An Alternate Synthesis of 6A, 6B-Dideoxy6A, 6B-(9,10-Dicyanoanthracenyl-2, 3-Dimethylene)-Cyclodextrin
____________
A Thesis Presented to the Faculty of
The Department of Chemistry at
The College of William and Mary
In Partial Fulfillment of the
Requirements for the Degree of
Bachelor of Science
____________
by
Michael A. Repucci
May 4th, 1998
Approval Sheet
This thesis is submitted in partial fulfillment of
The requirements for the degree of
Bachelor of Science
Michael A. Repucci
Approved May 4th, 1998
_______________________
Christopher J. Abelt, Ph. D.
_________________________
Carey K. Bagdassarian, Ph. D.
______________________
Deborah C. Bebout, Ph. D.
_______________________
Harvey J. Langholtz, Ph. D.
Table of Contents
ACKNOWLEDGEMENTS ........................................................................................................... iv
LIST OF FIGURES .........................................................................................................................v
ABSTRACT ................................................................................................................................... vi
INTRODUCTION..........................................................................................................................2
BACKGROUND ............................................................................................................................3
Cyclodextrins ...................................................................................................................................3
Dess-Martin Periodinane .................................................................................................................7
Dicyanoanthracene ...........................................................................................................................9
The Wittig Reaction .......................................................................................................................10
EXPERIMENTAL .......................................................................................................................15
Dess-Martin Periodinane ...............................................................................................................15
Polyformyl -CD ...........................................................................................................................16
2, 3-Bis(bromomethyl)-9, 10-dicyanoanthracene ..........................................................................16
9, 10-Dicyanoanthracenyl-2, 3-bis(methyltriphenylphosphonium bromide) ................................17
Polyformyl-6A, 6B-dideoxy-6A, 6B-(9,10-dicyanoanthracenyl-2, 3-dimethylene)--CD ..............18
RESULTS AND DISCUSSION ..................................................................................................19
CONCLUSION ............................................................................................................................23
REFERENCES .............................................................................................................................26
VITA..............................................................................................................................................28
iii
Acknowledgements
I would like to sincerely thank Dr. Christopher J. Abelt for having patience with my
irregular schedule and my endless questions, and for his nonchalant approach and witty sense of
humor. I am further indebted to Dr. Deborah C. Bebout, who tolerates my absent mindedness
and frequent interruptions. I would also like to thank Ahmed Hafez for his expert advice and
assistance, and his perpetual facetiousness. I offer my gratitude to Peggy Green for handling my
numerous administrative requests. And I am grateful to all my friends and family who have
always provided stress relief and helped to keep me sane in this insane world.
iv
List of Figures
1. Nomenclature and bonding in cyclodextrin ................................................................................3
2. Supramolecular geometry of cyclodextrin ..................................................................................4
3. Inclusion complex formation and the dissociation constant, Kd .................................................5
4. An example of A, B cap notation of -CD .................................................................................6
5. Photocatalytic cyclodextrin derivatives from the literature ........................................................7
6. The synthesis of DMP .................................................................................................................7
7. Polyformyl cyclodextrin regioisomerism ...................................................................................9
8. 9, 10-Dicyanoanthracene (DCA) ................................................................................................9
9. The fluorescence quenching of 6A, 6D/C-(DCA-2, 6-disulfonyl)--CD ....................................10
10. Phosphonium ylide resonance structure..................................................................................11
11. Preparation of the Wittig reagent ............................................................................................11
12. General mechanism for the Wittig reaction ............................................................................13
13. Tethered and capped DCA--CD ...........................................................................................14
14. The synthesis of 9, 10-dicyano-2, 3-bis(bromomethyl)anthracene ........................................17
15. The oxidation of -CD using 1.5 equivalents of DMP ...........................................................20
16. The synthesis of the bis-phosphonium ylide ...........................................................................21
17. 1H NMR spectrum of polyformyl--CD .................................................................................24
18. 1H NMR spectrum of 2, 3-bis(bromomethyl)-9, 10-dicyanoanthracene ................................25
v
Abstract
6A, 6B-Dideoxy-6A, 6B-(9,10-dicyanoanthracenyl-2, 3-dimethylene)--cyclodextrin was
synthesized via the Wittig reaction of polyformyl -cyclodextrin and the ylide of 9,10dicyanoanthracenyl-2, 3-bis(methyltriphenylphosphonium bromide), followed by reduction with
sodium borohydride. The -cyclodextrin cavity was effectively lengthened as a result of the
perpendicular position of the dicyanoanthracene cap to the primary face of the -cyclodextrin.
The two olefinic bonds of the cap also help to increase the rigidity of the -cyclodextrin. The
resulting molecule contains the oxidative features of dicyanoanthracene in the context of the
stereospecific -cyclodextrin cavity.
vi
An Alternate Synthesis of 6A, 6B-Dideoxy6A, 6B-(9,10-Dicyanoanthracenyl-2, 3-Dimethylene)-Cyclodextrin
Introduction
Catalysts are molecules that are able to increase the rate of reactions, by providing a more
energetically feasible pathway from reactants to products, without being consumed. The use of
catalysts is widespread in chemistry, but few synthetic catalysts demonstrate the efficiency and
specificity of natural catalysts, or enzymes. Therefore much scientific research is aimed at
understanding the mechanisms behind biological enzyme-substrate catalysis. By mimicking
natural systems, researchers have developed many synthetic chemical catalysts whose
applications include drug delivery macromolecules, fermentation methods, and the simplification
of organic synthesis.1
Photocatalysis is a particularly useful methodology for organic chemical synthesis,
allowing scientists to use light, rather than excessive heat that may degrade reactants or products,
to drive particular reactions. Photooxidative catalysis requires the photon-induced excitation of
an acceptor molecule electron from its ground state to an excited state, and subsequent electron
transfer or hydrogen abstraction from a donor molecule, thus leaving the donor oxidized and
returning the acceptor to its ground state. Many photooxidative catalysts are known, including
anthraquinone, benzophenone, and 9,10-dicyanoanthracene (DCA); however, they are often
plagued with inefficiency and a lack of regio- or stereospecificity.1
Cyclodextrins, cyclic oligomers of glucose, participate in regio- and stereospecific
catalysis. Not surprisingly, there are several examples in the literature where photocatalytic
moieties have been attached to cyclodextrins, thus producing photocatalysts with regio- and
stereospecificity.2 The goal of this project is to attach DCA by a relatively simple method to cyclodextrin (-CD), thereby forming a novel regio- and stereospecific photocatalyst, DCA
capped -CD.
2
Background
Cyclodextrins
Villiers first discovered cyclodextrins, also called Schardinger dextrins, cycloamyloses,
or cyclogulcans, in 1891 as byproducts of the action of Bacillus macerans amylase on starch. In
the 1920’s Schardinger developed a detailed method for the preparation and separation of
cyclodextrins, which takes advantage of the differing solubilities of cyclodextrin oligomers,
using organic solvents to induce the selective precipitation or solvation of particular oligomers of
cyclodextrin. With the discovery later in this century that cyclodextrins are able to form
inclusion complexes (i.e. host-guest non-covalent interactions similar to enzyme-substrate
complexes), and act as catalysts that mimic enzymes in their regio- and stereospecificity, interest
in these organic molecules has increased.2 Recent industrial applications are ubiquitous:
everything from the chemistry of food, pharmaceuticals, cosmetics, pesticides, and polymers.3
Cyclodextrins are cyclic oligomers of -(1, 4)-linked D-(+)-glucopyranose units in the
shape of a torus. The preferred chair conformation of glucose is virtually undisturbed in
cyclodextrins. The nomenclature derived for convenience makes reference to the number of
interconnected glucose units; the prefixes , , , and  denote cyclodextrin molecules consisting
OH O
of 6, 7, 8, and 9 glucose units, respectively (see Figure 1).
OH
OH
O
O
HO
O HO
OH
O
O
n = 5 ... -cyclodextrin
HO
OH
O
O
HO
OH
n = 7 ...  -cyclodextrin
HO
O
OH
n = 8 ... -cyclodextrin
OH
-CD
n = 6 ... -cyclodextrin
O
OH
OH
O
OH
HO O
O
GLUCOSEn
OH
HO
O OH
O OH
Figure 1. Nomenclature and bonding in cyclodextrin
3
OH
OH
HO
O
O
Cyclodextrins of fewer than six glucose units are too sterically strained to exist while those
greater than eight units are more challenging to synthetically create and isolate. To date, -, -,
-, and -cyclodextrin have been successfully isolated in good yields.2
The supramolecular geometry of cyclodextrins resembles a truncated cone with two
openings of different diameters (see Figure 2). The smaller opening, or primary face, consists of
primary hydroxyl groups at the C6 position of the glucose, while the secondary face contains
secondary hydroxyls at the C2 and C3 positions. The dimensions of -CD (MW 1135 g/mol) are
6.0 Å and 6.8 Å at the primary and secondary face, respectively, and 8.0 Å in height. The C6
hydroxyls are free to rotate, effectively blocking the opening of the primary face, or readily
substituted with various functionalities. The presence of opposing C-H bonds, hydrogen-bonded
C2 and C3 hydroxyls, and the ether-like oxygens that connect adjacent glucose units, give rise to
a relatively hydrophobic inner cavity. The well-defined size and features of -CD contribute to
its regio- and stereospecificity. As a result, -CD serves as an ideal enzyme model.2
6.0 Å
8.0 Å
6.8 Å
Figure 2. Supramolecular geometry of cyclodextrin
Based on the characteristics of cyclodextrin, it is not surprising that it readily forms
inclusion complexes with virtually any small molecule, usually in a 1:1 ratio. For instance, in
dimethyl sulfoxide (DMSO), -CD forms an inclusion complex with a single water molecule in
which C2 and C3 hydroxyls participate in strong hydrogen bonding, both inter- and
4
intramolecularly. Cyclodextrins are very soluble in water, relatively stable in basic solutions,
but susceptible to hydrolysis in acids. In some instances only one of two enantiomers efficiently
forms an inclusion complex with cyclodextrin, thus permitting a crude, but simple separation of
the D- and L-isomers.2
Dissociation constants (Kd) for cyclodextrin inclusion complexes are often desired, and
must be obtained empirically according to the relationship below (see Figure 3). The most
common empirical method is 1H NMR, which can be used to determine the relative amounts of
the host-guest complex and the dissociated host and guest by integrating the respective peaks.
Other types of spectroscopy have used the same relationship between peak areas to determine
Kd, including 13C NMR, fluorescence intensity, and FTIR.2
+
O
O
O
O
Kd =
Kd
[host][guest]
[host-guest]
Figure 3. Inclusion complex formation and the dissociation constant, Kd
There are two primary classifications for the types of catalysis that cyclodextrins can
perform. Non-covalent catalysis occurs when a molecule forms an inclusion complex with
cyclodextrin, permitting the molecule then to undergo chemical rearrangement that was
otherwise impossible in the surrounding solvent. Covalent catalysis begins with non-covalent
inclusion complex formation, but bond cleavage or rearrangement is coordinated between both
the cyclodextrin host and the guest molecule. If a compound such as pyridine is used in excess
to block the cyclodextrin cavity, the desired inclusion complex fails to associate, and catalysis is
effectively prevented.2
5
Many functional groups can be covalently attached to the cyclodextrin hydroxyl groups,
thereby altering the catalytic properties of the cyclodextrin. In 1994 Breslow and Zhang
developed a cyclodextrin dimer that catalyses the cleavage of phosphate esters.4 The attachment
of substituents by one bond to either the primary or secondary face of cyclodextrin is referred to
as a tether. When a substituent is attached to two points on a face of cyclodextrin, then the
functionality is termed a cap. To date, caps have only been attached to the primary face of
cyclodextrin. Glucose units are consecutively labeled to indicate the points of attachment to the
G
cap (see Figure 4).
A
OH O
OH
O
O
O
HO
O
F
HO
OH
O
OH
O
HO
OH
O
X
HO
O
B
O
OH
OH
HO O
O
OH
E
HO
OH
OH
HO
O OH
O
O
C
O OH
D
Figure 4. An example of A, B cap notation of -CD
The syntheses of numerous photochemically active derivatives of cyclodextrin appear in
the literature. In 1986 Neckers and Paczkowski reported the synthesis of a rose bengal tethered
-CD that has the capability of photooxidizing 1,2-diphenyl-p-dioxenes.5 Six years later, Ye et
al. synthesized a flavin tethered -CD that photocatalyzes the oxidation of substituted benzyl
alcohols to their corresponding aldehydes.6 Then in 1993 Kuroda and coworkers described the
photoreduction of quinones, through electron transfer, by utilizing a cyclodextrin-sandwiched
porphyrin (see Figure 5).7
6
CH3
N
ONa
CH2O2C(CH 2)4CH2O2C
NH
N
H2C
O
N
O
ROSE
BENGAL
PORPHYRIN
O
Figure 5. Photocatalytic cyclodextrin derivatives from the literature
Dess-Martin Periodinane
The Dess-Martin Periodinane (DMP) is a useful reagent for the selective oxidation of
primary and secondary hydroxyls to aldehydes and ketones. The original synthesis of DMP,
unfortunately, gives relatively low yield.8 However, Ireland and Liu have developed a method
that results in pure DMP in excellent yield; the synthesis is outlined below (see Figure 6).9 DMP
is very hygroscopic and therefore must be protected from exposure to atmospheric moisture.
Hydrolysis of DMP occurs readily at room temperature yielding the intermediate seen in figure
six, which the authors caution is explosive similar to trinitrotoluene (TNT), detonating as a result
of excessive heating (>200 ºC) or impact.8, 9
OAc
O
CO2H
I
KBrO3
H2SO4(aq)
O
O
O
I
OH
O
Ac2O
0.5% TsOH
I
OAc
OAc
Figure 6. The synthesis of DMP
Since its development, DMP has found widespread use in the oxidation of alcohols,
thereby virtually replacing the need for chromium (VI) reagents. Dess and Martin studied the
reaction of DMP with many alcohols (benzylic, allylic, or otherwise) and found consistently high
yields for the oxidation of alcohols in the presence of non-hydroxylic functional groups such as
7
sulfides, enol ethers, furans, and secondary amines. The reaction of DMP with a variety of
alcohols is rapid and essentially quantitative at room temperature; acetaldehyde is produced from
excess ethanol, cyclooctanal is afforded in 86% yield from cyclooctanol with 1.15 equivalents
(eq) of DMP, geranial is provided in 84% yield from geraniol with 1.1 eq of DMP, etc. Dess and
Martin site 74 papers that describe useful oxidations by DMP.8
Many researchers have found DMP to be a useful oxidant in the production of synthetic
biomolecules. Hanson and Lindberg report the use of DMP in the production of dipeptide
analogues containing novel ketovinyl functionalities that are useful as mechanism-based enzyme
inhibitors and proteolytically stable peptides.10 In 1988 Danishefsky et al. began using DMP in
the synthesis of enediyne antitumor antibiotics.11 Eight years ago, Robins and coworkers used
DMP for the preparation of ketonucleosides, analogues of the building blocks for DNA.12
DMP also provides a simple method for the oxidation of the primary alcohols of
cyclodextrin in high yield, furnishing formyl cyclodextrin, thereby simplifying the synthesis of
cyclodextrin-based catalysts. The secondary alcohols of cyclodextrins are relatively unreactive
due both to steric hindrance and intramolecular hydrogen bonds between the C2 and C3
hydroxyls, and are therefore unaffected by limited oxidation with DMP.13 The only
complication in the oxidation of cyclodextrins by DMP is that a mixture of regioisomers of
polyformyl cyclodextrin results. The number of regioisomers can be determined from the
equation below, where N is number of glucose molecules in the cyclodextrin, and n is the degree
of oxidation. For example, -CD after one degree of oxidation results in one regioisomer, 6Adeoxy-6A-formyl--CD, and after two degrees of oxidation produces three regioisomers, 6A, 6Bdideoxy-6A, 6B-diformyl--CD, 6A, 6C-dideoxy-6A, 6C-diformyl--CD, and 6A, 6D-dideoxy-6A,
6D-diformyl--CD (see Figure 7).
8
Two Degrees
of Oxidation
One Degree
of Oxidation
D E
C
B
D E
F
G
6A-deoxy6A-formyl-CD
C
Number of
Regioisomers
N = glucose units
n = degree of oxidation
D E
F
G
B
E
F
A
G
C
B
F
G
(N-1)!
(N-n)!n!
6A,
6A,
6B-dideoxy- 6A, 6C-dideoxy- 6A, 6D-dideoxy6B-diformyl- 6A, 6C-diformyl- 6A, 6D-diformyl-CD
-CD
-CD
Figure 7. Polyformyl cyclodextrin regioisomerism
Dicyanoanthracene
As a result of its three-ring aromatic -electron system, DCA is one of many molecules
capable of photoexcitation and subsequent photoinduced electron transfer oxidation reactions
(see Figure 8). For photooxidation to occur, a photosensitive acceptor molecule in solution must
be stimulated by electromagnetic radiation (typically in the UV or visible regions), and
subsequently enable the abstraction of an electron from a nearby donor molecule. In the present
study, the DCA capped -CD acts as the acceptor molecule, and the donor is theoretically the
guest molecule that resides in the cavity of the DCA capped -CD.
CN
CN
Figure 8. 9, 10-Dicyanoanthracene (DCA)
Abelt and coworkers have previously tethered and capped anthraquinone and
benzophenone functionalities to -CD, only to learn that the photoexcited functionalities abstract
hydrogen from the cyclodextrin moiety, effectively quenching the host molecule and rendering it
incapable of oxidizing the guest through electron transfer.14, 15 In 1994 Abelt and coworkers
began working on DCA substituted -CD, since its singlet excited state is much less likely to
9
abstract hydrogen than the triplet excited state of anthraquinone and benzophenone.16 DCA
exhibits a relatively low reduction potential (-0.82 V) and is thus capable of oxidizing a variety
of chemicals.17 Unfortunately it appeared likely from fluorescence quenching studies that the 6A,
6D/C-(DCA-2, 6-disulfonyl)--CD synthesized by Abelt and coworkers in 1994 would exhibit
both complexed (dynamic) and uncomplexed photooxidation, thus reducing the desired
stereospecificity of the compound (see Figure 9).18
Quenching
CN
O2S
CN
SO2
Quenching
Figure 9. The fluorescence quenching of 6A, 6D/C-(DCA-2, 6-disulfonyl)--CD
In hopes of maximizing the amount of dynamic quenching, Abelt and coworkers
synthesized various DCA substituted -CDs that have not yet been analyzed by fluorescence
quenching.19 Recently Abelt and Tan synthesized the same 2, 3-DCA capped -CD described in
this research. However, their method provided insufficient quantities of product, thereby
preventing fluorescence quenching analysis.20
The Wittig Reaction
One of the most convenient ways to introduce a carbon-carbon double bond to a molecule
is through nucleophilic addition to a carbonyl functionality by a phosphorus ylide, followed by
10
elimination, as reported by Wittig and Geissler (the Wittig reaction).21 In its general form, a
phosphorus ylide consists of a phosphorus atom doubly-bonded to an alkyl derivative. The
phosphorus also commonly bears three resonance stabilizing phenyl groups. The reactivity of
the ylide derives from the resonance form containing a carbanion and adjacent phosphonium ion
as shown (see Figure 10).22
P
CHR
P
CHR
Figure 10. Phosphonium ylide resonance structure
Preparation of the phosphonium ylide occurs through the reaction of an alkyl halide and
triphenylphosphine in the presence of potassium-t-butoxide (KOtBu), followed by abstraction of
an -hydrogen with a suitable base (see Figure 11). The base strength required to accomplish
hydrogen abstraction depends on the ability of the alkyl derivative to stabilize charge by
resonance or inductive effects; less stabilized ylides require a stronger base. A less stabilized
ylide is consequently more basic and may react with hydroxyls, water, oxygen, and carbon
dioxide.23 Therefore, the Wittig reaction has not found wide use in carbohydrate chemistry due
to the reactivity of strongly basic ylides with the relatively acidic hydroxyl groups. Solutions to
this problem include the formation of a less basic ylide through resonance or inductive
stabilization, or in the past by protection of the hydroxyl groups.24
Ph3P + BrCH2R
KOtBu
Ph3P
CH2R
BuLi
Br
Figure 11. Preparation of the Wittig reagent
11
Ph3P
CHR
The ylide can be stabilized through the use of conjugating substituents. These
substituents, such as carboxyalkanes, nitriles, and sulfones, help stabilize the carbanion through
resonance electron withdrawal. Less stabilizing substituents, including phenyls and allyls,
provide only semistabilized ylides. With stabilized ylides, the localization of charge on the
carbanion becomes reduced, and thus the general reactivity of the ylide is decreased. Although
the rate of the Wittig reaction is therefore slightly decreased, the ylide-hydroxyl acid-base side
reaction is dramatically reduced.24
The magnitudes of hydroxyl pKa are also important in the reactions of ylides. Hydroxyls
with a high pKa react more slowly with ylides. Sufficiently high carbohydrate pKa values can
often be obtained by using a slightly polar, protic solvent. However, a strongly protic solvent
would inhibit the Wittig reaction through proton-anion interactions, and therefore a slightly
polar, relatively aprotic solvent must be used. Common examples include tetrahydrofuran
(THF), N,N-dimethylformamide (DMF), DMSO, and pyridine. The hydroxyl groups of
cyclodextrins exhibit pKa values on the order of 12 in DMSO and 18 in DMF, thus in these
solvents ylides would be unlikely to condense with the hydroxyl moieties.24, 25
Through the use of semistabilized or stabilized ylides and proper solvents, one is able to
perform Wittig reactions on unprotected carbohydrates without significant side product
formation, and with yields greater than possible when employing conventional methods of
hydroxyl protection through acetylation or otherwise. Several examples of the Wittig reaction on
unprotected carbohydrates exist.26 Work on D-aldohexoses and their derivatives are most
relevant to cyclodextrins. Giannis and Sandhoff have conducted Wittig olefinations of
glucosamine derivatives and unprotected D-glucose and D-galactose, as well as related
compounds.27, 28 Since cyclodextrins exist as macromolecules of -1,4-glucose chains, the
12
reactions of Giannis and Sandhoff answer many of the questions regarding the analogous
reaction with cyclodextrins. Abelt and coworkers have recently used the Wittig reaction with CD successfully.20, 25
Ylide stabilization also effects the stereochemistry of the olefinic bond. As a general
rule, nonstabilized ylides tend to yield cis alkenes, and stabilized or semistabilized ylides favor
trans alkenes. Many studies have examined the formation of the Wittig intermediates which lead
to both cis and trans isomers.
31
P NMR studies of nonstabilized ylides have confirmed the
intermediate formation of oxaphosphetane compounds, while the presence of lithium salts, which
slow the reaction of nonstabilized ylides, appears to encourage the formation of the trans isomer
through phosphorus betaine intermediates.24 Current thinking suggests that for nonstabilized
ylides, the isomerism of the olefinic bond is governed by a kinetic mechanism, which results in
the cis alkene. However, when the Wittig reaction is sufficiently slowed, passing through the
reversible betaine intermediate, thermodynamic mechanisms predominate and typically lead to
the formation of the trans isomer (see Figure 12).23
R3
O
O
PPh3
C
CH
R3
R1
O
PPh3
C
CH
R3
R1
R2
H
R3
R1
C
Ylide
R2
R2
R2
Betaine
Ph3P
CH2R1
Oxaphosphetane
+
O
PPh3
Figure 12. General mechanism for the Wittig reaction
In 1997, Abelt and coworkers used the Wittig reagent 9, 10-dicyanoanthracenyl-2methylenetriphenylphosphonium, to attach the DCA moiety to 6-deoxy-6-formyl--CD. The
olefinic bond of the DCA tethered -CD was shown to be the trans conformation based on NMR
studies.25 Tan later demonstrated that the double Wittig product 6A, 6B-dideoxy-6A, 6B-(9,10-
13
dicyanoanthracenyl-2, 3-dimethylene)--CD could be produced from the reaction of the 9, 10dicyanoanthracenyl-2, 3-bis(methylenetriphenylphosphonium) Wittig reagent and the 6A, 6Bdideoxy-6A, 6B-diformyl--CD synthesized via the Nace reaction (see Figure 13).20
NC
NC
CN
CN
6A-Deoxy-6A-(DCA-2-methylene)--CD
6A, 6B-Dideoxy-6A, 6B-(DCA-2, 3-dimethylene)--CD
Figure 13. Tethered and capped DCA--CD
14
Experimental
-CD from Cerestar was recrystalized twice from water and dried under a vacuum of
approximately 0.1 Torr overnight. DMSO was distilled under reduced pressure from calcium
hydride in an oil bath heated to 60 ºC, and stored under nitrogen.
LRP-2 C-18 bonded silica gel (37-53 m) was used for reversed-phase column
chromatography under linear gradient elution. Eight 100 mL solutions of acetonitrile in water
were used: 0%, 1%, 2%, 4%, 8%, 10%, 15%, and 20%.
A Waters 244 system, equipped with an UV absorption detector (254 nm) and a
Whatman Partisil 10 ODS-3 column, was used for all preparative high performance liquid
chromatography (HPLC). A gradient elution from 5% to 83% aqueous acetonitrile was applied
over one hour at 6.0 mL per minute.
Thin layer chromatography (TLC) analyses were conducted on plates of 250 m silica
gel HLF (Uniplate™) with organic binder and UV254. A solution of n-butanol, ethanol, and
water (5:4:3) was used for the eluant, and products were detected with short wave UV light and
subsequent vanillin stain.
Proton NMR studies were conducted on a GE QE-300 spectrometer.
Dess-Martin Periodinane
2-Iodobenzoic acid (10.18 g, 41.0 mmol) was solvated in 90 mL of 0.73 M aqueous
sulfuric acid and heated to 60 ºC. Over a 30-minute period 8.93 g of potassium bromate (53.5
mmol) was added while vigorously stirring. The solution was heated to 68 ºC and allowed to stir
overnight. A white compound was collected on a Buchner funnel, washed with 1000 mL of
water and twice with 50 mL of ethanol, and added to 80 mL acetic anhydride. The solution was
15
heated to 80 ºC, 0.05 g tosyl alcohol hydrate (0.29 mmol) was added with stirring, and the
solution was allowed to stir overnight under a calcium chloride drying tube. The white solid (7.5
g, 17.7 mmol, 43% yield) was again collected on a Buchner funnel and washed with copious
amounts of anhydrous ether (5 x 50 mL).
Polyformyl -CD
Two grams of -CD (1.8 mmol) were dissolved in 50 mL of DMSO under nitrogen. Five
portions of 1.5 equivalents of DMP (each 1.5 g, 3.5 mmol) were added with stirring at room
temperature over 1.5 hours, 2.5 hours, 7.0 hours, 1.5 hours, and 30 hours. The solution slowly
changed color from white to a deep tan. Water (250 mL) was added and the suspension was
stirred overnight. The solution was filtered and the water was removed from the filtrate by
rotary evaporation. Acetone (500 mL) was added to the residue. After stirring for 2 hours, the
suspension was filtered and the filtrate was rotovapped. The DMSO was removed by distillation
at 60 ºC under a vacuum of 0.1 Torr. 1H NMR (see Figure 17).
2, 3-Bis(bromomethyl)-9, 10-dicyanoanthracene
One gram of 2, 3-dimethyl-9, 10-dicyanoanthracene (3.9 mmol) was dissolved in 500 mL
of carbon tetrachloride and heated to reflux at 96 ºC; the synthesis of 2, 3-dimethyl-9, 10dicyanoanthracene is described by Harwell (see Figure 14).29 Bromine (1.3 g, 8.1 mmol) was
weighed into 25 mL of carbon tetrachloride and added at an approximate rate of one drop per
second with stirring. A halogen floodlight was directed at the reaction flask and the solution was
heated to reflux at 96 ºC for 3 additional hours under a calcium chloride drying tube. The
majority of the carbon tetrachloride was distilled off, and 1500 mL of methylene chloride was
16
added. A yellow solid was precipitated from the methylene chloride and collected on a Buchner
funnel by sequential addition of 200 mL 2% aqueous sodium sulfate, 200 mL 2% aqueous
sodium carbonate, and lastly about 1000 mL of water. The yellow solid (1.57 g, 3.8 mmol, and
97% yield) was recrystalized from toluene (200 mL) by dissolving the solid in toluene, hot
filtering the solution, and carefully adding ethanol (400 mL) at boiling. (Caution! Since the
boiling point of toluene is greater than that of ethanol, rapid addition of large volumes of ethanol
may cause intense vaporization.) 1H NMR (see Figure 18).
CH 3
CH3
CH 3
HO
CH 3
CH 3
O
Al(s)
HgCl2
O
CH 3
H3 C
O
Br
Br2
Br
CH3
N
CH3
CuCN
N2
CH 3
CH 3
CH 2Br CH 2Br
Br2
CCl4
NC
CN
NC
CN
CaCl2
Figure 14. The synthesis of 9, 10-dicyano-2, 3-bis(bromomethyl)anthracene
9, 10-Dicyanoanthracenyl-2, 3-bis(methyltriphenylphosphonium bromide)
2, 3-Bis(bromomethyl)-9, 10-dicyanoanthracene (0.22 g, 0.53 mmol) was dissolved in 80
mL of benzene under nitrogen. Triphenylphosphine (0.28 g, 1.07 mmol) was added and the
solution was heated to reflux at 110 ºC overnight with stirring. A yellow solid (0.11 g, 0.16
mmol, and 31% yield) was collected on a Buchner funnel and dried under a vacuum of 0.1 Torr.
17
Polyformyl-6A, 6B-dideoxy-6A, 6B-(9,10-dicyanoanthracenyl-2, 3-dimethylene)--CD
Polyformyl--CD (0.40 g, 0.36 mmol) was dissolved in 40 mL of DMSO, 40 mL of
benzene, and heated to reflux at 190 ºC under nitrogen. Unfortunately, the condenser was
absent, the solvent was boiled off, and the polyformyl--CD was slightly charred. Another 40
mL of DMSO and 40 mL of benzene was added, the polyformyl--CD was solvated as much as
possible, and the solution was heated to reflux at 190 ºC under nitrogen in a Dean-Stark trap to
collect water. In a separate flask at room temperature, 0.11 g of 9, 10-dicyanoanthracenyl-2, 3bis(methyltriphenylphosphonium bromide) (0.16 mmol) was dissolved in 30 mL of DMSO,
yielding a yellow solution. Potassium-t-butoxide (0.04 g, 0.36 mmol) was added with stirring
under nitrogen. After 10 minutes a deep green color was achieved. The solutions were mixed
and heated overnight to 70 ºC under nitrogen. The benzene was removed by rotovap and the
DMSO was distilled off at 60 ºC under a vacuum of 0.1 Torr. Acetone (200 mL) was added to
the flask to precipitate a black solid, which was collected on a Buchner funnel. Product was
thought to be present according to TLC. The product was purified using reversed-phase column
chromatography and HPLC and showed a retention time of 6.66 minutes. 1H NMR did not show
presence of the desired compound.
18
Results and Discussion
The synthesis of 6A, 6B-dideoxy-6A, 6B-(9,10-dicyanoanthracenyl-2, 3-dimethylene)-CD is divided into four main steps (only three of which were attempted). First, the -CD needs
to be oxidized to polyformyl--CD by reaction with DMP to serve as an appropriate precursor
for the Wittig reaction. The second step is the synthesis of the Wittig capping reagent, 9, 10dicyanoanthracenyl-2, 3-bis(methyltriphenylphosphonium bromide). These two reagents are
then combined according to the Wittig reaction to produce polyformyl-6A, 6B-dideoxy-6A, 6B(9,10-dicyanoanthracenyl-2, 3-dimethylene)--CD. A final step is necessary to remove
additional formyl groups from the primary face of the -CD.
In the first segment of this synthesis, DMP was produced according to established
procedures.8, 9 However, the yield was much lower than reported in the literature (43%
compared to 85%), probably due the increase in reaction temperature (55 ºC vs. 60 ºC) and time
(3.6 hours vs. overnight), previously postulated as sources of decreased yield.9 Utilization of a
Dean-Stark trap, to remove any water before and during oxidation of -CD with the very
hygroscopic DMP, might also have improved the yield. The oxidation of -CD to 6A-formyl-CD requires 1.5 equivalents of DMP to reach completion, and can be rationalized nonstoichiometrically according to the mechanism below (see Figure 15). Even though five degrees
of DMP (7.5 eq) is theorized to completely oxidize the -CD at five of the seven glucose units,
the 1H NMR spectrum was not convincing (see Figure 17).13
19
O
O
AcO
OH
I
+
OAc
I
O
H
H
C
H
H
H2O
O
O ---- H
H
O
AcO
I
O
O
+
C
C
O
O
Figure 15. The oxidation of -CD using 1.5 equivalents of DMP
Furthermore, the Wittig capping agent is subject to strict bond restraints, which limit the
cap to A, B substitution. After multiple degrees of oxidation of -CD by DMP, only a portion of
the -CD will exhibit the required A, B-diformyl construction, and isolated formyl groups
(without an adjacent formyl group) will allow tethering but forbid capping. Cornwell et al.
suggest that multiple oxidations occur sequentially (as opposed to simultaneously) and without
regiochemical influence from the preexisting formyl groups.13 If we assume that oxidation is
complete, then the probability of finding a polyformyl--CD with at least two adjacent formyl
groups can be readily calculated to be 33% for two degrees of oxidation (see Figure 7), 60% for
three degrees of oxidation, 80% for four degrees of oxidation, 93 % for five degrees of oxidation,
and 100% for six or seven degrees of oxidation. Therefore, the Wittig reaction with polyformyl-CD leads to a small decrease in yield as a result of the fact that a maximum of 93% can be A,
B-capped.
The synthesis of the Wittig capping agent, 9, 10-dicyanoanthracenyl-2, 3bis(methyltriphenylphosphonium bromide), was based on the original construction by Wittig and
Geissler.21 However, in order to create a bis-phosphonium ylide, the quantity of
triphenylphosphine was doubled. The mechanism is outlined below; the phosphorus lone pair of
20
the triphenylphosphine attacks the brominated carbons of 2, 3-bis(bromomethyl)-9, 10dicyanoanthracene to produce the Wittig bis-phosphonium salt, and tert-butoxide in solution
abstracts an -hydrogen to produce the ylide (see Figure 16).
CN
CN
Br
Br
P
Br
PPh3
PPh3
CN
CN
Br
P
H
CN
PPh3
O-But
Br
CN
O-But
CN
CN
H
PPh3
PPh3
PPh3
PPh3
CN
CN
Figure 16. Synthesis of the bis-phosphonium ylide
The Wittig reaction of the polyformyl--CD and the bis-phosphonium ylide proceeds via
the general mechanism developed by Wittig and Geissler (see Figure 12).21 The Wittig capping
reagent initially creates an olefinic tether to one molecule of polyformyl--CD. Since the Wittig
capping reagent is a bis-phosphonium ylide, however, it may react with a second formyl group.
Due to bond constraints, the second formyl group must be on the adjacent glucose unit, thus
yielding an A, B-capped--CD. The HPLC retention time of the product isolated in this work
was significantly different than that expected based on the work of Tan. Furthermore, the A, Bcapped--CD product was not visible by 1H NMR, suggesting that the slight charring of the
polyformyl--CD that occurred may have prevented the Wittig reaction from proceeding as
expected.23
21
Completing the synthesis of the A, B-capped-b-CD would have required reduction of the
extra formyl groups remaining after the Wittig reaction. Since the Wittig product could not be
sufficiently identified or isolated, reduction was not possible. However, according to the
literature, reaction with sodium borohydride would sufficiently reduce all formyl groups back to
their corresponding hydroxyls without reacting with other functional groups present on the
molecule.30 This method may permit production of the desired 6A, 6B-dideoxy-6A, 6B-(9,10dicyanoanthracenyl-2, 3-dimethylene)--cyclodextrin in the future.
22
Conclusion
Mistakes in the research method prevented the isolation and positive identification of the
desired 6A, 6B-dideoxy-6A, 6B-(9,10-dicyanoanthracenyl-2, 3-dimethylene)--CD. However, the
synthesis seems to be far simpler than the previous synthesis developed by Tan, which utilized
the application of a 4,6-dimethoxybenzene-1, 3-disulfonyl chloride cap followed by removal
according to the Nace reaction in order to produce A, B-diformyl--CD.20 The majority of the
steps in this reaction are capable of providing product in high yield. However, the Wittig
reaction of the bis(phosphonium) ylide consistently results in relatively poor yield, probably due
to steric hindrance and bond restraints, and must be greatly scaled up. The possibility exists that
the -CD oxidation step and Wittig capping could be combined using a one-pot method
according to Barrett et al., thus permitting a faster, more efficient synthetic route.31 Finally,
fluorescence quenching studies need to be conducted to determine the ability of the product
molecule to act as a photocatalytic host.
23
Figure 17. 1H NMR spectrum of polyformyl--CD
24
Figure 18. 1H NMR spectrum of 2, 3-bis(bromomethyl)-9, 10-dicyanoanthracene
25
References
1
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2
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3
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20
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-Cyclodextrin. Master’s thesis at the College of William and Mary. 1997.
21
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27
Vita
Michael Anthony Repucci
Born the oldest of three sons to Michael Joseph Repucci and Janet Ruth Knorr Repucci
on July 9th, 1976 in Bethesda, Maryland. Graduated from Hopkinton High School in June of
1994 in Hopkinton, Massachusetts. Enrolled in the Bachelor of Science program in chemistry
and psychology at The College of William and Mary in August of 1994. After completing his
degree the author will continue his studies, at Cornell University Graduate School of Medical
Sciences, in the field of neuroscience and neuropharmacology.
28