate the products formed in the PEDA reaction (Chapter 1, Figure

7). Intramolecular hydrogen bonding of the hydroxy group to a group in the γ position

capable of hydrogen bonding may enhance the yield of the PEDA product by maintaining

the reactive geometry, and by reducing the amount of disproportionation.9 Thus, a series

of functionalized AQs have been synthesized and photolyzed under PEDA conditions to

examine if substituent effects and BR geometry govern the PEDA reaction outcome

(Table 2). Compounds 2, 4, 6, and 8 have been previously reported.24,33,34

Table 2: Synthesized AQs for photolysis in the PEDA reaction.

19

Based on the effects previously explained, it was hypothesized that the compounds with

the greatest electron density will yield the PEDA product as highlighted in Table 2

(compounds 6, 10, 19, and 20). It was also predicted that the compounds with a greater

ability to hydrogen bond the intermediate would have a higher yield of the PEDA

product, and fewer side reactions (compounds 10 and 19) (Figure 15).

Figure 15: Potential hydrogen bonding for intermediates 10 and 19.

Synthesis of Functionalized Anthraquinones

Before starting the synthesis of the methyl anthraquinone derivatives, the starting

materials were tested with known Friedel-Crafts reaction conditions. Thus, 3-methyl-

9,10-anthraquinone 2 was synthesized by combining a 1:2 molar ratio of phthalic

anhydride and aluminum chloride, respectively, in dry toluene.25,26

The reaction was

stirred and heated to 100°C for ~ 24 hours, quenched with 10% HCl, extracted with ethyl

acetate, and then concentrated to give 1. Lastly, compound 1 was added to concentrated

sulfuric acid in order to close the quinone. This mixture was stirred and heated to 100°C

for 4 hours and then poured over crushed ice. Compound 2 was extracted with ethyl

acetate and the structure was confirmed by 1H-NMR and

13C-NMR. It appeared that

compound 2 was successfully synthesized, thus the conditions should be suitable for the

other methyl anthraquinone syntheses (Figure 16). 33

20

Figure 16: Friedel-Crafts reaction condition control.

Compound 4 was synthesized by a Diels-Alder reaction by combining

naphthoquinone and piperylene with aluminum chloride in dichloromethane (DCM)

under reflux. The intermediate was treated with triethylamine and concentrated in vacuo

to yield 60% of a yellow solid, and the compound was verified by 1H-NMR and

13C-

NMR (Figure 17).24

Figure 17: Synthesis of compound 4.24

Compounds 6 and 8 were synthesized by a Friedel-Crafts reaction by combining

phthalic anhydride and 4-methylanisole in a 1:1 mole ratio in 1,2-dichloroethane (DCE)

under Ar.25,26

A 2:1 mole ratio of aluminum chloride was added slowly over 5 minutes to

the solution with stirring at 0°C. Then the solution was warmed to room temperature and

stirred for 3 days, then quenched with 10% HCl and extracted with ethyl acetate and

concentrated in vacuo. A small column was run with a gradient solution of hexane and

ethyl acetate in order to isolate the carboxylic acid intermediate. It was later found that

the purification of the intermediate carboxylic acid is not necessary and a lower yield

resulted from the column purification. Finally, the carboxylic acid was treated with

21

concentrated sulfuric acid to yield the final products. Both 6 and 8 were isolated from the

reaction by running through a silica column with a 2:1 mixture of hexane:ethyl acetate

and characterized by 1H-NMR and

13C-NMR (Figure 18).

34

Figure 18: Synthesis of compounds 6 and 8.

Compounds 10, 14, 15/16 were isolated from a single Friedel-Crafts reaction. A

1:1 mixture of 3-methyl phthalic anhydride and 1,4-dimethoxybenzene was added to

DCE (0.25 M) and 2 equivalents of aluminum chloride were added over 5 minutes. The

reaction was stirred at room temperature for 24 hours and then heated to reflux for an

additional 24 hours. An aqueous work-up was used and then the compound was stirred in

concentrated sulfuric acid and heated to 100°C for 4 hours. After quenching over

crushed ice, the final product was extracted with ethyl acetate and concentrated in vacuo.

A gradient silica column of hexane/ethyl acetate was used to isolate 10 and 14 (Figure

19). Compounds 15/16 were isolated as a mixture of isomers that both contained a

hydroxy or a methoxy group in either the 1 or 4 positions in the AQ.

22

Figure 19: Synthesis of compound 10, 14, 15/16.

Compounds 19, 20, and 23/24 were synthesized using the same Friedel-Crafts

conditions as compounds 10, 14, and 15/16. The hydroxy analog, 23/24, was isolated in

higher yields (64.3%) if heated to temperatures around 110°C when stirred with

concentrated sulfuric acid. High concentration of acid and higher temperatures resulted

in a greater amount of hydrolysis of the methoxy group to a hydroxy group. The

conversion of the isomeric mixture of compounds 23/34 to 19/20 was achieved by

stirring the AQ in 0.1 M DMF and adding 5 equivalents of TBAF and 15 equivalents of

iodomethane under Ar for 1 hour. The solution turned from dark purple to yellow after

the addition of TBAF. The reaction was quenched with 1% HCl, and extracted with ethyl

23

acetate. However, the final products for isomers 19 and 20 were extremely difficult to

separate and characterize due to similar polarity. A preparative TLC plate was used to

separate compounds 19 and 20 with a solvent mixture of 3:1 hexane/ethyl acetate (Figure

20).

Figure 20: Synthesis of isomers 19, 20, 23/24.

24

Compounds 19 and 20 formed in about an 15:85 isomer ratio according to 1H-NMR.

However, the identification of which isomer was the major product entailed additional

investigation. The compounds were analyzed by high-resolution MS to ensure that they

had the same molecular weight (MW). Isomer ‗A‘ had a m/z of 267.1012 with a

retention time of 6.98 minutes. Isomer ‗B‘ had a m/z of 267.1010 with a retention time

of 6.93 minutes. MS-MS was performed on both isomers in order to probe for potential

differences in fragmentation patterns. Isomer ‗A‘ had major fragmentation to yield ions

of 252.0745 m/z and 237.0695 m/z, indicating a loss of one methyl group, and a loss of

two methyl groups, respectively. However, isomer ‗B‘ only had one major fragmented

ion at 237.1011 m/z, which could have indicated the loss of two methyl groups, or an –

OCH2 group. X-ray crystallography was achieved on a crystal that was grown of the

major isomer intermediate, 31, in the Friedel-Crafts reaction between 3-methyl phthalic

anhydride and 4-methylanisole (Figure 21). According to the X-ray crystallography data

collected, compound 20 would likely be the major product (Figure 22).

Figure 21: Crystal structure of the intermediate, 31, for the major product from the

Friedel-Crafts reaction between 4-methylanisole and 3-methyl phthalic anhydride.

31

25

Figure 22: Predicted major Friedel-Crafts product: 20.

Theoretically, compound 17 should form the more stable isomer due to electron density

donation of the methyl group ortho to the carbonyl in isomer ‗B‘ (Figure 23). Although

isomer ‗B‘ is the more stable isomer, compound 18 is confirmed to be the major

intermediate based on x-ray crystallography data (Figures 21, and 22). This outcome

could be due to a faster reaction rate of the more reactive (less stable) isomer ‗A‘ to form

the intermediate 18.

Figure 23: Isomer formation prediction.

26

According to the Curtin-Hammett principle, reactive intermediates can interconvert in a

non-proportional equilibrium, but the final product distribution is dependent on the free

energy of the transition state for each conformer. Thus, the product distribution is not

dependent on the conformer equilibrium.4 Therefore, even though the equilibrium does

not lie towards isomer ‗A‘, compound 18 is the most abundant product due to the rate of

k2>>k1.

Photoreactions

General photolysis procedure

Photoreactions were set up as 0.5 M or 0.1 M solutions of AQ in benzene, and

stirred under Ar with 2 equivalents of dimethyl acetylenedicarboxylate (DMAD). Each

reaction was degassed with Ar in the dark for ~ 1 hour, and then the reaction vessel was

placed in a light box containing a 366 nm filter. After 24 hours, the reaction was checked

by TLC and 1H-NMR.

Control photolysis reaction

All photoreactions were run with a control that is known to yield the PEDA

product in order to ensure the functionality of the setup and light box (Figure 24). The

control reaction was set up by combining o-tolualdehyde and dimethyl

acetylenedicarboxylate in dry benzene to make a 0.5 M solution.21

27

Figure 24: Control PEDA reaction.21

The control photo reaction produced the PEDA product 26, but in low yields. This may

have been due to the dilute concentration of the control mixture, or perhaps the

electrophile was not as reactive as the electrophiles used in the studies reported by

Nicolaou.21

The 1H-NMR clearly shows the PEDA adduct through the disappearance of

the starting material methyl group singlet at δ 2.67 ppm, and the appearance of two

singlets of the two methoxy groups at δ 3.96 and 3.92 ppm (Figure 25).

Figure 25: 1H-NMR of control PEDA product superimposed with the tolualdehyde

starting material.

28

The singlet around δ11.92 ppm in the product seems to be shifted downfield due to

hydrogen bonding of the OH hydrogen with the carbonyl in the γ position.

Photolysis of functionalized anthraquinones

As previously described, AQs with varying functional groups were synthesized to

test the hypothesis of the substituent functionalization effects on the PEDA reaction. In

order to test the substituent effect on the PEDA reaction, 1-methyl-9,10-anthraquinone 4,

previously synthesized by Dr. Elkazaz, was photolyzed as a baseline control reaction.24

Compound 4 was photolyzed at a 0.5 M concentration and yielded 100% starting material

after stirring in the light box for 24 hours (Figure 26).

Figure 26: Photolysis of compound 4.

After characterization of compounds 6 and 8, both were photolyzed at 0.5 M

concentration (Figure 27). Photolysis of compound 8 yielded 100% starting material,

thus the PEDA product was not obtained. Compound 6 yielded several products detected

by gradient TLC; however, the products were not easily separated or isolated. Both a

gradient silica column of hexane/ethyl acetate and a preparative TLC did not produce

pure fractions that would indicate the PEDA product by 1H-NMR. There seemed to be

some decomposition in the photoreaction even after reacting in a more dilute 0.1 M

solution. Further investigation of reaction time might help to eliminate the amount of

product decomposition.

29

Figure 27: Photolysis of compounds 6 and 8

Compounds 10, 14, and 15/16 were photolyzed in 0.1 M solution due to the low

solubility of the compounds in benzene. Interestingly, of the compounds photolyzed,

only compound 10 produced a PEDA adduct. Compounds 14 and 15/16 produced 100%

starting material after irradiation (Figure 28).

Figure 28: Photolysis of compounds 10, 14, and 15/16.

30

Compound 29 was isolated by running a preparative TLC using a 1:4 hexane/ethyl

acetate solvent mixture and then characterized by 1H-NMR,

13C-NMR, high-resolution

MS, and MS-MS. The 1H-NMR of the product 29 showed the disappearance of the

methyl group in compound 10 and the addition of DMAD, which suggest that the

reaction underwent a PEDA type mechanism upon photolysis (Figure 29, 30).

Figure 29: Proposed PEDA mechanism to produce compound 29.

31

Figure 30: 1H-NMR of compound 29.

Compound 10 was excited to the S1 excited state and then intersystem crossed to the T1

excited state. It was in the triplet state that the γ hydrogen abstraction occurred to be able

to produce 1,4-BR 27. Once the diene was generated it could then react with the DMAD

in a Diels-Alder reaction to produce 29.

According to the hypothesis, the proposed mechanism would be enhanced by the

ortho methoxy substituent because of its ability to hydrogen bond the biradical

intermediate. The hydrogen bonding of intermediate 27 helps to prevent the generally

rapid conversion back to starting material. In addition, the geometry of hydrogen bonded

hydrogen is kept out of the physical space where the Diels-Alder reaction can occur with

the photo-induced diene (Figure 31).

32

Figure 31: Hydrogen bonding of intermediate 27.

While the di-methoxy analog undergoes the PEDA reaction, the hydroxy analog

does not. This is due to the fact that the hydroxy hydrogen can be abstracted by the same

mechanism described in Figure 32; however, the structure of the newly generated

carbonyl group will ultimately equilibrate back to starting material (Figure 32). Thus,

the hydroxy analog is unable to undergo the PEDA type reaction.

Figure 32: Predicted photo reaction of 14.

Like compounds 10-14, compounds 20, and 23/24 were photolyzed in a 0.1 M benzene

solution due to low solubility. Isomer 19 was not irradiated because only a very small

amount of it was isolated (~5 mg). As hypothesized, compounds 23/24 did not undergo a

photoreaction, but compound 20 yielded the PEDA product in 7% yield (Figure 33). In

order for 20 to produce the PEDA product 30, it must have gone through the same

mechanism illustrated in Figure 32. The PEDA product 30 was characterized by 1H-

NMR (Figure 34).

33

Figure 33: Photolysis of compounds 20, and 23/24.

Figure 34: 1H-NMR of compound 30.

34

CONCLUSION

The trends of the photoreactions seem to support the hypothesis that both

electronic effects and geometry play an important role in controlling the outcome of the

products. A general summary of the photoreactions and products are illustrated in Table

3. The data show that AQs with greater electron density and functionalized with

methoxy groups undergo the PEDA reaction. However, the AQ that was functionalized

with only one methyl group and one methoxy group, compound 6, did not undergo the

PEDA reaction. These results indicate that the PEDA reaction is likely to occur if the

AQ is functionalized with electron donating groups in the 1 and 4 positions (Figure 35).

Figure 35: Labeled positions on 9,10-anthraqinone.

In addition to electronic effects on the product formation, the stability of the

intermediate 1,4 BR through intramolecular hydrogen bonding also enhanced the yield of

the PEDA reaction. This is shown in the percent yield difference between the photo

products 29 and 30. Compound 29 is formed in a higher percent yield compared to

compound 30 potentially due to its ability to intramolecular hydrogen bond the

intermediate 27 (Figure 31). The intramolecular hydrogen bonding seems to have some

control over the lifetime of the 1,4 BR; thus, the longer the lifetime of the 1,4 BR, the

more likely it is to undergo the Diels-Alder reaction. However, both yields are low, so

further investigation is needed to conclusively identify the effects of intramolecular

hydrogen bonding. Overall, the outcome of the somewhat uncommon PEDA reaction has

35

been shown to be controlled by various factors using functionalized anthraquinones as a

model compound.

Table 3: Summary of photoreactions. All reactions were conducted using the

general photolysis setup.

36

EXPERIMENTAL

General

All reagents were purchased from commercially available sources. All

synthesized compounds were characterized by 1H and

13C-NMR on a Bruker Advance

300 or 500 MHz spectrometer. Thin layer chromatography was performed using 200 µm

fluorescein-doped silica gel on plastic-backed plates. The chromatography plates were

visualized using hand-held UV lamps with 254 nm or 365 nm wavelength light.

Photoreactions were carried out using the following photoreactors: 450 W medium

pressure Hg vapor lamp containing a UO2 doped glass 366 nm wavelength filter, a

Rayonet photoreactor containing eight lamps with a peak emission of 419 nm

wavelength, and a Rayonet photoreactor containing sixteen Hg vapor lamps with a peak

emission of 350 nm wavelength. High-resolution mass spectrometry (MS) and MS-MS

studies were performed on the Thermo Scientific LTQ Orbitrap XL, hybrid ion trap mass

spectrometer. The column used for the liquid chromatography (LC) was a Waters

Acquity Pro-shell UPLC 1.7 µm 2.1 x 50 mm C18 column. A specimen of C17H16O4,

approximate dimensions 0.110 mm x 0.130 mm x 0.240 mm, was used for the X-ray

crystallographic analysis. The X-ray intensity data were measured on a Bruker APEX

CCD system equipped with a graphite monochromator and a Mo Kα sealed x-ray tube (λ

= 0.71073 Å). The frames were integrated with the Bruker APEX2 software package

using a narrow-frame algorithm.29-32

37

LC Parameters

Solvents: A = water 0.1% formic acid. B = acetonitrile 0.1% formic acid

Gradient:

Time

(minutes) %A %B

0 95 5

1 95 5

7 5 95

7.1 95 5

10 95 5

Flow rate = 250 µL/min. Injection volume = 15 µL for full scan MS, and 20 µL for data

dependent MS-MS.

MS parameters

Source: Positive APCI

Vaporizer temp = 450 °C

Sheath gas flow = 70 au

Aux gas flow = 15 au

Capillary V = 42 v

Capillary temp = 225 °C

Tube lens V = 105 v

Resolution = 60,000 Hz. CID energy = 35%. Mass Range = 150-500 m/z

38

SYNTHESIS

Substituted phthalic anhydrides

Phthalic anhydride. 1.00 g (6.01 mmol) phthalic acid and 2.83 mL (30.0 mmol) acetic

anhydride were added to 12 mL (0.5 M) dry DCM. The reaction mixture was stirred

under Ar and heated to reflux for 24 hours. After a steady reflux the solution turned from

a cloudy grey to clear solution. After cooling, 20 mL of dry toluene was stirred into the

solution for 30 minutes. The mixture was then concentrated in vacuo yielding 0.850 g

(95.3%). No further purification was needed. 1H-NMR (300 MHz, (CD3)2SO) δ 8.05

(A2B2, 4H, J=12.61, 6.64, 3.91, 1.4 Hz) ppm.28

3-methyl phthalic anhydride. 1.00 g (5.55 mmol) 3-methyl phthalic acid and 2.62 mL

(27.75 mmol) acetic anhydride were added to 11.08 mL (0.5 M) dry DCM. Reflux

reaction under agron for 24 hours. The reaction went from cloudy to clear upon heating

to reflux. After cooling, 20 mL of dry toluene was stirred into the solution for 30

minutes. The mixture was then concentrated in vacuo yielding 0.820 g (91.1%). No

further purification was needed. 1H-NMR (300 MHz, (CD3)2SO) δ 7.84 (m, 3H), 2.64 (s,

3H) ppm.28

39

Substituted anthraquinones

1-methyl-9,10-anthraquinone (4). This compound was prepared by the method of

Elkazaz. 1H-NMR (300 MHz, CDCl3) δ 8.27 (m, 3H), 7.78 (m, 2H), 7.63 (m, 2H), 2.87

(s, 3H) ppm.24

2-methyl-9,10-anthraquinone (2). 30 mL of dry toluene (excess) was added to 0.430 g

(2.90 mmol) phthalic anhydride. The reaction was cooled in an ice bath and stirred under

Ar. 0.775 g (5.58 mmol) of aluminum chloride was added to the stirring reaction over

the course of 5 minutes. The reaction was then stirred at room temperature for 24 hours

and then worked up with 10% hydrochloric acid. The aqueous layer was extracted 3x

with 30 mL ethyl acetate and concentrated in vacuo. 30 mL of concentrated sulfuric acid

was stirred into the crude product and heated to 100°C for 4 hours. The reaction was then

subsequently quenched over 100 mL crushed ice and extracted 3x with 30 mL ethyl

acetate and was concentrated in vacuo. The final product was 0.505 g (78.4%) of a light

yellow solid. No further purification was needed. 1H-NMR (300 MHz, CDCl3) δ 8.31

(AA‘, 2H, J=6.0, 3.0 Hz), 8.22 (d, 1H, 7.9 Hz), 8.12 (s, 1H), 7.93 (BB‘, 2H, J=9.0, 6.0

Hz), 7.60 (d, 1H, J=7.71 Hz), 2.54 (s, 3H) ppm.33

40

1-methoxy-4-methyl-9,10-anthraquinone (6). 1-hydroxy-4-methyl-9,10-

anthraquinone (8). 0.200 g purified phthalic anhydride (1.35 mmol) and 0.170 mL 4-

methylanisole (1.35 mmol) were added to 1.35 mL (1 M) 1,2-DCE under Ar.34

Then the

reaction was cooled to 0°C and 0.359 g (2.7 mmol) aluminum chloride was added in 3

equal portions over 5 minutes. The reaction was subsequently warmed to room

temperature and stirred for 3 days. The reaction was quenched with 20 mL of 10% HCl

and was extracted 2x 20 mL with ethyl acetate, and then concentrated in vacuo. A 50:50

hexane:ethyl acetate mixture was used to run a silica gel column in order to isolate the

intermediate carboxylic acid (29.4%). 10 mL of concentrated sulfuric acid was added to

the carboxylic acid intermediate and heated to 100°C for 4 hours. The reaction was

quenched by pouring over 50 mL of crushed ice and extracting 2x with 30 mL ethyl

acetate. A 50:50 hexane:ethyl acetate mixture was used to run a silica gel column in

order to isolate the final products. Compound 6 Rf = 0.78, and the final product mass

was 0.040 g (40%). 1H-NMR (300 MHz, CDCl3) δ 8.16 (AA‘, 2H, J= 6.40, 3.9 Hz), 7.71

(BB‘, 2H, J=7.35, 2.21 Hz), 7.49 (d, 1H, J=8.7 Hz), 7.23 (d, 1H, J=8.7 Hz), 4.02 (s, 3H),

41

2.74 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ 184.74, 182.52, 157.89, 138.12,

133.51, 132.72, 132.60, 132.49, 132.10, 131.98, 125.50, 125.32, 121.78, 116.66, 55.52,

22.17 ppm.34

Compound 8 Rf = 0.96, and the final product mass was 0.015 g (15%). The

methoxy group decomposed to a hydroxy group 33% of the time after reacting with

concentrated sulfuric acid. 1H-NMR (300 MHz, CDCl3) δ 13.10 (s, 1H), 8.21 (AA‘, 2H,

J=6.81, 1.64 Hz), 7.72 (BB‘, J=7.31, 1.85Hz), 7.42 (d, 1H, J=8.7 Hz), 7.15 (d, 1H, J=8.7

Hz), 2.68 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ 188.12, 183.27, 160.97, 140.59,

133.62, 133.59, 133.36, 132.54, 131.56, 126.30, 125.41, 123.14, 115.56, 28.69 ppm.34

4,8-dimethyl-1-methoxy-9,10-anthraquinone (19). 1,8-dimethyl-4-methoxy-9,10-

anthraquinone (20). 1-methyl-4-hydroxy-8-methyl-9,10-anthraquinone plus isomer

(23, 24). 0.550 g (3.39 mmol) of purified 3-methyl phthalic anhydride, and 0.427 mL

42

(3.39 mmol) of 4-methylanisole was added to 13.56 mL (0.25 M) of 1,2-DCE under Ar.

The reaction was cooled to 0°C and 0.903 g (6.78 mmol) of aluminum chloride was

added in 3 equal portions over 5 minutes. The reaction was subsequently warmed to

room temperature and stirred for 5 hours, and then heated to reflux for an additional 24

hours. The reaction was quenched with 30 mL of 10% HCl and was extracted 2x with 40

mL ethyl acetate, and then concentrated in vacuo. 0.695 g (72.1%) crude product was

added to 30 mL concentrated sulfuric acid and heated to 100°C for 4 hours. The reaction

was then quenched by pouring over 100 mL of crushed ice and extracting 3x with 30 mL

ethyl acetate. A 50:50 hexane:ethyl acetate mixture was used to run a silica gel column

in order to separate and isolate 0.295 g (46.3%) of a yellow oil. The major products were

the hydroxy isomers (23, 24), thus methylation was achieved by adding 5 equivalents of

TBAF, and 15 equivalents of iodomethane to the isomer in 0.10 M solution of DMF and

stirred at room temperature for 1 hour. The product was then washed with 1% HCl and

extracted with ethyl acetate and concentrated in vacuo to yield 100% conversion of the

isomer mix. The Rf for compound 20 at a 50:50 hexane:ethyl acetate mixture was 0.75.

The two methoxy isomers were further separated by preparative TLC using a 3:1

hexane:ethyl acetate solvent mixture to give a 60% yield of a cream colored solid. 1H-

NMR (300 MHz, CDCl3) δ 8.05 (d, 1H, J=7.4 Hz), 7.55 (t,1H, J=7.6 Hz), 7.48 (d, 2H,

J=8.1 Hz) 7.17 (d, 1H, J=8.7 Hz), 4.01 (s, 3H), 2.75 (s, 3H), 2.68 (s, 3H) ppm. 13

C-NMR

(300 MHz, CDCl3) δ 188.65, 184.40, 157.98, 139.55, 138.76, 136.57, 136.09, 135.31,

132.51, 132.39, 132.00, 124.96, 122.22, 116.50, 56.47, 22.26, 22.11 ppm. High-

resolution MS (LTQ Orbitrap XL): retention time = 6.95 minutes, m/z = 267.1012. The

Rf for compound 19 was slightly larger than the Rf for compound 20. Compound 19 was

43

isolated in about a 5% yield. 1H-NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J=8.50 Hz) 7.50

(t, 2H, J=7.70 Hz), 7.43 (d, 1H, J=8.99 Hz), 7.19 (d, 1H, J=8.00 Hz), 4.00 (s, 3H), 2.78

(s, 3H), 2.71 (s, 3H) ppm. High-resolution MS (LTQ Orbitrap XL): Retention time =

6.94 minutes, m/z = 267.1014. The TLC results of compounds 23 and 24 were two spots

that could not be resolved and the mean Rf = 0.91. A 64.3 % yield of the final isomer

mixture was isolated and characterized. A 1:0.16 mixture of the constitutional isomers are

reported respectively: 1H-NMR (300 MHz, CDCl3) δ 12.89 (s, 1H), 8.11 (m, 1H), 7.51

(m, 2H), 7.37 (m, 1H), 7.06 (m, 1H), 2.73 (s, 3H), 2.62 (s, 3H) ppm. 1H-NMR (300

MHz, CDCl3) δ 13.20 (s, 1H), 8.11 (m, 1H), 7.51 (m, 2H), 7.37 (m, 1H), 7.06 (m, 1H),

2.78 (s, 3H), 2.64 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ 188.28, 186.03, 160.20,

140.43, 140.31, 137.56, 132.87, 131.97, 131.90, 131.45, 131.02, 124.14, 121.93, 115.16,

28.68, (isomer mix) 22.01, 21.58 ppm. Unable to collect high-resolution MS using either

positive or negative mode APCI.

44

1,4-dimethoxy-8-methyl-9,10-anthraquinone (10). 1,4-dihydroxy-8-methyl-9,10-

anthraquinone (14). 1-methoxy-4-hydroxy-8-methyl-9,10-anthraquinone plus

isomer (15, 16). 0.150 g (0.925 mmol) of purified 3-methyl phthalic anhydride, and

0.139 g (0.925 mmol) of 1,4-dimethoxybenzene was added to 3.70 mL (0.25 M) of DCE

under Ar. The reaction was cooled to 0°C and 0.269 g (1.85 mmol) of aluminum

chloride was added in 3 equal portions over 5 minutes. The reaction was subsequently

warmed to room temperature and stirred for 24 hours, and then heated to reflux for an

additional 24 hours. The reaction was quenched with 20 mL of 10% HCl and was

extracted 2x with 20 mL of ethyl acetate, then concentrated in vacuo. 0.137 g (49.5%)

crude product was added to 10 mL concentrated sulfuric acid and heated to 100°C for 4

hours. The reaction was then quenched by pouring over 50 mL of crushed ice and

45

extracting 2x with 30 mL ethyl acetate. A 50:50 hexane:ethyl acetate mixture was used

to run a silica gel column in order to separate and isolate compounds 10, 14, and 15,16.

Compound 10 was produced in a 17.9 % yield and had an Rf = 0.42. 1H-NMR (300

MHz, CDCl3) δ 8.01 (d, 1H, J=7.4 Hz), 7.50 (m, 2H), 7.27 (m, 2H), 3.98 (s, 3H), 3.97 (s,

3H), 2.75 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ 185.91, 184.16, 153.31, 153.08,

139.59, 136.71, 135.80, 132.91, 132.18, 125.35, 124.90, 122.71, 120.06, 118.74, 57.09,

56.90, 22.05 ppm. High-resolution MS (LTQ Orbitrap XL): Retention time = 5.90

minutes. m/z = 283.0963. Compound 14 was produced in a 17.4 % yield and had an Rf =

0.96. 1H-NMR (300 MHz, CDCl3) δ 13.06 (s, 1H), 12.82 (s, 1H), 8.24 (d, 1H, 7.1 Hz),

7.59 (m, 2H), 7.23 (m, 2H), 2.83 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ 188.53,

186.16, 156.42, 156.20, 141.80, 137.82, 133.89, 132.55, 130.00, 128.51, 127.31, 124.85,

112.62, 111.61, 28.69 ppm. Unable to collect high-resolution MS using either positive or

negative mode APCI. Compounds 15 and 16 were produced in a 26.8 % yield with an Rf

= 0.76. 1H-NMR (300 MHz, CDCl3) δ 13.07 (s, 1H), 12.77 (s, 1H), 8.20 (d, 1H, J=7.9

Hz), 7.59 (m, 2H), 7.32 (m, 2H), 4.01 (s, 3H), 2.86 (s, 3H) ppm. 13

C-NMR (300 MHz,

CDCl3) δ 206.86, 191.22, 156.98, 156.68, 153.65, 141.77, 138.82, 137.39, 136.66,

133.84, 132.29, 126.27, 126.17, 125.17, 125.02, 122.75, 57.19, 57.02, 30.92, 23.72 ppm.

High-resolution MS (LTQ Orbitrap XL): Retention time = 7.00 minutes. m/z =

269.0806.

46

PHOTOREACTIONS

Photoreaction Products

Compound 26. Photolysis of tolualdehyde with DMAD using the general photo set up at

0.1M generates 11% yield of compound 26 after running crude product through a

preparative TLC plate using a 3:1 mixture of hexane/ethyl acetate. 1H-NMR (300 MHz,

CDCl3) δ 11.92 (s, 1H), 8.42 (d, 1H, J= 7.475 Hz), 8.26, 7.63 (m, 3H), 7.79 (d, 1H, J=

7.868 Hz), 7.45 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H) ppm. 13

C-NMR (300 MHz, CDCl3) δ

170.35, 169.70, 160.94, 135.17, 130.26, 130.06, 128.05, 127.37, 125.42, 124.09, 119.70,

52.83, 52.61 ppm. High-resolution MS (LTQ Orbitrap XL): Retention time = 6.77

minutes. m/z = 229.0494, 197.0232.

Compound 29. Photolysis of compound 10 using the general photoreaction set up at

0.1M yields 13% of compound 29 after running crude product through a preparative TLC

47

plate using a 1:3 mixture of hexane/ethyl acetate. 1H-NMR (300 MHz, CDCl3) δ 8.49

(dd, 1H, J= 6.39, 1.00 Hz), 8.16 (s, 1H), 8.11 (d, 1H, J= 8.28 Hz), 7.77 (t, 1H, J= 7.627

Hz), 7.123, 7.168 (ABq, 2H, JAB= 9.140 Hz), 4.02 (s, 3H), 3.94 (s, 3H), 3.81 (s, 3H), 3.71

(s, 3H) ppm. High-resolution MS (LTQ Orbitrap XL): Retention time = 5.96 minutes,

m/z = 407.1124.

Compound 30. Photolysis of compound 20 using the general photoreaction set up at

0.1M yields 7.2% of compound 30 after running crude product through a preparative

TLC plate using a 1:2 mixture of hexane/ethyl acetate. Due to low sample concentration

(2 mg), the 13

C-NMR of 16,000 scans on compound 30 did not yield a spectrum that

could be interpreted. 1H-NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.17 (m, 1H), 7.66 (m,

1H), 7.49 (s, 1H), 7.25 (m, 1H), 7.07 (s, 1H), 4.11 (s, 3H), 3.91 (s, 3H), 3.74 (s, 3H), 2.85

(s, 3H) ppm. High-resolution MS (LTQ Orbitrap XL): Retention time = 6.76 minutes,

m/z = 391.2836.

48

APPENDIX A

X-ray Crystallography Parameters

The integration of the data using an orthorhombic unit cell yielded a total

of 39978 reflections to a maximum θ angle of 30.27° (0.71 Å resolution), of

which 4224 were independent (average redundancy 9.464, completeness = 99.7%,

Rint = 4.14%) and 3273 (77.49%) were greater than 2σ(F2). The final cell constants

of a = 21.501(3) Å, b = 8.3947(13)Å, c = 15.697(2) Å, volume = 2833.2(8) Å3, are based

upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were

corrected for scaling and absorption effects using the multi-scan method (SADABS). The

calculated minimum and maximum transmission coefficients (based on crystal size)

are 0.9780 and 0.9900.

The structure was solved and refined using the Bruker SHELXL software package, using

the space group P b c n, with Z = 8 for the formula unit, C17H16O4. The final anisotropic

full-matrix least-squares refinement on F2 with 197 variables converged at R1 = 4.73%,

for the observed data and wR2 = 13.91% for all data. The goodness-of-fit was 1.024. The

31

49

largest peak in the final difference electron density synthesis was 0.407 e-/Å

3 and the

largest hole was-0.208 e-/Å

3 with an RMS deviation of 0.052 e

-/Å

3. On the basis of the

final model, the calculated density was 1.333 g/cm3 and F(000), 1200 e

-.

Crystal data

C17H16O4 F(000) = 1200

Mr = 284.30 Dx = 1.333 Mg m-3

Orthorhombic, Pbcn Mo K radiation, = 0.71073 Å

Hall symbol: -P 2n 2ab Cell parameters from 8501 reflections

a = 21.501 (3) Å = 3.7–28.7°

b = 8.3947 (13) Å = 0.10 mm-1

c = 15.697 (2) Å T = 193 K

V = 2833.2 (8) Å3 Irregular chunk, colourless

Z = 8 0.24 × 0.13 × 0.11 mm

Data collection

Bruker APEX CCD

diffractometer

4224 independent reflections

Radiation source: fine-focus sealed tube 3273 reflections with I > 2(I)

Graphite Rint = 0.041

and scans max = 30.3°, min = 3.7°

Absorption correction: multi-scan

Data were corrected for scaling and/or

absorption effects using the multi-scan

technique (SADABS 2012/1). The ratio of

minimum to maximum apparent transmission

was 0.941. The calculated minimum and

maximum transmission coefficients (based on

crystal size) are 0.978 and 0.990.

h = -3030

Tmin = 0.702, Tmax = 0.746 k = -1111

39978 measured reflections l = -2222

Refinement

Refinement on F2 Primary atom site location: structure-invariant

direct methods

Least-squares matrix: full Secondary atom site location: difference Fourier

50

map

R[F2 > 2(F

2)] = 0.047 Hydrogen site location: mixed

wR(F2) = 0.139 H atoms treated by a mixture of independent

and constrained refinement

S = 1.02 w = 1/[2(Fo

2) + (0.0767P)

2 + 0.6188P]

where P = (Fo2 + 2Fc

2)/3

4224 reflections (/)max = 0.001

197 parameters max = 0.41 e Å-3

0 restraints min = -0.21 e Å-3

Special details

Geometry. All esd‘s (except the esd in the dihedral angle between two l.s. planes)

are estimated using the full covariance matrix. The cell esd‘s are taken into account

individually in the estimation of esd‘s in distances, angles and torsion angles;

correlations between esd‘s in cell parameters are only used when they are defined by

crystal symmetry. An approximate (isotropic) treatment of cell esd‘s is used for

estimating esd‘s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement

parameters (Å2)

x y z Uiso*/Ueq

O1 0.69935 (4) 0.30929 (12) -0.19574 (6) 0.0390 (2)

O2 0.52845 (4) 0.19131 (11) -0.08917 (6) 0.0345 (2)

H2O 0.4954 (9) 0.233 (2) -0.1078 (11) 0.055 (5)*

O3 0.57713 (4) 0.22363 (10) -0.21987 (5) 0.0309 (2)

O4 0.57350 (4) 0.35587 (12) -0.34354 (6) 0.0370 (2)

C1 0.69740 (5) 0.21422 (14) -0.12529 (8) 0.0318 (3)

C2 0.74999 (6) 0.14715 (16) -0.08805 (9) 0.0388 (3)

H2 0.7900 0.1686 -0.1110 0.047*

C3 0.74395 (6) 0.04914 (16) -0.01766 (9) 0.0405 (3)

H3 0.7801 0.0026 0.0066 0.049*

C4 0.68645 (6) 0.01703 (15) 0.01841 (8) 0.0362 (3)

C5 0.63415 (6) 0.08819 (14) -0.01836 (8) 0.0313 (2)

H5 0.5945 0.0699 0.0065 0.038*

C6 0.63829 (5) 0.18489 (13) -0.09008 (7) 0.0279 (2)

51

C7 0.57980 (5) 0.43999 (14) -0.12598 (7) 0.0258 (2)

C8 0.57784 (5) 0.54141 (15) -0.05683 (8) 0.0310 (2)

H8 0.5771 0.5023 0.0000 0.037*

C9 0.57695 (6) 0.70405 (16) -0.07451 (9) 0.0357 (3)

H9 0.5748 0.7777 -0.0287 0.043*

C10 0.57913 (6) 0.76126 (15) -0.15769 (9) 0.0358 (3)

H10 0.5793 0.8731 -0.1669 0.043*

C11 0.58104 (5) 0.65996 (15) -0.22797 (8) 0.0312 (3)

C12 0.58063 (5) 0.49727 (14) -0.20890 (7) 0.0264 (2)

C13 0.57776 (5) 0.35889 (15) -0.26625 (7) 0.0285 (2)

C14 0.58005 (5) 0.25957 (14) -0.12724 (7) 0.0270 (2)

C15 0.75775 (7) 0.3302 (2) -0.23649 (10) 0.0464 (3)

H15A 0.7859 0.3882 -0.1984 0.070*

H15B 0.7520 0.3911 -0.2892 0.070*

H15C 0.7756 0.2258 -0.2500 0.070*

C16 0.68008 (8) -0.09546 (18) 0.09253 (10) 0.0473 (4)

H16A 0.6623 -0.1964 0.0728 0.071*

H16B 0.6526 -0.0483 0.1355 0.071*

H16C 0.7211 -0.1150 0.1176 0.071*

C17 0.58370 (7) 0.72246 (19) -0.31758 (9) 0.0439 (3)

H17A 0.5776 0.8382 -0.3171 0.066*

H17B 0.5509 0.6725 -0.3516 0.066*

H17C 0.6243 0.6975 -0.3425 0.066*

Atomic displacement parameters (Å2)

U11

U22

U33

U12

U13

U23

O1 0.0282 (4) 0.0453 (5) 0.0434 (5) -0.0002 (4) 0.0064 (4) 0.0080 (4)

O2 0.0260 (4) 0.0377 (5) 0.0399 (5) -0.0032 (3) 0.0022 (3) 0.0088 (4)

O3 0.0324 (4) 0.0306 (4) 0.0298 (4) -0.0025 (3) -0.0017 (3) -0.0047 (3)

O4 0.0343 (5) 0.0512 (6) 0.0257 (4) -0.0024 (4) -0.0002 (3) -0.0039 (4)

C1 0.0289 (6) 0.0299 (6) 0.0366 (6) 0.0004 (4) 0.0006 (5) -0.0034 (5)

C2 0.0286 (6) 0.0375 (7) 0.0502 (8) 0.0024 (5) -0.0027 (5) -0.0050 (5)

C3 0.0376 (7) 0.0348 (7) 0.0492 (8) 0.0066 (5) -0.0132 (6) -0.0046 (6)

C4 0.0454 (7) 0.0264 (6) 0.0369 (6) 0.0012 (5) -0.0104 (5) -0.0034 (5)

C5 0.0357 (6) 0.0259 (5) 0.0323 (6) -0.0021 (4) -0.0018 (4) -0.0019 (4)

C6 0.0275 (5) 0.0249 (5) 0.0313 (5) -0.0001 (4) -0.0014 (4) -0.0028 (4)

52

C7 0.0231 (5) 0.0268 (5) 0.0274 (5) -0.0001 (4) 0.0008 (4) -0.0006 (4)

C8 0.0297 (5) 0.0352 (6) 0.0281 (5) -0.0010 (4) 0.0010 (4) -0.0041 (5)

C9 0.0332 (6) 0.0336 (6) 0.0402 (7) -0.0009 (5) 0.0016 (5) -0.0099 (5)

C10 0.0320 (6) 0.0268 (6) 0.0486 (8) -0.0022 (4) -0.0006 (5) 0.0006 (5)

C11 0.0242 (5) 0.0327 (6) 0.0367 (6) -0.0024 (4) -0.0009 (4) 0.0063 (5)

C12 0.0218 (5) 0.0303 (5) 0.0270 (5) -0.0012 (4) 0.0007 (4) -0.0001 (4)

C13 0.0210 (5) 0.0365 (6) 0.0279 (5) -0.0020 (4) 0.0007 (4) -0.0018 (4)

C14 0.0267 (5) 0.0276 (5) 0.0266 (5) -0.0025 (4) 0.0009 (4) -0.0003 (4)

C15 0.0349 (7) 0.0529 (8) 0.0514 (8) -0.0074 (6) 0.0128 (6) -0.0015 (7)

C16 0.0636 (9) 0.0364 (7) 0.0420 (7) 0.0002 (6) -0.0159 (7) 0.0049 (6)

C17 0.0419 (7) 0.0486 (8) 0.0413 (7) -0.0056 (6) -0.0015 (6) 0.0172 (6)

Geometric parameters (Å, º)

O1—C1 1.3643 (16) C7—C14 1.5147 (16)

O1—C15 1.4201 (16) C8—C9 1.3933 (19)

O2—C14 1.3844 (14) C8—H8 0.9500

O2—H2O 0.844 (19) C9—C10 1.392 (2)

O3—C13 1.3489 (15) C9—H9 0.9500

O3—C14 1.4863 (14) C10—C11 1.3935 (19)

O4—C13 1.2168 (15) C10—H10 0.9500

C1—C2 1.3918 (18) C11—C12 1.3981 (17)

C1—C6 1.4076 (17) C11—C17 1.5022 (18)

C2—C3 1.384 (2) C12—C13 1.4710 (16)

C2—H2 0.9500 C15—H15A 0.9800

C3—C4 1.386 (2) C15—H15B 0.9800

C3—H3 0.9500 C15—H15C 0.9800

C4—C5 1.3980 (17) C16—H16A 0.9800

C4—C16 1.5047 (19) C16—H16B 0.9800

C5—C6 1.3908 (16) C16—H16C 0.9800

C5—H5 0.9500 C17—H17A 0.9800

C6—C14 1.5170 (16) C17—H17B 0.9800

C7—C8 1.3801 (16) C17—H17C 0.9800

C7—C12 1.3878 (15)

C1—O1—C15 117.68 (11) C10—C11—C12 115.24 (11)

C14—O2—H2O 110.7 (12) C10—C11—C17 121.95 (12)

53

C13—O3—C14 110.90 (9) C12—C11—C17 122.81 (12)

O1—C1—C2 123.51 (11) C7—C12—C11 122.64 (11)

O1—C1—C6 116.64 (10) C7—C12—C13 107.44 (10)

C2—C1—C6 119.86 (12) C11—C12—C13 129.84 (11)

C3—C2—C1 119.98 (12) O4—C13—O3 121.32 (12)

C3—C2—H2 120.0 O4—C13—C12 129.03 (12)

C1—C2—H2 120.0 O3—C13—C12 109.57 (10)

C2—C3—C4 121.70 (12) O2—C14—O3 107.72 (9)

C2—C3—H3 119.1 O2—C14—C7 113.92 (9)

C4—C3—H3 119.1 O3—C14—C7 102.45 (9)

C3—C4—C5 117.75 (12) O2—C14—C6 108.94 (10)

C3—C4—C16 121.27 (12) O3—C14—C6 109.09 (9)

C5—C4—C16 120.94 (13) C7—C14—C6 114.28 (9)

C6—C5—C4 122.15 (12) O1—C15—H15A 109.5

C6—C5—H5 118.9 O1—C15—H15B 109.5

C4—C5—H5 118.9 H15A—C15—H15B 109.5

C5—C6—C1 118.54 (11) O1—C15—H15C 109.5

C5—C6—C14 119.97 (10) H15A—C15—H15C 109.5

C1—C6—C14 121.47 (10) H15B—C15—H15C 109.5

C8—C7—C12 121.62 (11) C4—C16—H16A 109.5

C8—C7—C14 128.85 (11) C4—C16—H16B 109.5

C12—C7—C14 109.52 (10) H16A—C16—H16B 109.5

C7—C8—C9 116.63 (11) C4—C16—H16C 109.5

C7—C8—H8 121.7 H16A—C16—H16C 109.5

C9—C8—H8 121.7 H16B—C16—H16C 109.5

C10—C9—C8 121.63 (12) C11—C17—H17A 109.5

C10—C9—H9 119.2 C11—C17—H17B 109.5

C8—C9—H9 119.2 H17A—C17—H17B 109.5

C9—C10—C11 122.21 (12) C11—C17—H17C 109.5

C9—C10—H10 118.9 H17A—C17—H17C 109.5

C11—C10—H10 118.9 H17B—C17—H17C 109.5

C15—O1—C1—C2 4.97 (19) C10—C11—C12—C7 -1.41 (16)

C15—O1—C1—C6 -175.01 (12) C17—C11—C12—C7 178.28 (11)

O1—C1—C2—C3 -178.61 (12) C10—C11—C12—

C13

175.12 (11)

C6—C1—C2—C3 1.37 (19) C17—C11—C12—

C13

-5.19 (18)

54

C1—C2—C3—C4 -1.1 (2) C14—O3—C13—O4 -177.42 (10)

C2—C3—C4—C5 -0.45 (19) C14—O3—C13—C12 -0.46 (11)

C2—C3—C4—C16 177.24 (12) C7—C12—C13—O4 174.88 (11)

C3—C4—C5—C6 1.70 (18) C11—C12—C13—O4 -2.06 (19)

C16—C4—C5—C6 -176.00 (11) C7—C12—C13—O3 -1.77 (12)

C4—C5—C6—C1 -1.40 (17) C11—C12—C13—O3 -178.72 (11)

C4—C5—C6—C14 -179.81 (11) C13—O3—C14—O2 122.70 (10)

O1—C1—C6—C5 179.81 (10) C13—O3—C14—C7 2.28 (11)

C2—C1—C6—C5 -0.17 (18) C13—O3—C14—C6 -119.19 (10)

O1—C1—C6—C14 -1.80 (17) C8—C7—C14—O2 59.36 (15)

C2—C1—C6—C14 178.22 (11) C12—C7—C14—O2 -119.40 (10)

C12—C7—C8—C9 -0.21 (16) C8—C7—C14—O3 175.39 (11)

C14—C7—C8—C9 -178.84 (11) C12—C7—C14—O3 -3.37 (11)

C7—C8—C9—C10 -1.20 (18) C8—C7—C14—C6 -66.77 (15)

C8—C9—C10—C11 1.34 (19) C12—C7—C14—C6 114.47 (11)

C9—C10—C11—C12 -0.01 (17) C5—C6—C14—O2 -10.95 (15)

C9—C10—C11—C17 -179.70 (12) C1—C6—C14—O2 170.68 (10)

C8—C7—C12—C11 1.57 (16) C5—C6—C14—O3 -128.29 (11)

C14—C7—C12—C11 -179.56 (10) C1—C6—C14—O3 53.34 (14)

C8—C7—C12—C13 -175.64 (10) C5—C6—C14—C7 117.73 (11)

C14—C7—C12—C13 3.23 (12) C1—C6—C14—C7 -60.63 (14)

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A

O2—H2O···O4i 0.844 (19) 1.96 (2) 2.7981 (13) 171.6 (18)

Symmetry code: (i) -x+1, y, -z-1/2.

55

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58

SCHOLASTIC VITA

Education:

2013 M.S. Candidate in Chemistry, Wake Forest University

2007 B.S. Biological Sciences, University of Maryland, Baltimore County

Experience:

2011-2013 Teaching Assistant, Wake Forest University

2008-2010 Research Technologist, Johns Hopkins University

School of Medicine

2006-2007 Undergraduate Researcher

University of Maryland, Baltimore County

Honors and Awards:

2013 NIEHS Training Grant

Ruth L. Kirschstein National Research Service Award Institutional

Training Grant – North Carolina State University

2010 Dean‘s Fellowship, Wake Forest University

Professional Memberships:

2013 American Chemical Society

59

Publications:

Weiss, Arking , Gina Hilton, et. al. on behalf of the Gene Discovery Project of

Johns Hopkins and the Autism Consortium. ‗A genome-wide linkage and

association scan reveals novel loci for autism‘. Nature. Vol 461, October 2009,

pp. 802-808.

Arking DE*, Reinier K*, Post W, Jui J, Gina Hilton, Ashley O‘Connor, Prineas

RJ, Boerwinkle E, Psaty BM, Tomaselli G, Rea T, Sotoodehnia N, Siscovick

DS, Burke GL, Marban E, Spooner PM, Chakravarti A, Chugh SS. ‗Genome-

Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective

against Sudden Cardiac Arrest‘. PLoS One. March 2010

Fox ER, Young JH, Gina Hilton, et. al. on behalf of the International Consortium

for Blood Pressure Genome-wide Association Studies (ICBP-GWAS);

CARDIoGRAM consortium; CKDGen consortium; KidneyGen consortium;

EchoGen consortium; CHARGE-HF consortium, Chakravarti A, Zhu X, Levy D.

‗Association of genetic variation with systolic and diastolic blood pressure among

African Americans: the Candidate Gene Association Resource study‘. Human

Molecular Genetics, June 2011, pp. 2273-2284.

Dan E. Arking, Gina Hilton, et. al. ‗Identification of a Sudden Cardiac Death

SusceptibilityLocus at 2q24.2 through Genome-Wide Association in European

Ancestry Individuals‘. PLoS Genetics, June 2011

Dan E. Arking, Gina Hilton, et. al. ‗Genetic Variants in Novel Pathways

Influence BloodPressure and Cardiovascular Disease Risk‘. Nature, October

2011, pp. 103-109.

Gupta, Halushka, Gina Hilton, Arking. ‗Postmortem cardiac tissue maintains

gene expression profileeven after late harvesting‘. BCM Genomics, 2012, 13:26.

http://www.biomedcentral.com/1471-2164/13/26.

Course Work

Inorganic Chemistry (CHM 661)

Advanced Organic Chemistry (CHM 721)

Chemical Separations (CHM 736)

60

Structure Identification in Organic Chemistry (CHM 725)

Reactive Intermediates (CHM 726)

Organic Synthesis (CHM 724)

Physical Organic Chemistry (CHM 722)

Transition-Metal Organic Chemistry (CHM 723)