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PORPHYRIN AGGREGATES AS REPORTERS OF
CHIRALITY USING EXCITON COUPLED CIRCULAR
DICHROISM

presented by

MERCY ANYIKA

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5/08 ICIPrcj/AooatPres/CIRCIDateDuojndd

 

PORPHYRIN AGGREGATES AS REPORTERS OF CHIRALITY USING EXCITON
COUPLED CIRCULAR DICHROISM

By

Mercy Anyika

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTERS OF SCIENCE
Chemistry

2009

Copyright by
MERCY AN YIKA
2009

ABSTRACT

PORPHYRIN AGGREGATES AS REPORTERS OF CHIRALITY, USING EXCITON
COUPLED CIRCULAR DICHROISM.
By

Mercy Anyika

Many important molecules required for life exist in two forms. These two forms
are non-superimposable mirror images of each other, i.e. they are related like our left and
right hands, a property called chirality. Despite the abundance of chiral molecules, there
is still much to be learned about about chirality. We are interested in using Exciton
Coupled Circular Dichroism to probe chirality in organic molecules.

Chiral compounds with only one site of attachment usually require derivatization
with carrier molecules before using ECCD method. The research presented herein is
focused on the absolute stereochemical determination of such compounds but without
requiring derivatization. To develop this method, we will design porphyrin systems
capable of undergoing self assembly into stable aggregates via non-covalent interactions.

Upon addition of the chiral molecule of interest, the molecule binds to the zinc
incorporated within the porphyrin core, upon which there is a transfer of chirality from
the molecule to the porphyrin aggregate. This induced chirality is then observed as an
ECCD curve.

A number of porphyrins have been designed, synthesized and employed as

reporters of chirality.

Dedicated to my mother, for her love and support.

iv

ACKNOWLEDGEMENTS

I would like to first express my gratitude to my research advisor, Professor Babak
Borhan. I have sincerely appreciated his encouragement and strong support for my
graduate career. I am grateful for the excellent education I received, and continue to
receive under his guidance.

I also appreciate the Borhan research group members from whom I learned a lot.
I want to give special thanks to Dr. Chrysoula Vasileiou, Dr. Marina Tanasova, Xiaoyong
Li and Dan Whitehead for their help and patience in reading and correcting my thesis,
and all their great suggestions.

I would like to thank the people who worked with me on the ECCD project:
Marina, Xiaoyong and Carmin. Through our discussions, I was able to learn a lot and
also obtain a greater understanding of my research, especially during my first years. I
also wish to thank everyone that I had the opportunity of working with in the Borhan lab.
Calvin, Camille and Wenjing deserve special thanks for making sure I retained some
sense of sanity during the writing of my thesis.

I wish to thank Dr. Rui-Huang for his assistance in running solid probe Mass
Spectroscopy.

Finally, I would like to thank my family for their love and support.

TABLE OF CONTENTS

List of Tables .............................................................................. vii
List of Figures ............................................................................. viii
List of Schemes ............................................................................ xi
Key to Symbols and Abbreviations ..................................................... xii

Chapter 1. Introduction

1-1 The Exciton Coupled Circular Dichroic Method (ECCD) ........... 1
1-1 .1 Introduction to chirality .......................................... l
1-1.2 Optical Rotatory Dispersion and Circular Dichroism ....... 7
1-1 .3 A brief introduction to Circular Dichrometers .............. 13
1-2 Exciton Coupled Circular Dichroism (ECCD) ....................... 15
1-2.1 Theoretical background of ECCD ............................. 15

1-2.2 The Quantum Mechanics explanation of ECCD............20
l-2.3 The application of the ECCD method to determine the

absolute stereochemistry of chiral molecules ............... 24
1-2.4 Use of chromophoric hosts such as porphyrins for ECCD
studies ............................................................ 27
1-25 Use of zinc porphyrin as chromophoric host ................ 31
References .......................................................................... 38

Chapter 2. Porphyrin aggregates as hosts for chiral discrimination

2-1 Introduction to porphyrin aggregation ................................. 47
2-2 Design of porphyrins for aggregation .................................. 51
2-3 Results and discussion” .6..2
References ............................................................................ 91
General Procedures ................................................................. 96
Synthesis of Compounds ........................................................... 97

vi

List of Tables

Table 1-1 Definition of Exciton Chirality for a Binary System ............... 21

Table 2-1 ECCD study of chiral monoamines with porphyrin 7 ............... 77

vii

Figure 1-1
Figure 1-2
Figure 1-3
Figure 1-4
Figure 1-5
Figure 1-6
Figure 1-7
Figure 1-8
Figure 1-9

Figure 1-10

Figure 1.11

Figure 1-12

Figure 1.13

Figure 1-14

Figure 1-15
Figure 1-16

Figure 1-17
Figure 1-18

Figure 1-19

List of Figures

Examples of chiral molecules ............................................ 1
Examples of some chiral molecules and their mirror images ........ 2
Enantiomeric forms of 3-mercaptohexanal and carvone ............. 4
Structures of (R)- and (S)-Thalidomide ................................. 5
Light as an electromagnetic radiation ................................... 7
Linearly and circularly polarized light .................................. 8
Circularly polarized light passing through a chiral medium ......... 9
Positive and negative Cotton effects ................................... 11
Electron redistribution upon light excitation for transitions ........ l l

The right hand rule to determine the direction of magnetic dipole
Transition moment ....................................................... 12

Schematic representation of a CD spectropolarimeter ............... 13

Exciton Coupled Circular Dichroism (ECCD) of steroidal
2,3-bisbenzoate ........................................................... 15

Splitting of the excited states of isolated chromophores by
exciton interaction ........................................................ 16

The UV and ECCD spectra upon through space interaction of

two degenerate chromophores .......................................... 17
A qualitative explanation of ECCD .................................... 18
The expected ECCD spectrum of dibenzoate, and its

rationalization ............................................................ l9
Dibenzoate chirality method — Distance effect ....................... 23
ECCD active abscisc acid ..... 7 .......................................... 25

Application of the ECCD method in absolute configurational

viii

Figure 1-20
Figure 1-21

Figure 1-22

Figure 1-23

Figure 1-24

Figure 2-1

Figure 2-2

Figure 2-3

Figure 2-4

Figure 2-5
Figure 2-6
Figure 2-7
Figure 2-8
Figure 2-9

Figure 2-10
Figure 2-11
Figure 2-12
Figure 2-13

Figure 2-14

assignment of natural products ........................................ 26
The induced chirality of biphenol upon binding to chiral amine...28
Determination of stereochemistry of chiral alcohols by ECCD...29

Derivatization methods for analysis of absolute configurations
with various chromophores ............................................. 30

Structure and schematic representation of a porphyrin tweezer. . .33

Assignment of absolute configuration of acyclic chiral
diamines using ECCD ................................................... 34

Application of carrier molecules for stereochemical
determination of molecules with one site of attachment ............ 4 7

Derivatization method for analysis of absolute configurations

of amino acids ............................................................ 48
Tripodal ligand incorporating TPP as chromophores ............... 49
Porphyrin tweezer system for stereochemical determination

of chiral monoamines .................................................... 50
Structures of some cyanine dyes ....................................... 52
Proposed arrangemnts for J-aggregates of cyanine dye 1 ........... 53
One dimensional aggregate structures ................................. 54
Porphyrin with four urea groups at its periphery ..................... 53

Induction of helicity in poly-l-HCI upon complexation with
(S)-BINOL and retention of memory after inversion of helicity....57

Porphyrins with chiral prolininium functionalities ................... 58
Aggregation of porphyrins triggered by n-stacking .................. 62
Aggregation of Zn TPP-tail porphyrin in hexane. . . . ...63
Addition of (S)-l ,2—diaminopropane to aggregate .................... 64
Induction of helicity into porphyrin aggregate ....................... 65

ix

Figure 2-15

Figure 2-16

Figure 2-17

Figure 2-18
Figure 2-19
Figure 2-20
Figure 2-21
Figure 2-22

Figure 2-23

Figure 2-24

Figure 2-25

Figure 2-26

Figure 2-27
Figure 2-28
Figure 2-29
Figure 2-30

ECCD spectum of Zn TPP-tail with chiral diamines ................ 65

Complexation of porphyrin monomer with L-lysine-methyl
ester ........................................................................ 66

Complexation of Zn TPP-tail aggregates with L—lysine-methyl

ester; and a pictorial representation of the complex formed ........ 68
Zn-2H-bis-tail porphyrin ................................................ 69
UVN is spectrum of porphyrin 7 in dichloromethane ............... 72
UV/V is spectrum of porphyrin 7 in hexane ........................... 73
UVN is titratibn spectrum of 7 with cyclohexyldiamine ............ 74

ECCD spectrum of Zn TPP-bistail with cyclohexyldiamine ....... 74

UVN is titration spectrum of porphyrin 7 with
(S)-cyclohexylpropane- l-amine in dichloromethane ................ 75

UVN is titration spectrum of porphyrin 7 with
(S)-methylbenzylamine in dichloromethane .......................... 76

ECCD spectrum of 7 with (S)-l-amino—2-ethylnaphthalene ....... 78

Possible different conformations upon binding of amines

to the porphyrin aggregate ............................................... 79
Induction of chiral twist by R enantiomer ............................. 79
Zn TPP-bistail porphyrin ................................................ 8O
UVN is titration spectrum of porphyrin l3 ............................ 84
Proposed porphyrin for improving aggregation studies ............. 90

Images in this thesis are presented in color.

Scheme 2-1

Scheme 2-2

Scheme 2-3

Scheme 2-4

Scheme 2-5

Scheme 2-6

Scheme 2-7

Scheme 2-8

Scheme 2-9

Scheme 2-10

Scheme 2-11

Scheme 2-12

Scheme 2-13

List of Schemes

Synthesis of porphyrin 3 via 2+2 condensation ...................... 69
Synthesis of dipyrromethane ester 5 ................................... 7O
Vilesemeier-Hack formylation of 5 and 6 ............................ 71
2+2 condensation of S and 6 to give bis—tail porphyrin 7 ........... 71
Retro-synthesis of monoacyl dipyrromethanes ....................... 81
Synthesis of monoacyl dipyrromethane l0 ........................... 82
Synthesis of bis-methyl ester porphyrin ll ........................... 82
Synthesis of bis-tail porphyrin 13 ...................................... 83
Formation of chiral salt upon addition of

(S)-l-amino-2-ethylnaphthalene to porphyrin l4 .................... 85
Synthesis of mono-tail porphyrin 14 ................................... 86
Proposed structure of chiral amide porphyrin ........................ 87
Synthesis of porphyrin 16 ............................................... 88

EDCI coupling of (S)-l-amino-2-methylnaphthalene with
porphyrin l4 .............................................................. 89

xi

[(1]

Ar
BF3°Et20
BINOL
Bn

BnBr
CD

CE
p-chloranil
cm

(I

DCM
DDQ
DMAP
DMF

DNA
Et3N

EtOH

Key to Symbols and Abbreviations

angle of rotation

specific rotation

angstrom

CD amplitude

aromatic

boron trifluoride diethyl ether
1 ,l ’-Bi-2—naphthol

Benzyl

benzylbromide

circular dichroism

cotton effect

tetrachloro—l ,4-benzoquinine
centimeter

doublet

dichloromethane
2,3-dichloro-5 ,6-dicyano-l ,4—benzoquinone
4-diaminopyridine
NN-dimethylformamide

deoxyribonucleic acid
triethylamine

ethanol

xii

ECCD
EDCI
EtMgBr
EtOAc

equiv

HPLC

HRMS

IR

KI
K2C03
LDA

LAH

MeOH
min
mg

MHz

molar absorption coefficient

Exciton Coupled Circular Dichroism
N-(3-DimethylaminopropyI)-N’-ethyl-carbodiimide
ethyl magnesium bromide

ethyl acetate

equivalents

gram

high pressure liquid chromatography
high resolution mass spectrometry
hour

infrared

NMR coupling constant

potassium iodide

potassium carbonate

lithium diisopropylamine

lithim aluminum hydride

magnetic dipole transition moment
multiplet

methanol

minute

milligram

megahertz

molar

xiii

11M

MS

NaBH4

NaOH
NaH
nm
NMR

ORD

POCI3

PCC

Ph

”PTNI'IZ

Rt

TFA
THF

TBP—tz

molar
micromolar
mass spectrometry

refractive index

sodium borohydride

sodium hydroxide

sodium hydride

nanometer

nuclear magnetic resonance

optical rotatory dispersion

phosphorous chloride oxide

pydidinium chlorochromate

phenyl
propyl amine

quartet

singlet

rotational strength
room temperature
triplet
trifluoroacetic acid
tetrahydrofuran

5-(4-carboxyphenyl)— 10,15 ,20-tri-3 ,S-di-t-butylphenylporphyrin tweezer

xiv

TPP-t2 5-(4—carboxyphenyl)- 10,15 ,20-triphenylporphyrin tweezer

UV-vis ultraviolet-visible spectroscopy

Zn-TPP zinc tetraphenylporphyrin

ZnTPP—tz zinc 5-(4-carboxyphenyl)- 10,15 ,20-tri-3 ,S-di—t- butylphenylporphyrin

IWCCZCI'

Zn(OAc)2 zinc acetate

XV

Chapter 1

Introduction.

1-1. The Exciton Coupled Circular Dichroic Method
l-l.l Introduction to Chirality

Ever since Van’t Hoff and LeBel suggested in 1874 that individual molecules
possess a three-dimensional structure that may gives rise to dissymmetry,12 the exact

orientation of the atoms in space, i.e. the absolute configuration, has been an intriguing

problem to be solved.

Chirality refers to non-superimposable mirror images and comes from the Greek
word cheir, meaning “hand”.3 Examples of chiral molecules can range from the simplest,
a single atom with four different substituents, such as 2-methylbutyric acid, to large

natural products with multiple chiral centers, such as Taxol®.

MeH

151/<

002H

 

A

Figure 1-1. Example of chiral molecules, (S)-2-methylbutyric acid (A)
and Taxol® (B)

The letters R (from Latin “rectus”) and S (from Latin “sinister”) are used to

indicate the configuration (arrangement of groups) on the chiral center, based on
priorities set in place by Cahn, lngold and Prelog.4 However, molecules do not have to
have a chiral center to be chiral; non—superimposability on the mirror image is the only

necessary requirement for chirality. Any molecule that lacks an element of symmetry is

considered chiral. Some examples of chiral molecules lacking a chiral center are shown

in Figure 1-2.
A B
Meg H H .‘Me Me : Me
Et/<002H i HOZCXEt Mfi'?=C=(H = H>=C=¥xe
2-methylbutyric acid allene
C

i H

H020 0 N02 . ozu

 

Figure 1-2. Examples of some chiral molecules and their mirror images

Figure l-2A shows a classic example of chirality, 2-methylbutyric acid, which
contains a chiral carbon center. Figure [-28 shows an allene5 where the overall molecule
is not planar, but rather the two it bonds are perpendicular to each other causing the

molecule to lack any plane of symmetry when both sides are unsymmetrically

substituted. Figure l-2C shows a biphenyl molecule, bearing large groups on each side
of the CC single bond. This molecule is chiral because of restricted rotation around the
single bond hence, it is “locked” into a chiral conformation since steric hindrance
between the ortho-substituents prevents bond rotation. This restriction of rotation is the
source of geometric isomerism (atropisomerism). Restricted rotation can also be found in
spiranes, which are compounds that have two rings with a common carbon atom, as

shown in Figure 1-2D. Because of this, the rings are perpendicular to each other giving

rise to axial chirality.6 Figure l-2E shows a classic example of an inherently chiral

chromophore,7 hexahelicene. Despite the fact that this molecule does not have any

asymmetric carbons, it is not planar, but rather lacks a plane of symmetry as it traces a
helix when one side of the molecule lies above the other due to crowding of the rings.

The defined helix can be either right-handed, (+)-hexahelicene, or left—handed, (~)-

hexahelicene and, therefore, non-superimposable on its mirror image .8

Chirality affects all of life, from the very simplest amino acids to pharmaceuticals
used to treat diseases. Living organisms use exclusively one chiral molecular form
(homochirality): virtually all active forms of amino acids are of the L-form (D-serine
being a notable exception) while most biologically relevant sugars are of the D-form.
Enzymes, which are chiral, often distinguish between two enantiomers of a chiral
substrate, and only one enantiomer can fit inside an enzyme’s binding cavity, while the

other cannot. Despite its ubiquity, the origin of chirality on earth is still not completely

understood?’18 Nonetheless, whatever its origin, chirality has been, and still remains one

of the most fundamental aspects of life on earth. The stereochemistry of molecules

affects their chemical and biological properties.

For example, while the (S) enantiomer of Carvone has the odor of caraway seeds,
its (R) enantiomer has the odor of Spearmint; also, (S)-mercaptohexanal has a pleasant,

fruity odour, while its
SH 0 SH 0

NH /\/'\/U\H (R) enantiomer has the

(38)-3-mercaptohexanal (3 R)-3-mercaptohexanal
pungent sulfur smell.

0 O Chiral organic molecules
are currently of
(R) carvone (S) carvone widespread interest to
organic and

Figure 1-3. Enantiomeric forms of 3-mercaptohexanal
and carvone . .
pharmaceutical chem1sts,

and currently, chirality plays a major role in the development of new pharmaceuticals.
This is because the two enantiomers of many natural products used as drugs have
different actions in the body, hence the resolution and clinical testing of both enantiomers
is prerequisite to the development of the optimum drug. Drugs generally work by
interacting with receptors on cell surfaces, or enzymes within cells. Receptors have a
specific three-dimensional structure, which will allow only the isomer that fits precisely

to bind preferentially while the other has little or no activity.

Most of the pharmaceuticals sold commercially are chiral compounds. Drugs
obtained from natural sources, or those prepared from natural materials are produced as
pure enantiomers, because chiral compounds from nature usually occur as the pure form

of one of the enantomers. However, until recently (19705) most chiral drugs produced

synthetically from achiral starting materials were produced and sold in their racemic
forms, even though their therapeutic effect was mainly due to only one isomer. In most
cases, the unwanted isomer was physiologically inactive, and did not cause any serious
side effects. However, that was not always the case. One tragic example of historical
note is thalidomide. Thalidomide was developed and sold from 1957 — 1961 in almost 50
countries. It was mainly prescribed to pregnant women as an antiemetic to treat morning

sickness and as a sleep aid.

0 O
NH NH
O O O O
(S)-Thalidomide (Fa-Thalidomide

Figure 1-4. Structures of (R)- and (S)—Thalidomide

As shown in Figure 1-4, thalidomide contains a stereocenter and so exists in its
two enantiomeric forms.4 Tragically, while the (S)-isomer had the desired anti-nausea

effects, the (R)—form was teratogenic and caused fetal abnormalities, such as severely

deformed limbs.

Most new drugs today and those under development consist of a single optically
active isomer. Chirality is not only becoming an important issue in the pharmaceutical
industry, but also in the agrochemical and other industries as well.‘9 As a result of this,
there is an increasing interest in determining molecular chirality,l and the need for simple

and effective ways for the determination of absolute configuration is more prominent

than ever. The stereochemical assignment of chiral compounds is a challenging task.

There are several methods that are used to establish the absolute stereochemistry

of chiral molecules, including chemical correlation with known chiral. compounds,3 the

NMR Mosher ester method13 as well as X—ray crystallography. The Mosher ester method

and its modified versions have been the most widely applied approach for configurational

assignments of chiral compounds. This method involves derivatization of the compound

of interest into two diastereomers containing an aryl ring. The 1H NMR spectra of the

two diastereomeric derivatives are compared, and the shielding effect values (A6“) for
the protons neighboring the chiral center are measured. The scope of the Mosher ester
method has been extended further,3 but generally, milligram quantities of the substrate

. are needed, and derivatization of the substrate is necessary, hence limiting the use of this

method.

X—ray crystallography is the most unambiguous method for absolute
stereochemical determination. Although X-ray crystallography provides full
stereochemical analysis of chiral compounds in a single experiment, there are some
shortcomings associated with the method. The most common are the difficulty in
crystallizing many molecules, the need for multi milligram amounts of compound, and
also the fact that suitable single crystals can be hard to obtain. These problems limit the
application of X-ray crystallography for absolute stereochemical determination. That is
why development of a general and more accessible protocol that allows for easy
stereochemical determination is key. In the past few years chiroptical methods based on

optical rotatory dispersion (ORD) and circular dichroism (CD) spectroscopy have been

developed. Their advantage is that they are easy to use and are very sensitive, generally

requiring only 11M concentrations of the compound of interest.

The goal of our research is to expand the use of CD-based spectroscopic
techniques by designing general and sensitive circular dichroic (CD) methods for the

absolute stereochemical determination of chirality.

1-l.2 Optical Rotatory Dispersion (ORD) and Circular Dichroism (CD)
spectrosopy

Optical Rotatory Dispersion and Circular Dichroism are both methods that make

use of the different chiroptical properties of enantiomers. In these methods, light is used

to distinguish between enantiomers. Light is a transverse wave, consisting of both an

electric and a magnetic field, which oscillate perpendicular to one another and to the

direction of propagation of light forming a right handed coordinate system.18 The

polarization of light is defined by the direction of its electric field vector.18

 

Direction of
Propagation

Figure 1-5. Light as an electromagnetic radiation

Light from ordinary light sources, such as the sun or a light bulb, is unpolarized,
since it consists of light waves propagating in all directions. On the other hand, when
unpolarized light passes through a polarizing filter, only the light waves with oscillation
parallel to the direction of the filter pass through. The light passing through the filter is
now aligned in one plane of oscillation, and is defined as linearly polarized light.

Linearly polarized light only oscillates in one specific direction, where the electric field
(E) remains constant in magnitude, but traces out a helix as a function of time,20 and can

be resolved into two circularly polarized light beams: a left circular component (L) and a

right circular component (R) as shown in Figure 1-6.

E

Polarizing

filter

 

Linearly Left and right circularly

light polarized polarized light

Figure 1-6. Linearly and circularly polarized light

When circularly polarized light passes through an achiral or racemic compound,

the velocity and absorbance of the left and right circularly polarized light is equally

affected.

 

r

x T Light propagation

 

Left and right circularly
polarized light Chiral sample Right circularly polarized light

Figure 1-7. Circularly polarized light passing through a chiral medium, which absorbs the left
circularly polarized component more than the right.

On the other hand, if it passes through an optically active medium, (Figure l-7)

the velocity and absorbance of either one of the circularly polarized components is
altered to a greater extent as compared to the other component.21 This is referred to as
the Cotton effect (CE, in honor of French physicist Aimé Cotton, who observed both
ORD and CD phenomena).

ORD results from the difference in velocity of the left and right components of
circularly polarized light. This difference correlates to the differences in “the respective

refractive indices, as can be shown in equation 1-1.18
An=nL-nR;-e0 (1-1)

Where nL and nR are the refractive indices for left and right circularly polarized light

respectively. Because the left and right circularly polarized light travels through the
optically active medium at different velocities, the two components are no longer in
phase, and the resultant vector has been rotated by an angle or relative to the original

plane of polarization. ORD spectroscopy is the measurement of specific rotation [a], as a

function of wavelength, and can be calculated from the observed angle of rotation, or, as

expressed by equation 1-2.18
[or] = (l/Cl (1'2)

Where a is the angle of rotation (degree units), c is the concentration of the sample (g
mL'l), and l is the path length (decimeters). Because ORD is only based on the

difference in the refractive indices, and all chiral molecules exhibit a molecular refraction
at almost any wavelength of irradiation, theoretically, ORD can be detected over all
wavelengths. Typically, the sodium D-line (589 nm) is used to detect and quantitate
optical activity.

When circularly polarized light passes through an optically active medium, there
is both a difference in the velocity of the left and right circularly polarized light, as well
as a difference in the absorbance of these two components (equation 1-4).18 The
difference in molar absorptivity, As, is Circular Dichroism (CD).

As =eL-8Rae0 (1-4)
8L and SR are the molar absorption cOefficients for left and right circularly polarized light.

CD is an absorptive process and therefore, CD only occurs in the vicinity of an
absorption band. Therefore, chiral compounds need to contain a chromophore in order
for a CD spectrum to be observed. The shape and appearance of a CD curve is very
similar to that of the ordinary UV-vis absorption curve of the electronic transition to
which it corresponds. The only difference is that, unlike the ordinary UV-vis absorption

curves, CD curves may be positive or negative as shown in Figure 1-8.

10

 

Ac

 

nm

 

 

Figure 1-8. Positive (A) and negative (B) Cotton effects

A. Positive CD 8. Negative CD

CD curves plot As vs. wavelength.‘8 CD and ORD are both manifestations of the same

phenomenon. The molar amplitude A of an ORD can be related to the intensity of the CD

curve, A8, by equation 1—5:22

A ~ 40.28A8

(1-5)

When a molecule absorbs light, an electron is promoted from its ground state to an

A B

‘0 \ID
/

O

coronene hexahelicene

netul Unetm

9

1:
II
o
3

ll

 

Figure 1-9. Electron redistribution upon light excitation
for a transition of (a) achiral and (b) chiral molecule.

excited state. This creates a
momentary dipole, referred to
as the electric dipole transition
moment, denoted by the
vector u. The direction in
which it points is the direction
in which the electrons move

during the transition.

In an achiral molecule, the net electron redistribution during the process is always

planar, while in a chiral molecule the electron rearrangement is always helical.23 In the

latter case, not only does the charge displacement take place during the electronic

transition, which generates the electric transition dipole moment, but also the rotation of

electric charge creates a magnetic field, the strength and direction of which may be

described by the magnetic transition dipole moment denoted by the vector m.3 The

direction of magnetic transition moment (m), can be determined by application of the

“right hand rule” (Figure 1-1024) to the rotation of the charge (circular electric current).

Instructively, the outstretched thumb points to the direction of the magnetic transition

dipole moment when the right hand fingers are curved in the direction of electron flow.25

The rotational strength, R, which is a theoretical parameter representing the Sign

 
    

electron .
' -_ flow-”

 

Figure 1-10. The right hand rule to
determine the direction of magnetic
dipole transition moment (m)

and strength of a CD Cotton effect (CE), is given
by the scalar product of the electric and magnetic
transition moments (equation 1-6):3
R=um=|u|lmlcosl3 (1-6)
Where it and m are the electric and
magnetic transition dipole moments,
respectively, and [3 is the angle between the two
transition moments. The sign of the CE is
positive when the angle is acute (0<B<90°) or, in
the limiting case, parallel, and it is negative when

the angle is obtuse (90°<B<180°) or, in the

limiting case, antiparallel. Dextrorotation results when R > 0, together with positive CD,
and levorotation is generated when R < 0, together with negative CD curve. There is no
CE when the electric and magnetic transition dipole moments are perpendicular to each

other.

1-1.3 A brief introduction to Circular Dichrometers (spectropolarimeter)
Circular dichrometers are used to record both ORD and CD spectroscopy. The

essential features of a spectropolarimeter are shown in Figure 1-11.

modulator

monochromator

“9ht source linearly polarized light

CD spectrum

> <— '
Lock-in amplifier photomultiplier tube

Figure 1-11 Schematic representation of a CD spectropolarimeter

 

 

 

A zenon lamp is typically used as the source of light. This light passes through a
monochromator consisting of a series of crystal prisms to produce linearly polarized
light. In the CD spectropolarimeter, the optical system comprises of two
monochromators (a double monochromator), which helps in reducing stray light. The
linearly polarized light is then modulated into left and right circularly polarized light.

The modulator consists of a thin crystalline plate known as a wave plate. When

13

linearly polarized light is incident on a wave plate at 45°, the light is divided into two

equal electric field components, one of which is retarded by a quarter wavelength by the

plate. This throws the two components 90° out of phase with each other such that upon

emerging, one is always maximum, while the other is always zero and vice versa. The

effect is to produce circularly polarized light. The 90° phase shift is produced by a
precise thickness d of the birefringent crystal, which, because of the 900 shift, is referred

to as a quarter wave plate. This then passes through the sample chamber. The light
transmitted through the sample is measured by a photomultiplier tube, which produces a
current whose magnitude depends on the number of incident photons. This current is
then detected by a lock—in amplifier and recorded.

Most CD spectropolarimeters measure differential absorbance, AA, between the

left and right circularly polarized light, which can then be converted to As based on the
Beer-Lambert law, using equation 1-7.3
AA = A8 c 1 (1-7)
Where AA is the difference in absorbance and As is the difference in molar
extinction coefficients (M'lL'l). Since Optical Rotatory Dispersion (ORD) and Circular

Dichroism (CD) are manifestations of chiral substances and are not observed for achiral
compounds or racemic mixtures, they can be used to detect and quantitate optical
activity. However, ORD and CD by themselves do not allow the configuration of a given

product to be defined.

14

1.2 Exciton Coupled Circular Dichroism (ECCD)
1.2-l Theoretical background of ECCD
The ECCD method is a non-empirical method to establish the absolute

configuration of chiral compounds. This method is developed from the simple
dibenzoate chirality method26 that was first applied to organic compounds by Mason to
determine the absolute sense of twist between two adjacent hydroxyl groups. The
dibenzoate chirality method is based on the nonempirical coupled oscillator theory27 and
group polarizability theory .28

ECCD is based on the through space exciton coupling between two or more
chirally oriented non—conjugated chromophores. The coupling of the chromophores’

electric transition dipole moment leads to the observed bisignate CD spectrum and the

nonempirical determination of their orientation. Figure 1-12 shows the exciton coupling

between two benzoates in steroidal 2,3-bisbenzoate.26

1“ Cotton effect

As A
0 nm
0

G9
|
NE
O._,__.H 2'“1 Cotton effect
syn

O
O

 

 

Positive ECCD

Figure 1-12. Exciton Coupled Circular Dichroism (ECCD) of steroidal 2,3-bisbenzoate.

15

Upon excitation, the through space interaction causes the energy level of the
excited state (exciton)3| to split into two states (a and B) by resonance interaction of the

local excitation. The transitions from the ground state to either the a state or B state, are
responsible for the two different UV-vis absorbances as shown in Figure l-13. The
transitions from the ground state to either the a state or B state, are responsible for the

two different UV-vis absorbances as shown in Figure 1-13.
The difference in the km,“ of the two UV—vis peaks is due to the energy gap, 2vij,
and is called the Davydov splitting,29 after the Russian physicist who developed the

theory of exciton coupling in the electronic spectra of molecular crystals.

 

/ .. \ Excited state

 

 

energy

 

 

 

 

 

Ground state

 

 

 

 

 

chromophore i Exciton system chromophore 1'
local excitation delocalized local excitation
excitation

Figure 1-13. Splitting of the excited states of isolated chromophores iand j by exciton
interaction. The energy gap 2vij is called Davydov splitting.

If this energy gap is small, the two separate peaks overlap and appear as one in
the spectral trace. Because the two Cotton effects in a CD spectra are not in phase, the

Davydov splitting is also present in a CD spectrum (Figure 1-14).

16

'
\
I, \

Davydov splitting —.l 'e— A7»
\

 

 

 

Figure 1-14. The UV spectrum (A) and ECCD spectrum (B) upon through space interaction of
two degenerate chromophores. The two observed Cotton effects are shown using dashed
lines, while the observed, summation curves are in solid lines.

As mentioned before, upon light absorption by a chromophore, an electron gets
promoted from its ground state to an excited state. In a chiral molecule, this results in the
interaction between the electric dipole transition moments (edtm) of each chromophore in
a chiral, helical fashion, generating one of the two helices. Depending upon whether the
electric dipole transition moments are in phase (symmetric) or out of phase (anti
symmetric), a Cotton effect of different sign is produced, and so we expect to see a CD
spectrum with two peaks (bisignate curve), since the two Cotton effects, one positive and
one negative, are not in phase. This phenomenon is known as Exciton Coupled Circular

Dichroism, and can be further explained by examining its application to a specific
mOICCUIC, bearing two identical benzoate groups.25

The coupling of two identical chromophores is shown in Figure l-15, where

benzoate esters of a vicinal cyclohexanediol are interacting. Benzoate esters have a

17

strong UV—Vis absorption band at around 230 nm, arising from the it —> :rt* transition
involving the benzene ring and the ester group.30 The large electric dipole transition

moment it of each benzoate group is oriented colinearly with the long axis of the
molecule, almost parallel to the direction of the GO bond and oscillates in both
directions (Figure 1-15A). Determination of absolute configuration means
determination of the absolute sense of chirality between the C(2)-O and C(3)-O bonds, by
looking down the CC bonds from front to back, the orientation of the two benzoate
groups is set in a clockwise manner, which leads to positive chirality. The absolute sense

of twist is the same regardless of whether it is viewed from C(3) to C(2) or vice versa.

 

Figure 1-15. A qualitative explanation of ECCD. A. Structures of benzoate and dibenzoate
esters. edtm’s are shown in red; B. Possible in phase (i) and out of phase (ii) interactions of
the edtm’s of the degenerate chromophores (shown in blue)

18

Despite the free rotation about the two C-O bonds, ester bonds are known to he s-

trans,23 placing the axial hydrogen on the ring syn to the carbonyl of the ester.

‘ C-
(i) ’

(ii) Low Energy

 

 

High Energy _
Counterclockwise CIOCKW'Se l:> A8 A
nm
H ——>
Negative t Positive
2"d Cotton effect 15 Cotton effect Positive ECCD spectrum

Figure 1-16. The expected ECCD spectrum of dibenzoate, and its rationalization.

The individual edtm ,u of an electric transition, for each chromophore, couples to
the other in phase (symmetric) or out of phase (asymmetric), Figure 1-16 i and ii
respectively. In the case i, where the two electric transition dipole moments couple in

phase, the “total” electric transition dipole moments are oriented along the chromophoric

C2 axis, and in case B, where they couple out of phase, the “total” electric transition

moments are oriented perpendicular to the chromophoric C2 axis.

The helix associated with the charge rotation generated from the transition can be
visualized by placing the partial edtm in a cylinder, aligned along the axis of the “total”
edtm, p. As shown, in Figure 1-16 (i), the symmetric coupling results in a
counterclockwise helical movement and, therefore, according to the right hand rule, the

magnetic transition dipole moment (m) is anti-parallel to ,u. As expected, the out of phase

19

interaction causes the opposite effect, leading to parallel m and [.t vectors (Figure 1-16 ii);
and that leads to a negative Cotton effect (negative CD band), and positive Cotton effect
(positive CD band) respectively. According to Equation 1-6, R = pm = | pl |m I cos [3,
the sign of a Cotton effect depends exclusively on the angle between the electric and the
magnetic transition dipole moment. Therefore, the symmetric coupling of the edtm will

result in a negative peak (fl = 180°, cos/3 = -l), while the anti-symmetric will result in a
positive one (B = 0°, cosfi = I), both of equal magnitude. The positions of these two

Cotton effects relative to each other (which defines whether the overall ECCD spectrum
is positive or negative) depends on the relative energies of the two occurring transitions.
The in phase coupling is of higher energy because of the repulsion between like charges,
and so the corresponding negative Cotton effect will appear at a lower wavelength.
Because nomenclature dictates that the bisignate ECCD curve be named after the lower

energy 1St Cotton effect, the spectrum of the dibenzoate discussed above (Figures 1-15

and 1— 16) will be referred to as a positive ECCD curve.

1.2-2 The Quantum Mechanics explanation of ECCD
The ECCD theory can also be explained by Quantum Mechanical theories. As
mentioned previously, when a molecule contains two identical chromophores, because of

the through space interactions, excitation is delocalized between the two chromophores,

and the excited state“ is split into two states or and B (Figure 1—10).

—0

1 _. _.
Rafi = i_2_"7t()“0Ri_/' . (“1'00 X “10(1) 1,8

20

Based on theoretical calculations on the binary system, the rotational strength, R,

which represents the sign and the strength of a CD Cotton effect, can be defined by

Equation 1—8,26 where the positive and negative signs correspond to 01- and B— state,

respectively, Rij is the distance vector between two chromophores, um and ,ujoa are the

etdm of excitations, and 00 is the excitation number of transition from 0 to a state.

Table 1-1. Definition of Exciton Chirality for a Binary System

 

 

(Diiiiifiitgne Quantitative Definition Cotton effects
“6?.
positive Ril- 0011-00 x fijoa)ViJ' > 0 positive first, then
chirality negative Cotton
effects
_ negative first, then
nfigaltive 9 positive Cotton
0 Iran 4 a a
ty (61> Rr'j ' (Mioa x ujoa)Vij < 0 efieCts

If Equation 1-8 is positive, the observed ECCD spectrum is positive, and if it is
negative, then the observed ECCD spectrum is negative. From the equation above, the

sign of the bisignate curve completely depends on the spatial orientation of the two
chromophores.32 As shown in Tablel-l ,33 if the electric transition dipole moments of the

two chromophores from front to back constitutes a clockwise orientation, then according

to Equation 1-8 above, a positive bisignate spectrum will be observed, which refers to a

21

positive ISt and negative 2nd Cotton effects, while an opposite but otherwise identical

spectrum is produced by the counterclockwise orientation.”35

Therefore, the sign of an ECCD spectrum for a chiral molecule can be predicted
as long as the spartial orientation of two chromophores is known. Moreover, the sign of a
bisignate ECCD spectrum can enable the determination of the relative orientation of two

chromophores in space in a non-empirical manner.

The difference in As between the 1St and 2nd Cotton effects is called the

amplitude, A, of the ECCD couplet (Figure 1-14). This amplitude depends on several

36
factors:

a. Molar absorption coefi‘icient (8) 0f the interacting chromophores. The amplitude
is proportional to 82. Therefore, in order to have increased sensitivity in the
ECCD methods, chromophores with strong absorptions are preferred. These
highly active chromophores enable CD measurements to be performed at micro
molar concentrations, which make it an extremely useful property when only
limited amount of chiral compound is available.

b. lnterchromophoric distance (R). The amplitude is inversely proportional to the

37,38

distance R, between the interacting chromophores. To achieve enhanced

interaction, the coupling chromophores should be oriented close to each other in

space. This tendency is exemplified by a series of dibenzoates as shown by

Nakanishi,29 (Figure l-17) where remote dibenzoates generally exhibit weaker

amplitudes.

22

,N
(no
0
O
0% r
\l‘

1,4- dibenzoate 1,6- dibenzoate
+89 .4 +27. 5

      

 

1,8— dibenzoate
-26.4

Figure 1-17. Dibenzoate chirality method - Distance effect

Although the 1,8-dibenzoate has an interchromophoric distance of 12.8 A, a
relatively strong ECCD is still observed. Generally, a distance of about 13 A is enough

to observe ECCD for most organic molecules. However, strong chromophores such as

porphyrins (Soret band Max at 415 nm, e = 350,000 M'l cm") are known to couple at

distances of up to 50 A9941

23

c. Projection angle between the interacting chromophores. The A value is maximal

at a chromophoric projection angle of around 70°. There is no exciton coupling

when the chromophores are either parallel or perpendicular to each other.
d. Number of interacting chromophores (X, Y, Z). The A value of the whole
molecule is the summation of the A value of each pair of interacting

chromophores, i.e. the principle of pair-wise additivity holds in systems

comprising of three or more chromophores: Atom] = Ax).+AXZ+AVZ. This

. . . . 42-44
observation has been proven by expenments and theoreucal calculat1ons.

Not only can exciton coupling take place between identical chromophores, but it can

also occur between different chromophores, but the UV—vis absorption Amax values for

the interacting chromophores need to be close for the coupling to be effective.
In systems containing two different chromophores, two opposite Cotton effects

appear, slightly red- and blue-shifted from the respective maxima of the interacting
chromophores.26 The interacting chromophores do not have to be within the same
molecule, as long as they are in close proximity in space. In particular, supramolecular
compounds, like stacking of anthocyanins45 and porphyrin containing brevetoxins“ have

been reported to give rise to exciton coupled CD bands.

1.2-3 The application of the ECCD method to determine the absolute
stereochemistry of chiral molecules
The Exciton Coupled Circular Dichroic (ECCD) method is a method based on

sound theoretical calculations as seen in the previous section, therefore, the absolute

24

stereochemistry of chiral organic compounds exhibiting typical bisignate ECCD
spectrum is assignable in a non-empirical manner. The ECCD method is a versatile and
sensitive method requiring only microgram amounts of sample. Because the ECCD
spectrum originates as a direct result of the relative orientation of two interacting
chromophores, nonempirical applications have been developed for the absolute
stereochemical determination of both chemical and biological interest, including
polyols,46 carbohydrates,47 quinuclidines,48 hydroxy acids,49 and others.29 Figure 1-18 is
an example of determining the absolute stereochemistry of (+)-abscisic acid by the ECCD

method .5 05 1 Abscisic acid, a plant hormone, contains two non-conjugated chromophores,

an enone and a dienoic acid, separated by the only chiral center, a tertiary alcohol.

/
/
ll

 

Figure 1-18. ECCD active abscisic acid

The enone and the dienoic acid moieties interact through space, resulting in a positive
ECCD couplet. Based on the sign of the spectrum, the two chromophores must be

oriented in a oriented in a clockwise manner, which directly indicates the ,B-configuration

of the hydroxyl group.

25

 

 

i-Pr

 

reduction lll
0\
O 0‘“ OH O 0‘ 082 I
benzoyl protection
I i-Pr r-Pr

Flgure 1-19. Application of the ECCD method in absolute configurational assignment of
natural products.

Figure 1-19 shows some additional examples of chiral molecules, whose absolute
stereochemistry has been determined using the ECCD method.

In A, the configuration of the lS—glcNAc group in Pavoninin—4, which is a shark
repellant, has been determined according to the ECCD couplet between the enone and the

bromobenzoate moiety .52

26

In order to use ECCD, there has to be spatial interaction between two
chromophores. Therefore, in order to determine the absolute configuration of the potent
cockroach sex excitant periplanone B, that has only one chromophore (the diene),
derivatization of the molecule had to be carried out first, so as to install the second

requisite chromophore. After stereoselective reduction of the carbonyl and benzoylation

of the resulting alcohol, the observed ECCD defines the absolute stereochemistry.53

1.2-4 Use of chromophoric hosts such as porphyrins for ECCD studies

As mentioned earlier, the ECCD method requires the presence of at least two
interacting chromophores in the molecule. This requirement can significantly limit its
use, since the majority of chiral compounds do not fulfill this requirement. One way to
overcome this problem is by introducing a second chromophore, usually in the form of a
benzoyl group, as in the Periplanone B case discussed above. However, that is not always
feasible, since a great number of chemically and biologically important compounds do
not include any chromophoric moiety within their structures and the opportunity for
derivatization is not always present. In order to address this issue, chromophoric
receptors have been designed to act as hosts for non-chromophoric, chiral molecules.
Once the chiral substrate binds to the host receptor either covalently or non-covalently, it
will induce the host to adopt a preferred chiral conformation, which can then be observed

as an ECCD couplet. This chiral induction was first demonstrated on dyes bound to
polypeptides in their helical conformations.54 This binding induced a helical orientation

within the chromophoric molecule producing an ECCD-active species. The process for

transmission of configurational information comprises of at least two elementary

27

processes: (1) complex formation between the chiral molecule (guest) and the

chromophoric receptor (host) and (2) some dynamic processes associated with it, usually

55 .56

a conformational change of interacting molecules that can induce the signal. If the

interactions between the two molecules are strong enough, this will lead to efficient
transmission of information. In order to simplify the observed ECCD signal, the
chromophoric hosts used for ECCD studies are either achiral or in the form of racemates.
When an achiral host is used, it can adopt the dictated chirality of the chiral substrate that
binds to it through chiral induction. This induction leads to the formation of a preferred

helical conformer, the orientation of which can be determined by ECCD.

Br HO OH Br
H 0 R, .- ,R
o... No. {A N“ HN
tBu H H
+ . 2° B ‘o 0’ Br
Br HO OH Br "NA/‘3“ '

2 2

02
Figure 1-20. The induced chirality of biphenol upon binding to chiral amine
Binding between the host and guest molecules can either be covalent or non-
covalent, depending on the complex being formed. One example of induced chirality on
a prochiral host, upon interaction with a chiral guest, is shown in Figure 1—20.57
The biphenol shown is an ECCD active molecule (atropisomeric molecule); due to
steric interactions between the two hydroxyl groups the molecule is not planar but exists
as a mixture of the two enantiomeric forms.
When the chiral trans-1,2-cyclohexane diamine is added, a preferred complex is

formed as shown, due to the hydrogen bonding between the phenols and the amine

28

groups.58'60 The observed ECCD spectrum is determined by the induced complex and is

57

dictated by the absolute stereochemistry of the chiral diamine. This is an example of

non-covalent complex formation. In a similar manner, covalent bonding has been used to
form chiral complexes of binapthalenes to determine the absolute stereochemistry of
chiral secondary alcohols.61 As shown in Figure 1-21, the chromophoric reagent, 3-
cyanocarbonyl-3’-methoxycarbonyl-2,2’-binapthalene, can be esterified with chiral
secondary alcohols and the resultant complex exhibits induced ECCD as a result of
favoring one atropisomer, due to restricted rotation about the CC phenyl bonds.

The chirality has been transferred from the chiral alcohols to the binaphthylene

O R*OH COOMe
. O COOR*
DMAP, CH30N

 

Figure1-21. Determination of stereochemistry of chiral alcohols by ECCD.

system by minimizing the steric interaction between the substituents on the chiral

alcohols with the methyl ester group in the binaphthylene.

29

N \ H O
O . N .
Ix _, Negative
moo ECCDcouplet
N
° .. file
0
x= Nb
0

1 o o t. $3.3 ..
(ii/OW 1 El) :QEZ‘ Egsggiouplet
\
O O N
C3 = .6, \ 7
all)

Sh

 
   
 

CU(CIO4)2 S'COnlIguratlon

NH4SCN

   

Ff-configuration

Figure 1-22. Derivatization methods for analysis of absolute configurations with various
chromophores.

30

In recent years, several methods for the determination of absolute stereochemistry
of difunctional amines have been developed and widely studied by ECCD, after
derivatization of the functional groups to introduce the required chromophores. Figure l-

22 shows a few examples of chromophores that have been applied.
In A, Gawronski et. al.62 used pthalimide to study the absolute stereochemistry of

diamines. Their study also included the use of benzoate as the chromophore for hydroxyl

and carboxyl groups to include the study of absolute stereochemistry of amino acids and
amino alcohols. Lo et al.63 have used 7-diethylaminocoumarin-3-carboxylate shown in B

for amines, hydroxyl and carboxyl functional groups.

66

Canary and coworkers have published a number of systems,“ one of which is

shown in C, where they make use of quinoline chromophores for the formation of chiral
propellers. In these systems, a tripodal system bearing a chiral group on one of the arms
is synthesized. Upon complexation of Cu(II) or Zn one of the two possible propeller
conformations is formed, depending on the chirality of the original molecule, giving rise

to the corresponding characteristic ECCD couplet.

1.2-5 Use of zinc porphyrin as chromophoric host

Throughout literature, there is a predominance of porphyrin-based systems as
chromophoric hosts for application in the ECCD method of stereochemical
determination. The study of porphyrins has received increased interest in recent years

since they have been utilized for the development of various projects, both of chemical

and biochemical interest.67 Especially in the case of chromophoric receptors for the

31

determination of stereochemistry using ECCD, the unique features of these highly
conjugated rings have made them extremely attractive targets:68

(1) Their planar structures provide a well-defined binding pocket that is
accentuated by substitutions on the ring. There are many sites that can be derivatized,
such as the meso and B-positions, the central metal and the inner nitrogen atoms. By
varying the substituents on the periphery of porphyrins, the solubility of the porphyrin
containing compounds can be easily modified, for use in both polar and non-polar
solvents.

(2) Porphyrins are excellent chromophores, with an average molar absorption

coefficient of around 400,000 M"l cm]; the amplitude (A) of the ECCD couplet is

proportional to 82, so that the method’s sensitivity is greatly enhanced in the presence of a

strong chromophore.

(3) UV-vis absorption maximum of porphyrins rests around 418 nm for the main
absorption band (Soret band), located in a region of the spectrum far red shifted than
most chromophores that likely preexist in the analyte (typically carbonyls and olefins).
This prevents the unwanted interaction between the introduced chromophore and the
chiral substrate that can potentially complicate the spectral analysis.

(4) Metal incorporation into the porphyrin ring can be easily achieved, providing a
coordination center for the binding of the chiral molecule. Metalloporphyrins, such as
zinc porphyrins and magnesium porphyrins, can provide extra stereodifferentiation with
their Lewis base binding sites. Therefore, porphyrins have been recognized as the ideal
chromophores for detecting subtle changes in their close environment, including chirality

induction.

32

Porphyrins have been widely utilized in stereochemical studies by CD. These
include absolute configurational assignments,40‘69‘70 stereochemical differentiations of

71 .72 73 .74

sugars and amino acids, and interactions with bio~macromolecules.

Porphyrins, as the alkyl connected bis-metalloporphyrins shown in Figure 1—23, can
be used as chromophoric host systems for stereochemical determination of chiral
compounds because of their ability to bind to the chiral compounds at the metal centers,
and report the chirality of bound guests based on Exciton Coupled Circular Dichroic

Spectroscopy (ECCD).67'75'78

 

Figure 1-23. Structure and schematic representation of a porphyrin tweezer

Binding of chiral diarrrines forces the complex to adopt a helical conformation that
results in an observable ECCD spectrum. In turn, the helicity of the receptor reflects the
chirality of the bound compound.

As shown in Figure 1-25, when zinc tweezer is added to the solution of chiral
diamine (S)-methyl-2,6-diaminohexanoate, the porphyrin tweezer binds to the chiral

. . . . . . . 77
dramrne vra Zn-N coordmatron to form a “sandw1ch” structure.

33

The interaction between the porphyrin coordinated to the end closer to the chiral
center and the chiral groups is such that the steric interactions between them are kept at
minimum. In order to achieve that, the porphyrin ring ‘slides away’ from the large group
on the chiral center and covers the small group. This conformation is more stable than
the alternative (Figure 1-24), in which the porphyrin ring ‘slides away’ from the large
group and interacts with the small group instead. The more stable conformation leads to
the two porphyrin planes adopting a counterclockwise orientation and a negative ECCD

couplet is predicted. This prediction matches the CD observation.

HZNngHZ

MeOzC,,_ H _ KQ/gv zinc porphyrin \ / \ I
H2NWNH2 = NH A, Zn n

Z
M
. 2 eezer \(OMOWIJ
O O

 

 

 

 

® 180
A 130 ~
I 80 .
D << 0 30 .,
. fi 5’ 0. -2o «
2 ~70 "
positive negative "120 ‘
ECCD ECCD -17O *
couplet couplet
-220

400 420 440
wavelength (nm)

Figure 1-24. Assignment of absolute configuration of acyclic chiral diamines using ECCD

34

This tweezer approach has been extended for the determination of the absolute
stereochemistry of chiral amino acids and amino alcohols which have a primary amino
group directly attached to the stereogenic center. After simple chemical modifications,
amino acids or amino alcohols can be converted to diamines (derivatization of amino

acids with ethylene diamine, derivatization of amino alcohols with glycine) and the above
rationalization is followed.77

As previously mentioned, zinc porphyrin tweezers cannot be used directly to
determine the absolute stereochemistry of chiral compounds that have only one site of
attachment. In order to overcome this problem, carrier molecules have been designed to
convert compounds with only one site of attachment to molecules possessing two sites of
attachment. Carriers are achiral molecules, which can be derivatized with the chiral
substrates to provide the requisite two sites of attachment for binding to zinc porphyrin
tweezer.

The carrier, upon derivatization with chiral compounds, should exhibit a rigid and
predictable conformation about the free rotating single bonds. Rotation along any of the
single bonds can dramatically alter the position of the large, medium, and small group
with respect to the porphyrins. An ideal carrier molecule needs to possess the following
characteristics:79

1) They should have a functional group that can be derivatized with the chiral
molecules. For example, a carboxylic acid will serve well when a chiral amine is
to be analyzed;

2) The derivatized carriers should be able to bind to the porphyrin tweezer at 1:1

ratio;

35

3) The carrier derivatized conjugates should be rigid, since flexible structures will
give multiple conformations leading to weak or even complex CD spectra;

4) The carriers should be achiral, since the introduction of an extra chiral center into
the system will result in diastereomers, which will complicate interpretation of
the ECCD spectrum.

Ultimately, the success of this carrier method relies on identifying the most
energetically favored conformation of the derivatized carrier. This is imperative because
the conformation of the derivatized carrier dictates the position of the substituents at the
chiral center in space relative to the porphyrins, and therefore will dictate the spatial
orientation adopted by the two porphyrin planes.

Utilizing this method, a series of systems have been designed and successfully

applred for the stereochemrcal assrgnment of derrvatrzed chiral secondary monoamrnes, 6

and or-chiral carboxylic acids.78'80

As mentioned above, the use of porphyrin tweezers requires the use of a chiral
molecule bearing two sites of attachment. An exception to this rule is the work by [none
and coworkers.“82 They have developed, a methodology for the assignment of the
stereochemistry of monoamines and monoalcohols, without the need for derivatization,
using a porphyrin tweezer with a very short linkage. The major drawback of this method,

believed to be based on induced supramolecular chirality, involves the need for a great
excess of chiral molecule (mM concentration), and low amplitudes, < 50 M'lcm'l for

most substrates.
Our research has focused on exploring and expanding this latter approach. We are

interested in designing a porphyrin-based system that can be used for the assignment of

36

the stereochemistry of compounds with only one site of attachment, without the need for
derivatization, in uM scale. In particular, we wish to employ the use of porphyrin
aggregate systems as reporters of chirality for monoamines.

The controlled organization of molecules into self-assemblies has seen an explosion
of interest in the recent past because of the ability to create novel supramolecular

83-88

architectures with useful properties. Porphyrins are known to align into one-

dimensional aggregates by 313-313 interaction, electrostatic forces, or Van-der-Waals forces.
The control of chirality in porphyrin-based self-assemblies is of increasing interest both
in biological applications, for the construction of systems mimicking biological functions,
for example Cytochrome P-450 activity, as well as in material science and chemistry, for
example creating nanowires, or new molecules.

This research will focus on taking advantage to the rt-tt stacking ability of
porphyrins in order to form aggregate systems. Once the aggregates are formed, we wish
to use chiral monoamines to induce chirality into the aggregate system, which will then

be studied by CD spectroscopy.

37

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428.

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45

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chirality of achiral amphiphilic metalloporphyrins" Journal of Colloid and
Interface Science 2008, 326, 460-464.

46

CHAPTER 2
PORPHYRIN AGGREGATES AS HOSTS FOR CHIRAL DISCRIMINATION

2-1. Introduction to Porphyrin Aggregation

Figure 1—24 shows the use of the bis-zinc porphyrin dimer (porphyrin tweezer) for
stereochemical determination of chiral molecules bearing two sites of attachment
(diamines, diols, amino alcohols). However, as discussed previously, this method cannot
be directly applied for the stereochemical determination of compounds with one site of
attachment, (carboxylic acids, monoamines and alcohols) since the two porphyrins cannot
be oriented relative to each other. Nakanishi, Berova, and co-workers, developed a
method that enables the stereochemical determination of such compounds that lack a

second site of coordination. This method requires derivatization of the chiral compound
with a carrier molecule which functions to provide the second binding site (Figure 2—1).1

This method has been

Carbox llc Aclds Carrler
y extended to the
NH2
H COOH BocHN O O
-. H ' '
ROM 0 7A” determrnatron of
NH2 L M
Amlno Alcohols stereochemistry of
.. 1L 2
Ha. N142 chiral carbox lic acids,
BocHN:1"H BocHNACOOH Bro y
R NH2
amino acids and
Amlno Acids
coon o alcohols,‘ which have
BocHN/EH BocHNANHZ EBAfl/VNHZ
NH2 an amino group directly

attached to the
Figure 2-1. Application of carrier molecules to the
stereochemical determination of molecules with one site of

. . . . _ 0 ' .
attachment: carboxylic acrds, amrno alcohols, amino acrds. stereogenic centre

47

 

Fl NH2

 

R—configuration

Figure 2-2. Derivatization method for analysis of absolute configurations of
amino acids

Canary and co-workers have developed several modifications to the tweezer

system, where instead of using a carrier for derivatization, they make use of quinoline
chromophores for the formation of chiral propellers.3'5 As shown in Figure 2-2, the chiral

molecule is derivatized onto a tripodal system as one of the arms. Upon complexation of
Cu(II), depending on the chirality of the molecule, one of the possible propeller

conformations is formed, giving rise to the corresponding characteristic ECCD couplet.
In this case, S-amino acids result in negative ECCD and vice versa.4 This system works
for chiral primary amines, B-aminoalcohols and N,N,dialkyl or-amino acids,35 with

appropriate derivatization.
More recently6 in 2007, they reported a chiral tripodal ligand containing two

monosubstituted tetraphenylporphyrin (TPP) moieties, (Figure 2-3) and used it for the

48

stereochemical detemiination of chiral amino alcohols and amino acids. The ligand

incorporates the porphyrins as chromophores to enhance the CD amplitude.

oumooz
NH4SCN

   

SCHS

Figure 2-3. Tripodal ligand, derived from methioninol, incorporating TPP as
chromophores

The tripodal system is flexible. and can adopt different conformations in solution,
but once it complexes to the Cu(II), the ligand wraps around the metal, fixing the
geometry of the chromophores in a way that positions the porphyrins such that the strong
Soret electronic transitions couple to give ECCD. A strong negative CD spectrum was
obtained for this system, which indicated a spatial orientation of the net transition dipole
from the Soret bands in the porphyrins with a counterclockwise twist, corresponding to
the S configuration of the chiral center.

In their systems however, the chirality is incorporated within one of the arms of
the tripod, and the chiral amine to be studied requires derivatization into the tripopdal

system, which may not always be feasible.

49

In 2001 , a new methodology7'9 was developed by Inuoe et al. for the assignment

of the stereochemistry of monoamines and monoalcohols without the need for
derivatization. As shown in Figure 2-4, their method calls for the use of a porphyrin
tweezer with a very short linker. In this system, the achiral folded syn conformer of the
ethane-bridged porphyrin switches to the corresponding chiral extended anti conformer

upon ligand binding.

 

 

\ a \

L \ N\ N—

\ NZn\ /

\ \ / /
1 1
syn anti

Figure 2-4. Porphyrin tweezer system used for stereochemical determination of chiral
monoamines. For the second ligation step, the ligand approaches from the same face.
(asymmetric approach)

The mechanism of the chiral induction is based on the chiral ligand binding to
zinc, and subsequent formation of either right- or left-handed twist, due to steric
interactions between the ethyl groups on the porphyrin ring, and the largest substituent on
the asymmetric carbon on the ligand. The major drawback of this method is the

requirement of an excess of the chiral molecule (mM concentration) and low amplitudes
less than 50 M’lcm'l observed for most substrates.

Our main interest is to develop non-tweezer host systems that can be used for the
assignment of stereochemistry of compounds with only one site of attachement, without

derivatization, and in 11M concentration. This requires that the host system should have

50

the capability to bind chiral molecules that contain a single site of attachment, be
sensitive to the chiral disposition of the substituents, and adopt an induced asymmetry
that results in an observable ECCD signal. The readout would then correlate to the
absolute stereochemistry of the bound chiral guest. Because porphyrins lead to high

amplitudes, we wish to use porhyrins as the two required chromophores.

2-2. Design of Porphyrins for Aggregation

Supramolecular chrralrty10 1 14 rs a relatively new area of research that combrnes

supramolecular chemistry and molecular chirality. The most important part of this field
is supramolecular chirogenesis, which is “symmetry breaking” in intrinsically achiral
multi or unimolecular systems and chirality amplification in supramolecular assemblies
consisting of chiral components upon interaction with a chiral enviroment, via a chirality
transfer mechanism.

Molecular self—assembly is the spontaneous association of molecules into stable,
structurally well—defined aggregates by non-covalent interactions such as hydrogen
bonding, rt-rt interactions, electrostatic interactions, etecetra. The first technological
application of molecular assemblies was the Langmuir-Blodgett technique where layers
of amphiphilic molecules are deposited onto a solid from the surface of a liquid. This is
done by immersing the solid substrate into a liquid, adding a monolayer with each

15-17

immersion step to form the Langmuir-Blodgett films. Because of this, films with very

accurate thickness can be formed. These films have been used in material science in

optical and electronic devices.18

51

More recent applications of molecular assembly is in DNA nanotechnology.19

The basic idea behind DNA nanotechnology is to use the unique molecular recogition
properties of DNA to form target materials with predictable and controllable 3D

structures. One interesting recent example is where Chichak and co-workers use DNA

to prepare a molecular analogue of the Borromean rings.20

Molecular self-assembly is common in biological systems and underlies the
formation of many complex biological processes8 like protein folding and pairing of

nucleotides. Molecular assemblies of chromophores in particular are important; for

example the light harvesting complex employed for photosynthesis by green plants and

purple bacteria,” as well as molecular assemblies in technological applications like

sensors and nonlinear optics can be cited.8‘2122 Currently the main problem faced during

the application of molecular assemblies and aggregates is the difficulty in controlling the
arrangement and orientation of the monomers in the aggregates.

The chirality of

H
\ / S C s
\ \Ol \r/ \WGD supramolecular systems can
N C N N .N
F'i H R

R
be produced through direct

H Cl
0 /C 0 s nthetic modifications
Y re CC 36:1 , ’
N R’N Cl ”a f”
,‘q RMC‘ ‘R and/or by asymmetric
induction via self-assembly,

Me
Me 8 \ \
s
N>§\ S\®N ‘Er Et/N axial ligation, or aggregation
5‘; R'/C\ \

processes. Of these,

Figure 2-5. Structures of some cyanine dyes. aggregation processes have a

52

greater possibility for control of chirality induction .7

The monomeric units of the chromophores can be arranged in different ways in an
aggregate structure due to rt-stacking, which may or may not be ordered. These

aggregates, if ordered, can form highly organized structures classified according to the

23 .24

orientation of the induced transition dipole of their constituent monomers. The most

studied aggregate system is that of the cyanine dyes, (Figure 2-5) that were first

synthesized over a century ag0.2526

Cyanine dyes are characterized by two heterocyclic components joined by a

polymethine chain that has an odd number of carbons. Cyanine dyes and their aggregates

are one of the most important photofunctional materials used in photography,27'31

information storage,32 (CDs and DVD’s) and nonlinear optical devices.22

Cyanine dyes are known to aggregate into J- and H—aggregates, in which the

 

 

 

 

 

 

 

 

 

 

 

 

 

molecular
\ / arrangement is
| if ll 11 J :9
m0 4‘3 c’ I II 1r 1f _ M
I}, H Fl string highly ordered.
Cyanine Wm H The J-aggregate is
Q. U, 3:1fizCA one of the most
11:1 LE]: 1 Al AF if 3‘
El [:53 "2 Jfijfgl J important dye
[:3 [5:1 r JVAF if
[:j :53 1,1 ribbon assemblies for
3 11 photographic
staircase ladder

Figure 2-6. Arrangements proposed for J-aggregates of cyanine

 

dye 1.

: transition dipole moment, - - -: line connecting

monomer centres and w: direction of growth of aggregate.

53

spectral

sensitization.”31 The first independent observation of J-aggregates was in l,1’-diethy1—
2-2’cyanine chloride by Jelly25 and Scheibe26 in 1936. In these structures, the molecules
are arranged in the “head—to-tail” manner such that the transition dipole moments of the
monomers comprising the aggregate are parallel to the line connecting their centers. In

the ideal case, the angle between the molecular centers is zero .3 3

There are several arrangements that have been proposed for J -aggregates, some of
which are shown in Figure 2-6. From these models, the brickstone model (string and
ribbon) is the most widely accepted model, because, as discussed above, the transition
moment must be parallel to the long axis of the chromophore. The staircase and ladder
models are not in agreement with this requirement since their transition moments are

perpendicular to the lines connecting the centers of their monomers.

 

 

 

 

 

H-aggregate J-aggregate
® 9
O O 69 O
out-of-phase

® . h 9 interaction of

. rn-p 3.38 transition moments

rnteractronof Low energy
transition moments transition

High energy

transition

 

 

wavelength (nm)

Figure 2-7. One dimensional aggregate structures. Sandwich structures (left) give a blue
shifted H-aggregate whereas brickwork structures (right) are characterized by a red shift
J-aggregate of the Soret band.

54

In the recent past, porphyrins have been shown to be well suited for studying the
process of supramolecular chirality inductionmz‘l‘m’40 Porphyrins have an ease of self—

assembly due to the facile it-rt interactions, allowing for the formation of different types
of dimeric and multi-molecular assemblies. They also have well-resolved and red-shifted
intense Soret bands in the spectral region where most chiral molecules to be studied do

not absorb.

The J-aggregate of porphyrins is characterized by an intense narrow absorption
band (red curve) that is red shifted relative to the Soret band (black curve) of the
monomer (Figure 2-7). This spectroscopic property is explained by the interaction

between the transition dipole moments of the monomers arranged in the “head-to-tail”

2 .3 .
manner. 4 539

On the other hand, H-aggregates are structures arranged in one dimension, in

such a way that the transition dipole moments of the monomers are perpendicular to the

24.35.39

line connecting their centers (a “face-to-face” arrangement) resulting in a

characteristic blue shift in the UV/vis (Figure 2-7).

There are many examples of aggregation of porphyrins in the literature, some of
which study the self-
aggregation of various

R: x. JL (CsznMe neutralf’O cationic,35 or

. .4] . .
anronrc porphyrrns 1n

 

aqueous or organic

Figure 2-8. porphyrin with four urea groups at its periphery solvents. Others have

55

studied the factors influencing these aggregations, be it it—rt stacking, solvent effects,
covalent or non-covalent interactions and temperatured'z'45 Of note however, are those

that have formed porphyrin aggregates to study memory of chirality.
Small chiral molecules and biopolymers are often the choice for templates for
induction of chirality. Shun—ichi et al. make use of four chiral urea derivatives on the

periphery of the porphyrin, which cause the porphyrins to form fibrous aggregates by

inducing a chiral twist (Figure 2-7).38

56

 

 

 

 

 

‘" Mai—r
Ce “trailer; as
(S) (”TY-$31909 ionic H4TPPS2'
poly-1-HCI ______________ ' exterior

helicity induction

   

Induction of chiral J-
aggregates

Retention of memory of
chiral J-aggregates

Figure 2-9. Induction of helicity in poly-1-HCI upon complexation with (S—BINOL) induces
formation of chiral J-aggregates, and retention of memory after inversion of helicity of the poly-
1-HCl by addition of excess (R)-BINOL.

Onouchi et al. demonstrated that a charged poly(phenylacetylene) could trap
hydrophobic chiral guests (in its helical cavity), in water, which will then induce helicity
within the poly(phenylacetylene), and this could then serve as a template for induction of
supramolecular chirality in achiral porphyrins forming optically active J-aggregates.37

Once the J—aggregates are formed, they are able to maintain the induced chirality without

57

further assistance from the template. By inversion of the helicity of the poly-l-HCI, it is
expected that the helicity of the aggregate would be affected and change from J— to H-
aggregate. (Inversion of the helicity of the poly-l-HCI is done by addition of excess (R)
BINOL to the formed J-aggregates). However, retention of helicity of the J-agregate is
observed (Figure 2-9). If there was no retention of chirality, the helicity of the aggregate
should have changed from J - to H-aggregate. This suggests that the porphyrin assembly
is able to retain the initial memory of chirality even after inversion of helicity of the poly-
l-HCl.

Most recently, Monti et al. made use of electrostatic-templated heteroaggregation

of porphyrin derivatives shown in Figure 2-10. In their system, they derivatize a chiral
cationic functionality and a chiral anionic functionality into the porphyrins.36 In this
case, they use (L)-
prolininium moieties which
help steer the self—

aggregation process

 

towards the formation of

HM v0
5 @CH3
'cr-r3

large porphyrin aggregates

 

with high supramolecular

Figure 2-10. porphyrins with a) chiral cationic b) chiral

anionic prolininium functionalities. chrralrty '

They co-aggregate
the two porphyrins forming a template due to electrostatic forces between the positive

and negative charges, giving rise to a negative ECCD spectrum. In this work, they have

58

the chirality incorporated into the porphyrin, which limits the scope of chiral molecules
that can be used with the system.

As seen in Chapter One, the coordination of a chiral diamine to the bis-porphyrin
system induces an asymmetric environment into the complex resulting in a helical
arrangement of the chromophores. We envisioned that a similar approach might be taken
for the formation of chiral aggregates in non-aqueous media. This would exclude the use
of charged species, due to their poor solubility in organic solvents. Lack of charged
species however, may affect the geometry of the porphyrin interaction, especially if

electrostatic interactions between cationic and anionic porphyrins (as in the case of Monti
et al.36) leads to the formation of the aggregate with specific geometry (mostly J—

aggregates). Because spontaneous self-assembly triggered by rt-stacking leads to the
formation of a mixture of both H- and J-aggregates, by incorporating a coordination site
(Zn metal) within the porphyrin, upon coordination of a guest molecule, this mixture of
aggregates can then be transformed into a single superstructure, either H or J by induction
of chirality. We also believe, as shown by Monti and co-workers, that the asymmetry of
the bound guest can affect the handedness of the formed assembly and generate an
optically active aggregate (Figure 2-10), the helicity of which can be identified through
Exciton Coupled Circular Dichroism (ECCD). DeteCtion of exciton coupling brings up
the issue that must be considered for the ECCD method, that is a relative orientation of
the transition moment of porphyrins in the assembly. Appearance of ECCD signal and

correlation of its sign with the helicity of the aggregate is based on the relative orientation

of the electric transition moments of porphyrins,46 and thus depends on the existence of

such transition. Defined orientation of electric transition moment (C15-C5 direction) can

59

be achieved by breaking the symmetry of the porphyrin through introduction of an
electron withdrawing carboxylate group onto the mesa-position of the porphyrin (Figure
2-10). The large electric transition moment in this porphyrin is oriented approximately
collinearly with the long axis of the porphyrin ester and almost parallel to the direction of
the C-0 ester bond.

Another aspect to consider is that, unlike porphyrin tweezer complexes that have
only two porphyrin molecules, porphyrin aggregates are able to incorporate an infinite
number of molecules of the guest molecule. In this case, each of the complexes formed

within the aggregate can give rise to a CD bisignate curve, and the overall spectrum
should be interpreted as a summation of the signals of all chiral complexes.47 The goal of

this project is the formation of chiral porphyrin aggregates through an induction of
chirality by chiral monoamines in non—chiral porphyrin assemblies. The ECCD method
will be used to determine the absolute stereochemistry of the formed aggregates. In order
to form the chiral ECCD active assemblies, the following conditions have to be met:

a) The porphyrin aggregate should be formed. This can be achieved by increasing
the porphyrin concentration in the solution.

b) The two interacting porphyrins have to come close together so as to experience
exciton coupling. This can be achieved with both the formation of the aggregate,
and by the metal-substrate binding interaction.

c) There should be a fixed direction of the permanent dipole moment within the
porphyrins. This can be controlled by the introduction of a group with different

electronic properties at the meso-position of the porphyrin ring.

60

d) The alignment of the porphyrins in the aggregate has to be controlled, i.e. the
permanent dipole moments of the porphyrins in the assembly have to be oriented
in the same direction.

Conditions c) and d) can be achieved by the introduction of a hydrophilic tail that
should enable intermolecular hydrophilic interaction with a similar part of the
neighboring porphyrin rings (Figure 2-11a). Consequently, while spontaneous
aggregation of hydrophobic porphyrin rings triggers the formation of a mixture of H- and
J-type assemblies, hydrophilic interaction between oxygenated tails might stabilize the
relative orientation of electric transition moments in the assemblies. A controlled
orientation of the transition moments will also be helpful for the interpretation of the sign

observed upon chiral induction.

For these reasons, the TPP porphyrin mono-tail shown in figure 2-11b, was

proposed as the first system for investigation.

61

A
chiral or

_ chiral J-aggregate chiral H-aggregate
erture of aggregates

 

B
hydrophobic head

Ph

rt-stacking

hydrophilic

hydrophilic tail interactions

   

Figure 2-11: A) Triggered by n-stacking, aggregation of porphyrins results in
formation of a mixture of H- and J-assemblies. B) Controlled by
hydrophobic/hydrophilic interactions aggregation of porphyrins leads to fixed
relative orientation of transition moment in the assembly and makes possible
detection of chirality by ECCD and identification of relative orientations of
porphyrins in the assembly.

Results and Discussion

ZnTPP mono-tail porphyrin shown in Figure 2-11b was synthesized48 and used
for initial aggregation studies. For the UV/vis studies, 1 mM porphyrin solution is added
in 1 (LL portions into a 1mm UV cell containing the solvent of choice (0.2 mL) and the
UV spectrum obtained. This titration is repeated until the porphyrin starts to aggregate at

40 11M concentration (Figure 2-12, yellow curve). Increasing the concentration to 50 11M

62

concentration leads to splitting of the Soret band mixture into two geometrically different

assemblies, the H- and J-aggregates.

    

 

 

—10 M
2-5 1 J-aggregate u
H-aggregate 421 nm —30 uM
2 412 nm 40 uM
. ——-50 uM
—55 uM
8 1.5 -
E
e
8
2 1 ‘
0.5 -
0 - r ' . .
375 395 415 435 455 475

wavelength, nm

Figure 2-12: Aggregation of Zn-TPP-tail porphyrin in hexane starts at

3x10_5 M (broadening of the Soret band). Further increase of porphyrin
concentration (40 11M and higher) results in a split of the Soret band.

Formation of a complex between the chiral amine and the aggregate system can
be monitored by UV-vis spectroscopy. Taking (S)-l,2-diaminopropane, complexation
studies were first performed in hexane. However, upon addition of the diamine to the
porphyrin aggregate leads to formation of a precipitate.

Performing the same UV-vis titration studies in methylcyclohexane preceeds
without precipitation and gives the porphyrin aggregate complexed with (S)-1,2—
diaminopropane with absorption at 423 nm (Figure 2-13). CD studies were therefore

done with 50 11M ZnTPP-tail solution in methylcyclohexane. Upon addition of (S)-l,2-

63

diaminopropane to the porphyrin aggregate, chiral induction is observed at

porphyrin/substrate ration 1:0.2 as a positive ECCD curve (Figure 2-14).

 

 

3.5 -
—1:0
3 ‘ —1:o.2
2'5 _ —1:1
—1:3
§ 2 . —1:6
6
a —1:7
3 15 - /
2 .
1 .
0.5 -
o . . . .
375 400 425 450 475

wavelength. nm

Flgure 2-13. Addition of (S)-1,2-diaminopropane to the porphyrin aggregate in
methylcyclohexane yields the formation of a single assembly (UV-vis spectra).

The UV/vis spectra of the (S)-1,2-diaminopropane complexes shows a red shift of
both the H- and J-bands (414 nm and 420 nm respectively) to a single transition at 423

nm, which could indicate the formation of a new assembly (Figure 2-13).

Both L-omithine methyl amide and L-lysine methyl ester cause a similar
transformation of the J- and H-species into a single assembly absorbing at 423 run when
subjected to UV-vis spectroscopy. They also both induce negative helicity (Figure 2-15)
of the porphyrin aggregate in CD spectroscopy, consistent with results obtained with

zincated bis-tetraphenyl porphyrin tweezer (ZnTPP—t2).49

64

CH3

   

Mol. CD

 
 

 

 

0 It
1 .' —0.2 equiv ——1 equiv
' ' ., 6 equrv — 7 equrv
— 5 equiv — 3 equiv
-2 4 ‘ — 0.5 equiv
-3 I I I I
375 400 425 450 475

wavelength, nm

Figure 2-14. Induction of helicity into the porphyrin
aggregate (50 (M) with (S)-2-diaminopropane yields
a positive ECCD spectrum

Increase of diamine concentration leads to the gradual enhancement of ECCD

amplitude that leveled off after addition of more than 5 equiv of diamine, probably due to

saturation of the coordination sites of zinc.

Absorbance

20-
15.
10-

5.1

-5 .
-101
-15 1
-20«

 

 

 

390 400 41 0 420 430 440 450 460

wavelength, nm

Figure 2-15. ECCD of ZnTPP-tail with: Magenta - L-Drnithine methyl
amide; Blue - L-Lysine methyl ester at aggregate/substrate ratio 120.1.

65

This consistency in ECCD sign for both the aggregate system and the zincated
bis-tetraphenyl porphyrin tweezer method suggests that the complexation in both systems
occurs through an identical binding mode and similar ECCD active conformation of the
substrate in the formed complex. In every case, the helicity of the chiral assembly can be
retionalized on the basis of steric interaction taking place between the porphyrin and the

two substituents at the asymmetric centre of the chiral substrate.49 Reducing this steric

strain in the complex with (S)—l,2-diaminopropane leads to a clockwise relative
orientation of the porphyrins, and results in a positive ECCD signal. Similarly, the
negative ECCD observed with L-ornithine methyl amide and L-lysine methyl ester is due
to the counterclockwise orientation of the porphyrins induced by steric interaction

between the porphyrin and the carbonyl group.l

    

 

 

—1:0
2 .
—1:0.2
1.8 . .
902MB 1 6 _ —1.0.4
-Ph W 4 —1:°'5
”2 NH? 0 1‘ ' —1:0.6
g 1.2 - —1:0.7
.9 1 -
'6 —1:0.8
. w 0.8 -
Zn-TPP tarl complexed 2 —1:0.9
with L-lysine methyl ester 0-5 - 1.1
0'" ‘ 1:1.1
0.2 -
0 . . '1 .
375 400 425 450 47s

wavelength, nm

 

Figure 2-16. Complexation of porphyrin—tail monomer with L-lysine-methyl ester results
in 12 nm red shift upon formation of 1:1 complex.

66

The next step was to look into the type of porphyrin aggregate being formed (H-
or J-aggregate). Experiments to grow crystals of the complex for X-ray crystallography
were unsuccessful, probably because of the flexibility of the oligomeric tail. However, it
is possible to analyze the change in the absorption of monomeric complexes upon
aggregation because, the absorption of the porphyrin-amine complex should be altered if
porphyrin aggregates are formed. Formation of aggregate can either contribute positively
to a shift of the Soret band of the complex (J-type) or negatively, i.e. induce a blue shift

of the Soret band of the aggregate upon H-aggregation.

It is well known that coordination of an amine with a metalloporphyrin induces a
red shift in the Soret band.49 In addition, complexation of bis-porphyrin tweezer with
diamines results in the formation of a 1:1 complex at equimolar ratio of diamine to

porphyrin tweezer. For example, complexation of ZnTPP to a monoamine results in a 12

nm bathochromic shift of 3» indicating the formation of a 1:1 porphyrinzamine

max’

complex.

Addition of L-lysine methyl ester to the monomeric Zn-TPP tail (at 5 11M, no
aggregate) leads to the formtion of new complexed species that absorbs at 427 nm, a 12
nm shift from the Soret band of the free porphyrin. This shift corresponds to the

formation of a 1:1 porphyrin-amine complex (Figure 2-16).

Complexation of ZnTPP—tail aggregate with 0.1 equivalents of L-lysine methyl
ester in methylcyclohexane gives rise to a single new transition at 421 nm and the
disappearance of the blue shifted absorption absorption of the H-aggregate at 412 nm.

The overall 9 nm shift of the H—transition is in agreement with formation of monomeric

67

porphyrin-diamine 2:1 complex reported for the bis-porphyrin systems.| Moreover,
presence of a single band refers to equilibration of both H- and J-aggregates in one chiral
superstructure that is blue shifted with respect to the monomeric complex. Since the
formation of H-aggregates is accompanied by a blue shift in the Soret band, we can
identify the geometry of the formed chiral aggregate as face-to-face H-aggregate. (Figure

2-17)

complex H-aggregate

902Me
HZNWNHg

Absorbance

    

375 400 425 450 475
wavelength, nm

Figure 2-17. Complexation of the ZnTPP-tail aggregates (H- and J-) with L-lysine methyl
ester in methylcyclohexane results in the equilibration of a single UV-vis transition A) Teal —
porphyrin aggregate, Brown - aggregate with 0.2 equiv of diamine (421 nm); Blue —
aggregate with 1 equiv of diamine (423 nm); B) Pictorial representation of the H-aggregate-
diamine complex formed in solution.

However, when the Zn—TPP porphyrin system was applied to the study of
monoamines, they were ECCD silent. This could be due to the porphyrin aggregate

falling apart upon the amine binding to the metal and in the proCess, disrupting the rt-rt-

68

stacking interaction, and the hydrophilic interaction not being strong enough to keep the

  

20

Figure 2-18. Zn-2H-bis-tail porphyrin

aggregate. In the case of diamines, the second
amine can still coordinate to the zinc of the
maintain the

second porphyrin and

bisporphyrin tweezer-like system.

In order to solve this problem, bis-tail
porphyrin (Figure 2-18) was proposed as a
solution, where a second hydrophilic tail was

introduced in order to keep the aggregate from

falling apart. Absence of aromatic rings at positions 10 and 20 in the porphyrin will

reduce the steric interaction between the plane of the porphyrin rings, thus strengthening

the its-It stacking. The first approach to the synthesis of this porphyrin was that of acid

catalyzed 2+2 condensation as shown in Scheme 2-1.

 

 

O H
H CH0 H : POCI3, DMF, 0°C 0 H HN \
N 1. TFA, 90°C I N 30min H l N "
U + 2_ NaOH 7 / 46% DCM, reflux 2h 7 /
COZMe 800/0
0 O
MeO MeO
2
1 n-PrNHZ, Zn(OAc)2
+

 

EtOH, reflux 16h
59%

/
MeOzC 0 w 0 COQMe
3

Scheme 2-1: Synthesis of porphyrin 3 via 2+2 condensation.

69

Condensation of terepthaldehydic acid methyl ester in neat excess pyrrole yielded

dipyrromethane 1. This was purified by column chromatography as a white solid.

Vilsmeier-Haack formylation of this dipyrromethane with excess POCl3/DMF in

dichloromethane followed by hydrolysis with aqueous KZCO3 resulted in the

diformyldipyrromethane 2 in 46% yield. A [2+2] condensation of 1 and 2 with propyl
amine, in the presence of zinc acetate yielded dimethylester-porphyrin 3, which was
isolated using column chromatograhy as a purple solid in 59% yield. This was then
hydrolyzed to the di-carboxylic acid under basic conditions. After the reaction mixture
was refluxed overnight in NaOH solution, it was acidified with 6N hydrochloric acid and
extracted with methylene chloride. Unfortunately at this stage, the di-acid was extremely

soluble in water and it was impossible to extract it from the aqueous phase.

In order to circumvent this issue, we decided to put on the oxygenated tail first to

avoid the hydrolysis step. This was done as described below.

H HN \ O
I 2M NaOH, THF I EDCI, DMAP, DCM / | 050);
= > N
reflux, 16h O 16 h H
95% H01» )5 ' HN \
O __
HO

N \
O
MeO
1 4 5

\ZI
\ZI

 

 

Scheme 2-2. Synthesis of dipyrromethane ester 5

Dipyrromethane 1 was hydrolyzed to carboxylic acid 4 under basic conditions.
After the reaction mixture was refluxed overnight, it was acidified with 6N hydrochloric

acid and extracted with methylene chloride as a brown oil. The oxygenated tail was then

70

introduced by EDCI coupling of the carboxylic acid with triethylene glycol to give the

triethylene glycol dipyrromethane ester 5.

 

O O
O
1] l 01V 1‘3 POCI3, DMF, 0°C H / ( ofVO)
30 min N 3
H 4 O H
HN_\ DCM, reflux 2h HN \
54% _
H
5 0

Scheme 2-3. Vilesemeier —Hack formylation of dipyrromethane 5 to
diformyldipyrromethane ester 6

Vilsmeier-Haack reaction with excess POCl3/DMF was then employed to
introduce the di-aldehydes, forming the diformyldipyrromethane ester 6. This was then

coupled with 5 in a 2+2 coupling reaction to give the bis—tail porphyrin 7.

 

 

O
O
/ l O(\/ l
N 3
H
HN \
_ 5
D'PI'NHQ, Zn(OAC)2
+ EtOH, reflux16h T
O 10%
H O
/ ‘ 01V )\
o N 3
H
HN \
H
O 6

Scheme 2-4. 2+2 condensation of 5 and 6 to give bis-tail porphyrin 7.

Porphyrin 7 was isolated from a mixture of several side products as a purple solid using

column chromatography, and was used for UVN is and CD studies.

71

UV/V is and CD studies

We first carried out a solvent study to identify the best solvent suitable for

aggregation of the porphyrin. Titration of the porphyrin was done at room temperature

using various HPLC grade solvents (CHZCIZ, hexanes, methylcyclohexane), in a 1 mm

UV cell. At lower temperatures, the porphyrin precipitates out of solution. For detection

of the aggregation process, 1 mM porphyrin solution is added in 1 (LL portions into a 1

mm UV cell containg the solvent of choice. After addition of the first portion (C = 5 x

10'6 M), the Amax of the Soret band of the monomeric porphyrin is measured as follows:

dichloromethane: km, = 408 nm, methylcyclohexane Am, = 408 nm, hexane: Am, = 408

nm. Addition of the porphyrin is continued until aggregation is observed.

 

 

NM
3.5 ‘ 3uM
— SUM
—— 7uM
'"'—- 9uM
lluM
13uM
15uM
— 17uM
19uM
‘ ZluM
‘—‘ 23uM
— 25uM
‘ — 27uM
350 370 390 410 430 450 —- 2911M

 

 

 

 

 

 

wavelength

Figure 2-19. UVNis of porphyrin 7 in dichloromethane
at room temperature. Aggregation of porphyrin starts at
25 11M (dark blue curve).

Dichloromethane was
found to be the best solvent
for the aggregation of the
porphyrin (Figure 2-19). It is

a well-documented fact”'3451

that aggregation of
porphyrins is typically
accompanied by the splitting,
hypochromicity, and

broadening of the soret band.

As can be seen from the UV titration curve (Figure 2-19), the porpyrin begins to

aggregate at around 27 11M concentration, to form a mixture of both H- and J- aggregates

72

(lack of a significant blue or red shift in the soret band). Increasing the concentration

leads to a split in the Soret band (Figure 2-22, yellow curve).

absorbance

 

wavelength (nm)

Figure 2-20. UVNis of porphyrin 7 in hexane. Titration from
1 (1M (blue curve) until 65 BM (pink curve). Increasing the
concentration beyond 65 (M does not result in aggregation.

In the case of hexane, aggregation is not observed even at high porphyrin
concentration (Figure 2-20). Methylcylohexane behaves in a similar manner to hexane,

failing to promote aggregation.

After identifying the concentration at which aggregation is achieved, the next
thing to do was a binding study of amines. We first studies chiral diamines in order to

investigate their behaviour with the aggregate system.

For the UV-vis studies, a 30 11M porphyrin solution in dichloromethane is added
into a 1 mM UV cell. Upon addition of the first two equivalents of (IR, 2R)-
cyclohexyldiamine, both the H— and J-aggregates get transformed into one assembly with

transition at 417 nm (Figure 2-21).

73

J-aggregate

  

 

 

 

 

 

 

 

412 nm Chiral aggregate
417 nm
3-5 ‘ H-aggregate
403 nm

3 .

2.5 ‘ . . _
-— 1.5 equrv diamine

2 ‘ _1 equiv diamine
1.5 4 0.5 equiv diamine

1 1 -— porphyrin aggregate
0.5 1

0 T g

350 400 450

"VOW (MI)

Figure 21. UV-vis titration of porphyrin aggregate 7 (light blue curve) with (1R.
2R)—cyclohexyldiamine. Addition of 1 equiv of amine in dichloromethane results in
formation of red-shifted complex with absorption at 420 nm (30 11M, pink curve).

ECCD studies were therefore done with 30 uM ZnTPP-bis tail solution in
dichloromethane. Upon addition of (IR, 2R)-cyclohexyldiamine to the preformed

aggregate of porphyrin 7, chiral induction is observed at porphyrin/substrate ratio 1:0.5 as

a negativECCD curve (Figure 2-22).

O“\NH2

.a
&
O

absorbance
O

L 1'6
0 O
1 J

6:
o

 

 

60
o

350 400 450
wavelength (nm)

Figure 2-22. ECCD of ZnTPP-bistail with (1 R,2R)—
cyclohexyldiamine at aggregate/substrate ratio 1:0.5

74

Both L-Lysine methyl ester and (R)-2-diaminopropane cause a similar transformation of
the J- and H-species into a single assembly absorbing at 419 run when subjected to UV-
vis spectroscopy. They also induce a negative helicity of the porphyrin aggregate in CD

spectroscopy.

Binding studies for chiral monoamines was done by titrating (S)-1-
cyclohexylpropan-l-amine (Figure 2-23) as well as (S)-Methyl-benzylamine (Figure 2-
24), against the aggregate (29 11M). Both amines are able to bind to the aggregate

system, inducing a red shift in the Soret band.

 

 

 

 

 

— 2911M porphyrin
3'5 with 0.5uM amine
—with 1uM amine
3 l —with SuM amine
2.5 —with 10uM amine
with 15uM amine
8 2 , ”‘r with 20uM amine
5 with 25uM amine
$1.5 . —with 30uM amine
g - -- with 35uM amine
1 . —with 40uM amine
—-with 45uM amine
0.5 —with 50uM amine
—with 55uM amine
0 ' —with 60uM amine
350 370 430 450

390 410
wavelength (nm)

Figure 2-23. UV-vis titration of porphyrin aggregate 7 with (S)—cyclohexylpropane-1-
amine in dichloromethane. Addition of amine to the aggregate results in formation of
red-shifted complex.

75

It is clear from Figure 2-24 that upon addition of amine, both H- and J-aggregates
get transformed into one assembly with transition at 417 nm This could indicate the
formation of a new assembly.

J-aggregate .
412 nm Chiral aggregate
4

  

 

 

 

 

 

 

 

3 g 17 nm
H-aggregate
2-5 ‘ 403nm
8 2 1
: Zeq amine
g 1.5 1 “1eqamine
.9 1 , porphyrin aggregate
a
0.5 1
o ”T “ . .
350 400 450
wavelength (nm)

Figure 2-24. UV-vis titration of porphyrin aggregate 7 (yellow curve) with (8)-Methyl-
benzylamine. Addition of 1 equiv of amine in dichloromethane results in formation of

red-shifted complex with absorption at 419 nm (30 (M, pink curve).

76

Table 2-1. ECCD study of chiral monoamines with porphyrin 7

 

entry amine amplitude

1 ©ANH2 +5
2 ©/\NH2 '6

H2N Et

1;:1
4 O/\NH2 -5

 

5 \/i\,NH2 -3
6 >4.
NH2 '4

 

Data obtained in dichloromethane at 29 uM porphyrin concentration,

at 25°C. Data reported for porphyrin:substrate ratio 1:2

Table 2-1 shows the ECCD results obtained with a number of monoamines. This
was done at room temperature, for reasons discussed above, using dichloromethane at 29
11M porphyrin concentration. The titration of the amines was done starting at 1:1
equivalent of porphyrin to amine, and increasing the concentration of amine, until the

concentration where the aggregate was disassembled, as evident by UV-vis spectroscopy.

77

The monoamines follow a trend where (S) enantiomers result in a negative
ECCD. However, it is noteworthy that all of the ECCD signals obtained are not the
typical smooth ECCD bisignate curves as shown in a representative spectrum for (8)-l-

amino-2-ethylnaphthalene. (Figure 2-25)

30 ~ H2N Et

2° ‘ 0C
10 ‘

mol. CD
8

 

25uM amine

 

 

410 420 430 440 450

wavelength (nm)

Figure 2-25. ECCD spectrum of (8)-1-amino-2-ethylnaphthalene with
porphyrin 7. Negative signal is obtained at porphyrinzsubstrate ratio
of 1:1.

This could be due to the different possible conformations in solution upon binding
of the amines due to the free rotation about the coordination Zn-N (N of bound amine)

bond (Figure 2-26).

78

    

tail tail tail tail tail tail tail tail

Figure 2-26. Possible different conformations upon binding of the amines to the porphyrins.
A) sliding of the aggregate towards the smaller group (H), results in a negative ECCD signal.
B) sliding of the aggregate towards the largd group (phenyl) results in a clockwise orientation
of the dipole moments, resulting in a positive ECCD signal.

For ECCD to be observed in the porphyrin tweezer method, steric interaction
takes place between the porphyrin facing the chiral carbon and the two substituents at the
asymmetric centre. In order to alleviate this strain the porphyrin slides away from the
larger substituent towards the smaller substituent. The helical twist thus induced leads to

ECCD signal.

/‘

HZN

Figure 2-27. Induction of chiral twist by R enantiomer inducing a
clockwise chiral twist

79

For example, in order to obtain the positive ECCD spectra for the (R)-
enantiomers, once the amine binds to one of the porphyrins, the neighbouring porphyrin
will twist away from the large group towards the small group inducing a chiral twist

(Figure 2-27) resulting in the observed positive ECCD spectrum.

Ph In an attempt to further investigate

this, porphyrin 8 was proposed as the next

chromophoric host for aggregation studies.
Ph Here, phenyl groups are introduced at

positions 10 and 20 of the porphyrin that

/O\/\O/\/O\/\O 0

could serve to increase steric

\O/\/O\/\O/\/O o

differentiation, but even more important,

Figure 2-28. ZnTPP-bis tail porphyrin
because of increased rt-u: interactions
between the introduced phenyl rings, this could lead to increased ability of the porphyrin

to aggregate, which could help stabilize one conformation over the other, hence improve

the quality of the ECCD signals obtained.

The condensation of an aldehyde with a dipyrromethane that has a sterically
unhindered aryl substituent at the 5-position usually results in very low yield and a
mixture of porphyrin products as a result of scrambling. Rao et al. published a procedure

for the efficient synthesis of monoacyl dipyrromethanes and used them to prepare
sterically unhindered trans-porphyrins (Scheme 2—5).52 The initial approach was to use

this procedure towards the synthesis of porphyrin 8.

8O

A
/
self \ NH HN / reduction

> B >
condensation OH

 

A

monoacylation M
x /
2 \ N HN

 

 

 

Scheme 2-5. Retro-synthesis of monoacyl dipyrromethanes

Thioester 9 was readily prepared in high yield by condensation of benzoyl
chloride with 2-mercaptopyridine. Treatment of dipyrromethane 5 at 1M with 2.5 eq
EtMgBr was followed by addition of thioester in THF. This resulted in a product mixture
that composed primarily of monoacyl dipyrromethane 10, and unreacted dipyrromethane
5. The product was eluted from a silica column with CHzClz/EtOAc, 25:1, as a brown
oil. The dipyrromethane was then subjected to reduction conditions using NaBH4
(dashed box), in a mixture of methanol and THF. However, instead of obtaining the
desired carbinol, decomposition products were obtained, and these could not be separated

for characterization.

81

i

 

O DCMrt O 1:)
etc» + C - (:48

 

 

 

o o / 0
O('\’Og 1. EtMgBr,THF; Ph Nl O('\/Ol
. r H
5 2. 9, 411,153/o HN: 1o 3
--------------------------------------------------- Ho /0 l 5 -
(V015 NaBl-(i4 4 Ph ”1 o(\,o)
Me10H§T131= HN \ 3 '

 

------_ ..................................................................................................

Scheme 2-6. Synthesis of monoacyl dipyrromethane 10

As a result, this route was abandoned and instead, the condensation procedure was

applied (Scheme 2-7).

COzMe

0

002MB
benzaldehyde, BF3°OEt2
p-chloranil DCM, 7%

 

Ph

2122/

002MB
Scheme 2-7. Synthesis of bis-methyl ester porphyrin 11

82

Condensation of dipyrromethane 5 and benzaldehyde was carried out in CHZCIZ,
catalyzed by BF3'OEt2, and dimethylester porphyrin 11 was isolated using column
chromatography as a purple solid (Scheme 2-7). This was then hydrolyzed to the di-acid

12 under basic conditions, which was then subjected to EDCI coupling with triethylene

glycol to yield the desired bis—tail porphyrin 13 (Scheme 2-8).

2M NaOH, THF

reflux, 16h w
72%

 

 

EDCI, DMAP. DCM
HONOwONO\ v
Zn(DAc)2
rt, 16h, 30%

‘

 

Scheme 2-8. Synthesis of bis-tail porphyrin 13

83

UV/V is and CD studies

As with porphyrin 7, we first carried out a solvent study to identify the best
solvent suitable for aggregation of the porphyrin. The titration of the porphyrin was done
at room temperature in various HPLC grade solvents (CHZCIZ, hexane, methyl
cyclohexane), in a 1 mm UV cell. At lower temperatures, the porphyrin precipitates out
of solution. The best solvent for aggregation of this porphyrin was found to be hexane.
As can be seen from the UV-vis titration curve, (Figure 2-29) the porphyrin is aggregated
at M concentrations, and also forms a mixture of both H- and J-aggregates with Am”
425 and 432 respectively. It is worth noting that the monomeric porphyrin corresponding
to non-aggregated porphyrin is not observed even at concentrations less than 3 11M. This
is because of the presence of the incorporated phenyl rings, which help to improve the it-

:t interactions, hence improve the porphyrins’ aggregation properties.

 

 

0.5 ‘
--3.SuM
8 0'4 --7.1uM
10uM
1: .
'E 0'3 —14uM
-——17uM
E 0'2 " —21uM
' —25uM
0'1 ‘ —28uM
0 ..
-0.1 I I v r 1
375 395 415 435 455 475

wavelength

Figure 2-29. UVNis titration curve of porphyrin 13

84

Binding studies for ECCD analysis were then carried out using (S)-amino-2-
methyl—phenyl amine. As was the case for porphyrin 7, the chiral amine was able to bind
with the aggregate of porphyrin 13. Having verified the binding of the amine, CD studies
were then carried out in hexane, and at room temperature. The CD studies were carried
out on the same substrates as those in Table 2-1. However, only one substrate (S-l-

amino-2-ethylnaphthalene) showed an ECCD signal with amplitude, A = + 40.

The fact that this porphyrin works worse than porphyrin 7 could be attributed to
the presence of the phenyl groups at positions 10 and 20. These phenyls could be
increasing the :t-n: stacking of the porphyrin, making it aggregate much more as
evidenced by the UV-vis data. Because of this, it is harder for the monoamines to disrupt
this aggregation to induce helicity. It is possible that in the case of entry 3, the
naphthalene is able to have it-tr interactions with the porphyrin, hence compensate for the
disruption of the 71-11: stacking. However, this compensation is still not sufficient and can

be seen in the drop

in amplitude.

In order to
chiral amine solve these

problems, we

wanted to use a

0 05/0); 0 0&0); different approach

14

 

in generating the

Scheme 2-9. Formation of chiral salt upon addition of (8)-1- helrcal aggregates.

amino-Z-ethylnaphthalene to porphyrin 14.

85

This approach is to induce the asymmetry from a point external to the face of the
porphyrin ring. With this idea in mind, porphyrin 14 was designed, where upon addition
of a chiral amine should result in the formation of a chiral salt at the periphery of the
aggregate, and hence, it should not interfere with the aggregate assembly (Scheme 2-9).
Prediction of the ECCD spectra for this assembly is more difficult, and testing of the
system with a variety of chiral amines should lead to a better understanding of the

important elements in the induction of helicity within the aggregate.

The synthesis of this porphyrin started from di-carboxylic acid 12, which was
encountered during synthesis of porphyrin l3. EDCI coupling with 1.2 equivalents of
triethylene
glycol resulted

in formation of

EDCI, DMAP, DCM
triethylene glycol

both the bis-tail

 

151213.09? porphyrin 13, as
well as the
O
0 01V lg desired mono-
12 14
tail porphyrin
Scheme 2-10. Synthesis of mono-tail porphyrin 14. 14. These were

separated, by

column chromatography.

Aggregation studies were done in various HPLC grade solvents including
CHZCIZ, hexane, ethanol, ethanolzwater at various ratios, water, toluene, petroleum ether

and acetonitrile. However, there was no aggregation or amine binding observed in these

86

solvents. As expected, no ECCD spectrum was observed with any amine when the

porphyrin was subjected to CD studies (due to a lack of aggregation).

Unfortunately, it appears that when the chiral salt is formed upon addition of the
amines, there is electrostatic repulsion between the charged species that would be brought
close together by aggregation, as seen by the lack of aggregation detected in UV-vis. In
order to avoid this scenario, we then decided to introduce a covalent bond. This would
require derivatization of the amines onto the porphyrin, forming either an imine (Scheme

2-1 I), or an amide bond (Scheme 2-13).

 

 

o ofvolg o ofvolg

Scheme 2-11. Proposed structure of chiral amide porhyrin

Synthesis of the porphyrin for derivatization begun with the DIBAL reduction of
methyl ester 1 to alcohol 15 (Scheme 2-12). This resulted in formation of the desired
product as well as recovery of the starting ester. The alcohol was isolated from column
chromatography as a brown oil. This was then reacted with di-aldehyde 6 to give
porphyrin 16, which was purifed using column chromatography and obtained as a purple

solid. However, attempts to carry out PCC oxidation of 16, led to a decomposition of the

87

starting alcohol to unidenfiable products, and without any recovery of starting material.
To avoid using oxidation, we went back to a porphyrin that we had encountered before,
porphyrin 14. We decided to do an EDCI mediated coupling of this porphyrin with the
amine, to form the amide. This was not the original method of choice because it requires
coupling of every amide with the porphyrin, which is extra chemistry and wasteful of the
porphyrin, but in order to investigate whether the system would be ECCD active, we tried

it nonetheless with one chiral amine. This is shown in Scheme 2-13.

 

 

OMe DH

\ DIBAL-H, ether ‘ \
I N ‘ 35°/o I N .

H HN / 1 H HN , 15 HO

O C, C
01" 3
o /N\ + 15 PrNH2 EtOH : Ph Ph

H HHN \ reflux, 16h10%

HO 6 0
(Ofioo 16

Scheme 2-12. Synthesis of porphyrin 16.

EDCI coupling was carried out using 14, and (S)-1-amino-2-methylnaphthalene,

resulting in 17, in moderate yield.

88

HOO ONH

 

O O
m EDCI, DMAP, DCM w
Ph Ph = Ph Ph
H2N
0 16h, rt, 38% O

. M .. 01”)
3 3
1 4 1 7

Scheme 2-13. EDCI coupling of (S)-1-amino-2-methylnaphthalene with
porphyrin l4.
Aggregation studies were done in various HPLC grade solvents including
dicloromethane, hexane and methylcyclohexane. Unfortunately, there was no
aggregation observed for this system in all the solvents, and when it was subjected to CD

studies, it was also ECCD silent.

From these studies, it seems that having the chiral groups at the periphery is not
aiding with the aggregation process, and might even be interfering with it. So we should
revert back to binding at the zinc in the porphyrin, but with some improvements in the
porphyrin design. For example, since it seems that having phenyl groups in the system
seems to interfere with induction of helicity, we can design a new porphyrin without any
phenyl groups like that shown in Figure 2-30. This should improve its ability for

induction of chirality due to decreased it—rr stacking.

89

 

Figure 2-30. Proposed porphyrin
structure for aggregation.

However, due to lack of time, efforts to use

90

porphyrin aggregates as reporters of
chirality were stopped. However,
considering the interesting and promising
results obtained, perhaps more time spent

on this idea is worthwhile.

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Takeuchi, M.; Tanaka, S.; Shinkai, S. "On the influence of porphyrin pi-pi
stacking on supramolecular chirality created in the porphyrin-based twisted tape
structure" Chemical Communications 2005, 5539-5541.

Yin, C. X.; Tan, X. L.; Mullen, K.; Stryker, J. M.; Gray, M. R. "Associative pi-pi
interactions of condensed aromatic compounds with vanadyl or nickel porphyrin
complexes are not observed in the organic phase" Energy & Fuels 2008, 22,
2465-2469.

Nakanishi, K. B. W., R. W. "Circular Dichroism, Principles and Application"
New-York 1994.

Zhou, R; Zhao, N.; Rele, D. N .; Berova, N.; Nakanishi, K. "A CHIROPTICAL
CHEMICAL STRATEGY FOR CONFIGURATIONAL ASSIGNMENTS OF
ACYCLIC 1,3-SKIPPED POLYOLS - MODEL l,2,4,6-TETROLS" Journal of
the American Chemical Society 1993, 115, 9313-9314.

Tanasova, M. PhD Thesis 2008.

Huang, X. F.; Rickman, B. H.; Borhan, B.; Berova, N.; Nakanishi, K. "Zinc
porphyrin tweezer in host-guest complexation: Determination of absolute
configurations of diamines, amino acids, and amino alcohols by circular
dichroism" Journal of the American Chemical Society 1998, 120, 6185-6186.
Kuhn, H. K., C.; Kobayashi, T., "J-Aggregates" 1996, Chapter 1.

Mosinger, J .; Janoskova, M.; Lang, K.; Kubat, P. "Light-induced aggregation of

cationic porphyrins" Journal of Photochemistry and Photobiology a-Chemistry
2006, 181, 283-289.

94

(52) Rao, P. D.; Littler, B. J.; Geier, G. R.; Lindsey, J. S. "Efficient synthesis of
monoacyl dipyrromethanes and their use in the preparation of sterically
unhindered trans-porphyrins" Journal of Organic Chemistry 2000,65, 1084-1092.

95

Materials and Methods
A. General Procedures

Anhydrous CHZCI2 was dried over CaH2 and distilled. The solvents used for CD and UV
measurements were purchased from Aldrich and were spectra grade. Column
chromatography was performed using silica gel (230-400 mesh). lHNMR spectra were
obtained on Varian Inova 300 MHz or 500 MHz instruments and are reported in parts per
million (ppm) relative to the solvent resonances (d), with coupling constants (J) in Hertz
(Hz). UV/Vis spectra were recorded on a Perkin-Elmer Lambda 4O spectrophotometer,
and are reported as hm, [nm]. CD spectra were recorded on a Jasco J-810
spectropolarimeter, equipped with a temperature controller (Neslab 111.) for temperature

studies, and is reported as 1» [nm] (Acmax [mol’1 cm"]).

General procedure for UV-vis and CD measurement: All the UV-vis and CD spectra
were taken with uM solution of porphyrin tweezer in methylcyclohexane, hexane or
methylene chloride. The UV-vis and CD spectra were carried out in 1 mm cells of 240

ML. The CD spectra were measured in millidegrees and normalized to Ae/K [nm] units.

96

B. Synthesis of Compounds

1. Synthesis of 3

 

H COZMG
N
<\ /;
1
CHO
2

3

Terephthalaldehydic acid methyl ester 2 (4g, 0.0244 mol) was dissolved in
pyrrole l (72 mL) and heated to 50°C after which the heating source was removed and
TFA (0.6 mL, 1 mmol) was added. The temperature of the mixture increased to 80°C.
This was left stirring for 15 min, then cooled to room temperature and quenched with 2M
NaOH, (10 mL) and EtOAc (200 mL). The organic layer was extracted with ethyl
acetate, washed with water, and dried with anhydrous NaZSO4. The solvent was removed
under reduced pressure after which the residue was transferred into a silica gel column
and eluted with a solution of CHzClz/Hexanes 4:1 to give the desired product 3 as a white

solid in 62% yield.
Rf (CHzClz/Hex 4: 1) = 2.4; m.p.= 155°C

1H NMR (CDCl3, 300 MHz,): 6 4.03 (s, 3H), 5.51 (s, 1H), 5.87—5.86 (m, 2H), 6.14 (m,
2H) 6.71-6.69 (m, 2H), 7.26 (d, 2H, J=8.1 Hz), 7.96 (d, 2H, J = 8.1 Hz), 7.97-7.94 (5, br,
2H (NH). 13C NMR (CDCI3): 5 44.4, 52.4, 107.7, 108.8, 117.8, 128.7, 129.1, 130.2,

131.8,147.5,167.1

GC/MS: M+ = 280 (obs), 280 (calc)

97

2. Synthesis of 4

 

Freshly distilled POCl3 (1.27 g, 0.054 mmol) was added dropwise to DMF (15
mL) in a 250 mL three necked flask at 0°C, under nitrogen. This was stirred for 30 min
before adding methyl 4—(di(1 H—pyrrol-2-yl)methyl)benzoate 3 (2.2 g, 8.8 mmol)
dissolved in CHZCl2 (150 mL). The ice bath was removed and the mixture was refluxed
for 2 h after which it was poured into water, followed by slow addition of KZCO3 until a
pH > 11 was reached. After 1 h, additional KZCO3 (10 mL) was added and the mixture
was left stirring overnight. The organic phase was separated, and the aqueous phase was
extracted twice with CHZClz. The combined organic phases were washed several times
with water, dried and evarporated to dryness. After flash silica gel chromatography, the

product was isolated as a brown oil.

R{ (40% EtzOH/Hex) = 0.5; 1H NMR (CDC13,300 MHz,): 6 3.88 (s, 3H), 5.6.1 (5, 1H),
6.00-6.01 (m, 2H), 6.83-6.85 (m, 2H), 7.35 (d, 2H, J = 8.4 Hz), 7.98 (d, 2H, J = 8.1 Hz),
9.14 (s, .1H), 10.57 (5, br, 2H). 13C NMR (CDC13): 6 44.61, 52.4, 112.0, 112.4, 128.8,

129.8, 130.5,133.0,140.9,144.4, 1668,1793

GC/MS: M+ = 336 (obs), 336 (calc)

98

 

3. Synthesis of 5

O OMe

 

o 0Me5

Methyl 4—(di(l H—pyrrol-2-yl)methyl)benzoate 3 (833 mg, 2.97 mmol) was added
to a stirred mixture of methyl 4-(bis(5-formyl-1H—pyrrol-2-yl)methyl)benzoate (1 g, 2.9
mmol) and "PrNHz (0.35 g, 6 mmol) in EtOH (29.7 mL). Zn(OAc)2 (1.9 g, 8.9 mmol)
was added in and the reaction was refluxed for 24 h. The reaction mixture was then
cooled, treated twice with THF (100 mL), and stirred vigorously for 20 min at room
temperature and then filtered through a Buchner funnel. The filtrate was concentrated,
dissolved in ether (300 mL), washed first with water and then brine, and dried with
anhydrous NaSO4, and concentrated. After flash silica gel chromatography (50%

CHzClz/Hex), the product was isolated as a purple solid in 59% yield.

Rf (CHzClz) = 0.46; 1H NMR (CDCl3,300 MHz,): 5 4.10 (s, 6H), 8.32 (d, 4H, J = 8.0
Hz), 8.45 (d, 4H, J = 7.7 Hz), 9.0 (d, 4H, J = 4.5 Hz), 9.43 (d, 4H, J = 4.5 Hz), 10.32 (s,

2H).

GC/MS: M+ = 578(obs), 578(calc)

99

4. Synthesis of 6

 

Methyl 4-(di(l H-pyrrol-2-yl)methyl)benzoate 3 (6.9 g, 0.02 mol) was refluxed in
2M NaOH solution (50 mL). The reaction was monitored by TLC, and upon complete
consumption of starting material (5 h), the THF was removed under reduced pressure.
The remaining solution was acidified with 10% HCl solution, and the product extracted
with CHzClz. The organic phase was concentrated to give 4-(di(1H-pyrrol-2-

yl)methyl)benzoic acid 6 as a white solid in quantitative yield.
m.p.= 160°C;

1H NMR (CDCl_,, 300 MHz,): 6 5.70 (s, 1H), 6.04— 6.06 (m, 1H), 6.31—6.32 (m, 1H),
6.87—6.88 (m, 1H), 7.47 (d, 2H, J = 8.1 Hz), 8.19 (8, br, 2H), 8.20 (d, 2H, J = 8.4 Hz).

13C NMR (CDC13): 6 44.3,107.8,108.9,117.8,127.6,128.8,130.8,131.6,148.5, 171.3

GC/MS: M+ = 266 (obs), 266 (calc)

100

5. Synthesis of 7

 

EDCI (0.31 mL, 2.25 mmol), DMAP (305 mg, 2.5 mmol), and triethylene glycol
(0.63 mL, 3.7 mmol) were added to a 100 mL flame dried flask containing 4-(di(1H-
pyrrol-2-yl)methyl)benzoic acid 6 (500 mg, 1.9 mmol) in freshly distilled CHzCl2 (50
mL). This reaction mixture was stirred at room temperature while monitoring by TLC.
Upon completion of the reaction (24 h), the sOlvent was concentrated under reduced
pressure. 2-methoxyethyl 4-(di(1H—pyrrol-2-yl)methyl)benzoate 7 was collected as a

dark brown oil from a silica gel column (20% EtOAc/Hex), in 58% yield,
Rf (20% EtOAc/Hex) = ()4;

1H NMR (CDC13,300 MHz,): 6 3.32 (s, 3H), 348—3 .50 (m 2H), 3.60-3.64 (m, 4H), 3.67—
3.68 (m, 2H), 378—3 .80 (m, 2H), 4.42—4.44 (m, 2H), 5.49 (s, 1H), 5.86 (m, 2H), 6.13 (q,
2H J = 2.5 Hz), 6.67— 6.69 (m, 2H), 7.25 (d, 2H J = 8.0 Hz), 7.96 (d, 2H J = 8.0 Hz),
7.99 3, br, 2H). 13C NMR (CDCI3): 6 44.2, 59.2, 64.3, 69.4, 70.8, 70.8, 70.9, 72.1, 1.07 .7,

108.7,117.7,128.6,129.0,130.2,131.8,147.7,166.5

GC/MS: M+ = 412 (obs), 412 (calc)

101

6. Synthesis of 8

 

Freshly distilled POCl3 (194 mg, 0.63 mmol) was added dropwise to DMF (92 g)
in a 250 mL three necked flask at 0°C , under nitrogen. This was stirred for 30 min before
adding 2—methoxyethyl 4-(di(1H-pyrrol—2-yl)methyl)benzoate 7 (200 mg, 0.4 mmol)
dissolved in CH2C12 (150 mL). The ice bath was removed and the mixture was refluxed
for 2 h. The reaction mixture was poured into water, followed by slow addition of KZCO3
until a pH > 11 was reached. After 1 h, additional KZCO3 was added and the mixture was
left stirring overnight. The organic phase was separated, and the aqueous phase was
extracted twice with CHZCIZ. The combined organic phases were washed several times
with water, dried with anhydrous NaSO4 and evarporated to dryness. After flash silica
gel chromatography (30% CHzClz/EtOAc), 2-methoxyethyl 4—(bis(5-formyl-1H—pyrrol-2-

yl)methyl)benzoate 8 was isolated as a brown oil in 54% yield.

R, (30% CHzClz/EtOAc) = 0.4; 1H NMR (CDC13, 300 MHz,): 6 3.32 (s, 3H), 3.48-3 .51
(m, 2H), 360—3 .68 (m, 8H), 3.78-3.81 (m, 2H), 4.42-4.46 (m, 2H), 5.60 (s, 1H), 5.98—
6.66 (m, 2H), 6.82—6.84 (m, 2H), 7.37 (d, 2H, J = 8.1 Hz), 8.01 (d, 2H, J = 8.4 Hz), 9.13

(s, 2H), 10.77 (3, br, 2H).

GC/MS: M+ =

102

7. Synthesis of 9

Miofloiw

2-Methoxyethyl 4—(di(1H-pyrrol-2-yl)methyl)benzoate 7 (0.44 g, 1.06 mmol) was
added to a stirred mixture of before adding 2-methoxyethyl 4-(bis(5-formyl-lH-pyrrol-Z-
yl)methyl)benzoate 8 (0.5 g, 1.06 mmol) and "PrNH2(0.2 mL, 2.13 mmol) in EtOH (10.7
mL). Zn(OAc)2 (0.7g, 3.2 mmol) was added in and the reaction was refluxed for 24 h.
The reaction mixture was then cooled, treated twice with THF (100 mL), and stirred
vigorously for 20 min at room temperature and then filtered through a Buchner funnel.
The filtrate was concentrated, dissolved in ether (300 mL), washed first with water and
then brine, and dried with anhydrous NaSO4, and concentrated. After flash silica gel

chromatography (EtOAc), the product was isolated as a purple solid in 10% yield.
Rf (EtOAc) = 0.44;

]H NMR (CDC13, 300 MHz,): 6 3.30, (s, 6H), 3.47-3.49 (m, 4H), 3.61—3.63 (m, 4H),
367—3 .69 (m, 4H), 3.76-3.78 (m, 4H), 3.93-3.95 (m, 4H), 4.61—4.63 (m, 4H), 8.31 (dd,
4H J = 2 Hz, 8 Hz), 8.45 (dd, 4H J = 3 Hz, 8 Hz), 9.06 (t, 4H J = 4 Hz), 9.43 (d, 4H J =

4.5 Hz), 10.31 (s,2H).

GC/MS: M+ = 906 (obs), 906 (calc)

103

8. Synthesis of 11

o
\ \
Cl I / )3 I /
HS N Ph 3 N
12 13 11

A solution of benzoyl chloride (5.6 g, 40 mmol) in CHzCl2 (100 mL) was added
over 10 min to a stirred solution of 2-mercaptopyridine (4.44 g, 40 mmol) in CHzCl2 (250
mL). after 1 h, 2M NaOH was added. The organic phase was isolated, washed with
water, and then dried with anhydrous NaSO4 and the solvent removed to afford a yellow
oil. This was dissolved in a minimum amount of EtOAc and precipitated with hexane.
Filtration afforded S—2-pyridyl-4~benzothioate 11 as colorless crystals in 75% yield.

Spectral data of 11 were identical to those reported .43

9. Synthesis of 14

   

7 11

A solution of EtMgBr in THF (2.5 mL of 3M solution in ether) was carefully
added via syringe to a stirred solution of 7 in THF (3.4 mL) under nitrogen. This was
stirred at room temperature for 10 min and then cooled to -78 °C. A solution of 11

(0.643 g) in THF (3.4 mL) was then added over 1 min. The reaction was maintained at -

104

78 °C for 10 min and then the cooling bath was removed. TLC showed complete
consumption of 11 after 4 h. The reaction was quenched with saturated NH4Cl (15 mL),
and poured into CH2C12. The organic phase was washed with water, dried with
anhydrous NaSO4 and concentrated. After flash silica gel chromatography (CHZCl2 to

CHZClz/Hex; 25:1), 14 was isolated as a viscous dark brown oil in 62% yield.
Rf (EtOAc) = 0.4;

1H NMR (CDC13, 300 MHz,): 6 3.32 (s, 3H), 3.49-3.51 (m, 2H), 3.59—3.68 (m, 6H),
3.78—3.81 (m, 2H), 4.42—4.45 (m, 2H), 5.59 (s, 1H), 5.85 (s, 1H), 5.93 (s, 1H), 6.02—6.04
(m, 1H), 6.11—6.14(m, 1H), 6.68-6.70 (m, 2H), 6.77-6.79 (m, 1H), 7.25 (d, 3H J = 7.8
Hz), 7.43 (t, 2H J = 7.5 Hz), 7.51 (d, 1H J = 7.2 Hz), 7.78 (d, 1H J = 7.0 Hz), 7.93—7.97

(m, 2H), 8.29, (br, s,1H), 9.86, (br, s,1H)

GC/MS: M+ = 516.2 (obs), 516 (calc)

10. Synthesis of 16

 

Methyl 4—(di(1 H-pyrrol-2-yl)methyl)benzoate 3 (4 g, 14 mmol), benzaldehyde
(1.6 mL, 1.4 mmol), and BF3'OEt2 (0.45 mL) were stirred in freshly distilled CHzCl2 (1.5

L) for 1 h. p-Chloranil (5.4 g, 14 mmol) was then added in and the reaction was stirred

105

for an additional 1 h at room temperature, after which the solvent was removed under
reduced pressure. After flash silica gel chromatography (50% CHzClz/Hex to CHzClz), 16

was isolated as a purple solid in 7% yield.
R,(CH2C12) = 0.5;

'H NMR (CDCl3, 300 MHz,): 6 -2.72 (3, br, 2H), 4.12 (s, 6H), 7.75—7.77 (m, 6H), 8.23
(d, 4H J = 8.1Hz), 8.32 (d, 4H J = 8.0 Hz), 8.46 (d, 4H J = 8.1 Hz), 8.83 (d, 4H J = 8.0

Hz), 8.91 (d, 4H J = 8.0 Hz)

GC/MS: M" = 730.1(obs), 730(ca1c)

11. Synthesis of 17

 

Eh
co \

0 )NH N“ o
\ ’ \ \ / \ / '1
HO — N HN OH
\‘ / /

Ph 17

Dimethyl ester porphyrin 16 (9.0 g) was refluxed in 2M NaOH solution (60 mL).
Upon complete consumption of the starting material, THF was removed under reduced
pressure and the remaining solution was acidified with 10% HCl solution. The product
was extracted with CHZCIZ, and the organic phase was concentrated to give di-acid

porphyrin 17 as a purple solid in quantitative yield.

1H NMR (DMSO, 300 MHz,): 6 -2.93 (br, s, 2H), 7.85—7.87 (m, 6H), 8.41 (d, 4H J = 8.0

Hz), 8.36 (d, 8H J = 8.1Hz), 8.86 (s, SH)

106

GC/MS: M“ = 702.1 (obs), 702(calc)

12. Synthesis of 19

 

EDCI (0.62 mL, 450 mmol), DMAP (610 mg, 5.0 mmol), and triethylene glycol
(1.26 mL, 7.4 mmol) were added to a 250 mL flame dried flask containing di-acid
porphyrin 17 (1.0 g, 3.9 mmol) in freshly distilled CH2C12 (100 mL) and stirred at room
temperature. The reaction was monitored by TLC, and upon completion (24 h), the
solvent was removed under reduced pressure. After flash silica gel chromatography (20-
30% EtOAc/Hex), bis-tail 19 was collected as a purple solid from a mixture of

monoalkylated product 20 (10% yield), and starting material in 30% yield.
19: Rf (20% EtOAc/Hex) = 0.4;

1H NMR (CDCI3,300 MHz,): 6 -2.72 (br, s, 2H), 3.43 (s, 6H), 356—3 .58 (m, 4H), 3.69—
3.76 (m, 12H), 380—3 .82 (m, 4H), 396—3 .99 (m, 4H), 4.65—4.68 (m, 4H), 7.80—7.84 (m,
6H), 8.27 (dd, 4H J = 2.4 Hz, 7.8 Hz), 8.36 (d, 2H J = 8.4 Hz), 8.52 (d, 2H J = 8.7 Hz),

8.87 (ddd, 8H J = 4.8Hz, 12.3Hz, 8.4 Hz).

107

GC/MS: M” = 995 .2(obs) , 995(calc)

20: Rf (50% EtOAc/Hex) = 0.2,

1H NMR (CDC13, 300 MHz,): 6 -0.06 (8, br, 2H), 3.37 (s, 3H), 353—3 .76 (m, 6H), 3.82
(m, 2H), 3.97 (t, 2H), 4.66 (t, 2H), 7.72—7.78 (m, 6H), 8.21 (d, 4H), 8.30 (d, 2H), 8.39 (d,

2H), 8.45 (d, 2H), 8.61 (d, 2H), 8.78-8.89 (m, 8H).

GC/MS: M+ = 849 (obs), 848 (calc)

13. Synthesis of 21

O OMe

 

Dibal (1.1 mL, 3.7 mmol) was carefully added via syringe to a cooled solution of
methyl 4—(di(1 H-pyrrol-2-yl)methyl)benzoate 3 (2.5 g, 1.85 mmol) in ether (40 mL) and
left to stir at room temperature for 3 h. After complete consumption of starting material
(from TLC), the reaction was quenched with Roschell’s salt (4 mL) and left to stir until
two distinct layers formed. The organic layer was separated and the remaining aqueous
layer was extracted using ether (2 x 10 mL). The combined organic layers were washed

once with water after which the solvent removed under reduced pressure. After flash

108

silica gel chromatography (20% EtOAc/Hex), 4-(di(1H-pyrrol-2-
yl)methyl)phenyl)methanol 21 was isolated as a brown oil in 35% yield.

Rf (CHZCIZ) = ; 1H NMR (CDC13, 300 MHz,): 6 1.77 (br, s, 1H), 4.82 (s, 2H), 5.62 (s,
1H), 6.04—6.07 (m, 2H), 6.02—6.32 (m, 2H), 6.83—6.85 (m, 2H), 7.35 (d, 2H), 7.45 (d,
2H), 8.11 (br, s, 2H). 13C NMR (CDCl,): 6 43.9, 65.2, 107.4, 108.6, 117.5, 127.5, 128.8,

132.6,]397, 141.9

GC/MS: M+ = 252 (obs), 252 (calc)

14. Synthesis of 23

 

EDCI (3.8 uL, 28 umol), DMAP (3.45 mg, 5.0 28 umol), and (S)-l-amino-2-
methylnaphthalene (1.26 mL, 7.4 mmol) were added to a 250 mL flame dried flask

containing mono-acid porphyrin 20 (8.1 mg, 47 28 umol) in freshly distilled CHZCl2 (10

109

mL). This reaction mixture was stirred at room temperature for 24 h, after which the
solvent was concentrated. After flash silica gel chromatography (20% EtOAc/Hex to

50% EtOAc/Hex), amide porphyrin 23 was collected as a purple solid, in 38% yield,
Rf (50% EtOAC/HCX) = O_4;

1H NMR (CDC13, 300 MHz,): 6 -2.78 (br, s, 2H), 1.99 (d, 3H), 3.41 (s, 3H), 3.60-3.63
(m, 2H), 373—3 .81 (m, 4H), 384—3 .88 (m, 2H), 4.02 (t, 2H), 4.70, (t, 2H), 6.37 (p, 1H),
6.70 (d, 1H), 75—7.63 (m, 2H), 7.70 (dt, 1H), 7.76—7.82 (m, 7H), 7.95 (dd, 2H), 8.16 (d,

2H), 8.21—8.34 (m, 8H), 8.39 (d, 1H), 8.48 (d, 2H), 8.80 (t, 4H), 8.89 (t, 4H)

GC/MS: M+ = 1001.0 (obs), 1001.4 (calc)

110

   

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_ .uA —

...d-n