FACULTY OF SCIENCE

UNIVERSITY OF COPENHAGEN
DEPARTMENT OF CHEMISTRY

Masters thesis
Denis Trpcevski

Azatrioxa[8]circulene

preface
The work presented in this thesis was conducted at the Molecular Engineering Group (MEG), at the Department of Chemistry at the Uni ersity of Copenhagen! "#d like to thank Michael $ittlekow for guidance and good ad ise throughout the work, as well as all the people in MEG who has helped me when times were tough, and %een there for synthetic discussions! &oth while conducting the work, and the time %efore and after! 'nd also for an e(cellent work en ironment, that made all the work a %it easier!

Denis Trpcevski

Abstract
To regret ones own experiences is to arrest ones own development )! -Oscar Wilde The purpose of the presented pro*ect was, first and foremost, to impro e my a%ilities as a synthetic chemist! Throughout the process strife to achie e this goal persisted, e en when all others seemed to fail! The e(perience in the la%oratory, helped me reach this goal! Under the course of the pro*ect many lessons ha e %een learned, most of them under the %rilliant super ision of Michael $ittelkow, as well a guidance and ideas from +,rn! &! Christensen! This thesis will present the work done at the la%oratory of the Molecular Engineering Group (MEG), at The Department of Chemistry at the Uni ersity of Copenhagen! The main goal for the work was to synthesi-e new ./0Circulenes! 1our of these compounds were attempted synthesi-ed2 an a-atrio(a./0circulene, a tetrao(a./0circulene, a dia-adio(a./0circulene and a tetraa-a./0circulene! There has %een de eloped synthetic routes for the preparation of the following compounds3 45&en-yl54H5car%a-ole, 45%en-yl56,75di%romo54H5car%a-ole, 45&en-yl5 6,75dimetho(y54H5car%a-ole, 45%en-yl58,95di5tert5%utyl56,75dimetho(y54H5car%a-ole, 6,75 dimetho(y58,95di5tert5%utyl54H5car%a-ole, 8,95di5tert5%utyl56,75dimetho(y545tosyl54H5 car%a-ole, naphthalene5:,;5diamine, naphtalene5:,;5di5p-toluenesulfonamide, :,;5 naphto<uinone5di5p5toulenesulfonamide! 'll compounds ha e %een characteri-ed %y :=5 >M?, :6C5>M?, melting point, mass spectrometry, and elementary analysis!

Resum p dansk:
1orm@let med dette pro*ekt ar primArt at for%edre mine e ner som organisk syntese kemiker! Gennem hele forl,%et %le der ar%e*det mod dette m@l, sel da alle andre syntes at fe*le! De erfaringer *eg har g*ordt mig " la%oratoriet har h*ulpet med at n@ dette m@l! Under pro*ektet er mange ting lArt, under glimrende e*ledning af Michael $ittelkow, samt +! &! Christensen! Denne rapport il fremlAgge det ar%e*de der er %le et la et ed Molecular Engineering Group (MEG), ed Bemisk "nstitut ed B,%enha ns Uni ersitet! M@let med ar%e*det ar at syntetisere nye ./0circulener! Cyntese af fire af denne type molekyler %le fors,gt3 En tetrao(a./0circulene, en dio(adia-a./0circulene en tetraa-a./0circulene, og en a-atrio(a./0circulene! Deraf %le kun a-atrio(a./0circulenen succesfuldt syntetiseret! Der er %le et la et synteser af de f,lgende stoffer3 45&en-yl54H5car%a-ol, 45%en-yl56,75di%rom54H5 car%a-ol, 45&en-yl56,75dimetho(y54H5car%a-ol, 45%en-yl58,95di5tert5%utyl56,75dimetho(y54H5 car%a-ol, 6,75dimetho(y58,95di5tert5%utyl54H5car%a-ol, 8,95di5tert5%utyl56,75dimetho(y545tosyl5 4H5car%a-ol, naphthalene5:,;5diamin, naphtalene5:,;5di5p-toluenesulfonamid, :,;5 naphto<uinone5di5p5toulenesulfonamid, og den ,nskede a-atrio(a./0circulene! 'lle de syntetiserede for%indelser er %le et karakteriseret ed h*Alp af := >M?, :6C >M?, smeltepunkt, masse spektrometri, og elementar analyse!

Contents Chapter 1 introduction to [n]circulenes 1.1 [n]circulenes :!8 Ctructure of .n0circulenes :!6 ?ecent ad ances in Circulene chemistry 1.4 "ntramolecular interactions 1.5 Ehere can circulenes %e usedF 1.6 G5<uadruple( D>' and circulenes Chapter 2: Synthetic work 8!: Choice of target molecules 8!8 General e(perimental $rocedures 8!63 Cynthetic work 8!; 1uture perspecti es 8!G3 E(perimental section 8!7 Cpectral data (:= >M?) 8!9 Cpectral data (:6C >M?) 8!/ GC5MC ?eferences p!8G p!84 p!6D p!64 p!;D p!G8 p!78 p!9: p!99 p.5 p!7 p!:D p!:/ p!8D p!8:

Chapter 1: Introduction to [n]circulenes

This chapter will include a %rief history of the class of compounds know as the . n0circulenes, an o er iew of the structure of .n0circulenes, an o er iew of what circulenes ha e %een used for, as well as the aim and outline of this report!

1.1: [n]Circulenes
"n :/66 Hie%ermann found that a polymeri-ation took place, when treating :,;5 naphto<uinone with sulphuric acid.:0! This reaction was in estigated in :466 %y =! Erdtman.80! =e found that when treating :,;5naphto<uinone and :,;5naphthydro<uinone with sulphuric acid in acetic acid, three main reaction products could %e isolated! ' phenolic trimer, the acetylated trimer, and it was mistakenly thought that the third compound isolated was a nonphenolic trimer! Hater =! Erdtman and =! E! =Ig%erg o%tained a mass spectrum of the compound, and this showed that a compound with the mass of G7D!:D gJmol, was the correct product.60! This mass corresponds to the nonphenolic tetramer, not the trimer! The structures are shown in figure :!:!

O
H

HO

(a)

(b)

Figure 1.1: (a) The nonphenolic compound isolated from treatment of :,;5naphto<uinone with sulphuric acid and acetic acid! (b) The phenolic compound isolated from treatment of :,;5naphto<uinone with sulphuric acid and acetic acid! The acetylated trimer was also collected from the reaction! 't the gi en time not much effort was put in to further in estigation of these types of compounds! $erhaps due to their ery low solu%ility, which made the characteri-ation and in estigation somewhat tedious! The work of Hie%erman and Erdtman resulted in a new

class of compounds2 the tetrao(a./0circulenes.;0! p5&en-o<uinone were also su%*ected to similar conditions %y =! Hie%erman and =! E! Erdtman, and the products was identified! This yielded a series of different dimers, trimers, and tetramers, shown in figure :!:%! 'fter separation of these products, further condensation was made with :,;5naphto<uinone .;0, and this yielded the mi(ed tetrao(a./0circulenes! 'nd important intermediate to the circulenes was the dihydro(ydi%en-ofuran! This work has inspired the work presented here!
O
O
H O
H O
H O
O
O
H

O
O
H O
H O
H

HO

O
H

HO

O
O
O
O
HO
O
H O
H HO
O
H O
HO
O
O

Figure 1.1b: Come of the products isolated from treatment of p5%en-o<uinone with acid, as reported %y =! Erdtman and =! E! =Ig%erg in :49/ .;0!

1.2: Structure o [n]circulenes

' mem%er of the class of compounds .n0circulenes, are characteri-ed %y ha ing an inner perimeter, which surrounds a ca ity in the center of the molecule, and an outer perimeter .G0! "n addition, the compound has a num%er of radial %onds, which links the inner and outer perimeter together! "n this way a macrocyclic compound of rings is formed! Ee shall consider .n0circulenes, where a mem%er consists of n rings in a macrocyclic arrangement, and where each ring is angularly annulated! Classic circulenes only consists of car%on and hydrogen .G0! 'n .n0circulene of this type may ha e n protruding corners, and no intruding corners! "n this case the inner perimeter is an n5mem%ered ring of n ertices and n edges, denoted %y Cn! 1urthermore the outer perimeter is an C6n cycle, and still the rings are all annulated and therefore apart of an fully con*ugated sp85hy%ridi-ed K5system! 'n e(ample would %e a .90circulene which has %een synthesi-ed (figure :!8).70! "n general, the com%ined length of the inner and outer perimeters is ;n in terms of the num%er of edges and erticies!

Figure 1.23 ' .90circulene consisting of an C9 inner perimeter, and a C8: outer perimeter, with 9 fully con*ugated rings making up the macrocyclic compound! Heft3 The drawn structure of the .90circulene, ?ight3 The crystal structure of the .90circulene! &y introducing one or more heteroatoms in the outer perimeter of a . n0circulene the connection %etween n for the outer5and inner perimeter differs from . n0circulenes made of only car%on and hydrogen atoms! 1irstly, the introduced heteroatoms must %e selected in such a manner that the con*ugated sp8 hy%ridi-ed K5system of the circulene is intact! This means that atoms with p5or%ital lonepairs will %e reasona%le heteroatoms to introduce, as these are a%le to %e part of the K5system! E(amples would %e o(ygen, nitrogen or sulfur, which all ha e lonepairs that can interact with the p5or%itals of the sp 8 hy%ridi-ed car%on atoms, as known from furan, pyrole and thiophene! Ehen these atoms are introduced, the connection %etween the inner and outer perimeter will %e C n for the inner, and C6n5h for the outer perimeter! Ehere the h is the num%er of heteroatoms introduced! Co an ./0circulene with four nitrogen atoms introduced in the outer perimeter would ha e an outer perimeter of2 (6 L /) M ; N 8D edges and eritcies! 'n e(ample of such a compound, a tetraa-a./0circulene, as well as a trio(a.70circulene! (these compounds ha e not %een syntesi-ed, chosen solely for theoretic purposes) is shown in 1igure :!63

HN

NH

HN

NH

Figure 1.!: Heft3 ' tetraa-a./0circulene! ?ight3a trio(a.70circulene! &oth ha e the configuration Cn for the inner perimeter, and C6n5h for the outer perimeter! Ctructural differences are e(pected in Oclassic) circulenes and heteroatomic circulenes!

Ctudies show that circulenes consisting of only car%on5and hydrogen atoms, wherein the inner perimeter is of lower order than the annulated rings that form the outer perimeter, o%tain a nonplanar conformation, they o%tain a %owl5shaped conformer .90! 'n e(ample of such a compound would %e the .G0circulene (coranulene) consisting of annulated %en-ene rings! &ut in circulenes where the inner perimeter and the rings that are annulated are of same order o%tain a planar conformation.90! This can %e made clearer %y the following considerations3 "t is assumed that there is two circles of fi(ed radii, r1 and r2, %oth which are (within limits) fle(i%le! These rings are connected %y spokes of fi(ed length a! The optimal geometry of the compound will then %e determined %y the following3 "f r1 P a N r2, then %oth rings will lie in a common plane, %ut if r1 P a Q r2, the compound will %e forced to o%tain a %owl5shaped conformation! Chown in figure :!;! "n e(amples where r1 P a R r2 the Oe(tra) diameter of the outer circle is taken up %y forming an unending wa e2 in other words the compound o%tains a saddle shaped conformer!

r2 r2 r1 a a r1

Figure 1."3 Geometry of compounds with different %ond lengths! Heft3 ' planar conformation, ?ight3 ' %owl5shaped conformation! =eteroatomic circulenes most often consist of annulated rings of different si-es! S5ray studies of these compounds suggest that these in fact often are planar molecules ./0! This is necessary for the compound to %e a completely con*ugated system, as the lone pair interaction with the car%on5car%on K5or%itals are crucial! "t gi es rise to the o%ser ation3 the sta%ility gained from the completely planar con*ugated system, are in fact more %eneficial than the %ond distortion needed to o%tain the out5of5plane conformation! Electronic considerations of circulenes gi es rise to a theory of whether these compounds are in fact neutral (noncharged), or if a charge separation could actually %e the most sta%le ground form for these types of compounds! "f we look at a Oclassic) .G0circulene, and assume that it has a charge separation in the groundstate we get a representation as shown in figure :!G%! Ee can look at this compound as two interacting annulated systems2 the inner5and the outer

perimeter! 'nd with this assumption we get an electronic configuration of the outer system to %e a :; electron system, and the inner system to %e a 7 electron system! &oth which satisfy the =Tckel theory for aromacity2 ;n P 8!

C

C
+

#a$

#b$

Figure 1.%: (a) ' noncharged .G0circulene, (%) a .G0circulene with charge separation, to satisfy the =Tckel theory! "f in fact the charge separated form has a contri%ution, in the groundstate, it would ha e direct influence on the := and :6C chemical shifts in >M?!:6C >M? spectra for :!Ga ha e not %een pu%lished, due to the limited solu%ility of the compound in >M?5sol ents .90! =owe er, Dopper and Eyn%erg did pu%lish := >M? for the compound, as well as for se eral heterocirculenes.90, and none of them show chemical shifts that would suggest that the the charge separated form is in fact present in the ground state! The aromatic character of polycyclic systems ha e %een in estigated throughly, and Clar has defined a rule on the su%*ect, concerning aromatic se(tets .40! 'n aromatic se(tet is defined as a set of si( K5electrons locali-ed in a single %en-ene5like ring, separated from ad*acent rings %y C5C single %onds! 'ccording to Clar#s rule, the BekulU structure with the largest num%er of dis*oint aromatic K5se(tets will %e the most important, for the description of the reacti ity of a gi en polycyclic hydrocar%on! "n the case of .70circulene, coronene, symmetrical e<ui alent com%inations of K5se(tets can %e written! Coronene is not a totally resonant hydrocar%on, %ecause any one BekulU structure lea es some car%ons outside the se(tet rings .:D0! Clar proposed that if the three se(tets of coronene can migrate into the neigh%oring rings (figure :!7), an e(tra current will %e formed! "n this way he e oked the concept of superaromacity .:D0, originating from the molecular se(tet migration!

#a$

#b$

Figure 1.&: (a) Clar K5electron se(tets in coronene! The arrows indicate se(tet migration! (%) Clar K5electron se(tets in a hetero./0circulene! >o se(tet migration is possi%le in these cases (S N V, > or C)! "n the case of heteroatomic circulenes migration of the Clar K5electron se(tets are not possi%le, due to the ad*acent rings %eing G5mem%ered! Therefore, these compounds lack the superaromaticity descri%ed for coronrene! The most sta%le form of hetero./0circulenes, according to Clar, will therefore %e the one shown in figure :!7%! This means that the aromatic character of the 75mem%ered rings will %e higher, than for the heteroatomic G5 mem%ered rings! This is also the case in a simple comparison of %en-ene and furaneJpyrole, where %en-ene has a more aromatic character!

1.!: 'ecent ad(ances in Circulene che)istry

V er the last decades there has %een a growing interest in circulene chemistry! Warious compounds ha e %een synthesi-ed, since the work conducted %y Erdtman and co5workers in the :46D#s.80! &oth the synthesis of classic circulenes, and heteroatomic circulenes, ha e %een of interest, due to these molecules uni<ue properties! "n this section, a %rief summary of the work with %e presented! The %uckminsterfullerene C7D has %een know since :4/G, and classic .G0circulenes can %e iewed as fractions of a similar system.::0! Due to the high sta%ility of such compounds, the classic circulenes ha e %een of great interest for chemists as well as other natural sciences! The first synthesi-ed classic circulene was the .70circulene, achie ed in :468 %y Ccholl and Meyer.:80! Cince then others ha e reported impro ed syntheses of this molecule.:6,:;0! Ce eral years later, in :477, &arth and Hawton synthesi-ed the smaller .G0circulene (corannulene).:G0! These studies were the first of the classic circulenes! 'round :477 Groen and Eyn%erg started the study and preparation of

10

heterohelicenes.:70! This led to the preparation of the molecules shown in figure :!9%!

#a$

#b$

#c$

Figure 1.*: The molecules of interest for Groen and Eyn%erg! (a)3 The heterohelicene, (%)3 the dehydrohelicene, (c)3 the trithia.90circulene! Molecules of this type were called dehydrohelicenes, as the two helical termini are connected %y a X5%ond! This compound was of interest as it showed a lot of similarities to the hetero.90circulene! The earliest e(ample of synthesis of a heterocirculene, has already %een discussed, and is the work conducted %y Erdtman and =Ig%erg in the late :47D#s and the :49D#s! They cycli-ed a num%er of <uinones, under the influence of acids! ' tetrao(a./0circulene was synthesi-ed, in low yield, when p5%en-o<uinone was treated with a mi(ture of sulphuric acid, acetic acid and water (figure :!/)3

=P

Figure 1.+: ?eaction of p5%en-o<uinone with a mi(ture of sulphuric acid, acetic acid in water! "n :49G Dopper and Eyn%erg found that the dehydrohelicene (:!9%), that Groen and Eyn%erg earlier had worked with, could undergo Diels5'lder reaction with malonic anhydride in the presence of chloranil as an o(idi-ing agent to yield the

11

hetero.90circuleneanhydrid.90! This compound could %e further transformed to the hetero.90circulene %y decar%onylation, effected %y prolonged %oiling with copper5powder in <uinoline, or %y pyrolysis with a sodaJlime5mi(ture at ;DDoC, where the hydrocar%on su%limated and was collected (figure :!4).903

S
O

S
O

O
S
S
O
S
S

Figure 1.,: The synthesis of .90circulene as conducted!%y Dopper and Eyn%erg.90! "n the last decades more interest ha e %een paid to the synthesis of different heteroatomic circulenes! The most studied of these is without dou%t the octathia./0circulene, also known as the Osunflower) circulene! This was first synthesi-ed in 8DD7 %y B! Yu! Cherichenko and co5 workers.:90! They also successfully synthesi-ed the Celenum analogue tetraselenatetrathia./0circulene.:90! The preparation of the Cunflower circulene included2 the synthesis of cyclotetrathiophene from reaction of 6,;5di%romothiophene with a -ero5 alent >ickel comple(, and neutral ligands such as triphenylphosphine at 9DoC! The tetrathiophene was then con erted to the polythiolate intermediate %y lithation with HD', and reaction with elementary Culfur! This was acidified with =Cl to yield the polythiol! $yrolysis of the polythiol led to elimination of =8C, and elementary Culfur, to yield the octathia./0circulene! The reaction scheme is shown in figure :!::3
S
HS
HS
S
S
H S
H S
S
S

Br

Br

a
S
S

cPd
S
S
S
S
S

S
HS
S
HS
S
S
H S
H

Figure 1.11: Cynthesis of the octathio./0circulene (Cunflower)3 (a)3 >i(cod)8 J ligand, DM1, 9DoC (%)3 HD' (:7 e<!) J Culfur (:7 e<!), room temperature (c)3 a<! =Cl (d)3 acuum pyrolysis! This was the first successful synthesis of a fully heterocyclic circulene, meaning that it consists only of indi idual heterocycles2 thiophenes! The tetraselenatetrathia./0circulene

12

analogue, called Celeno5sunflower, was synthesi-ed in a similar manner, only replacing Culfur in step :!::(%) with Celenium, in diethylether and he(ane at room temperature! The selenosunflower was first synthesi-ed %y '! Dad and, B! Yu! Chernichenko and co5workers in 8DD7.:90! The sunflowers are organic semiconductors, and are useful in electronic de ices such as light5emitting de ices! The synthetic challenging .;0circulene, called Zuadrannulene, was recently (in 8D:D) synthesi-ed %y &! Bing and co5workes.:/0! The preparation of this circulene included the following steps2 photodimeri-ation of naphto<uinone, alkynylation with trimethylsilylacetylene, and n5&uHi in the presence of CeCl6 to suppress unwanted enoli-ation, elimination of water to yield the naphthalene framework, as well as desilylation! 1inally, cycli-ation of the tetraalkyne in the presence +onas#s catalyst (CpCo(C=8NC=8)8, with %is(trimethylsilyl)acetylene afforded the desired product! The synthesis of <uadrannulene is shown %elow in figure :!:8!
TMS
TMS

HO

O
H

HO

O
H

TMS
TMS
TMS

TMS

C
H

C
H

TMS

TMS

TMS

TMS

C
H

C
H

TMS

TMS

Figure 1.12: (a) Trimethylsilylacetylene, n5&uHi, CeCl6, T=1, 59/oC to 8GoC, (%) :! TsV=, toluene, reflu(, 8! BV=, MeV=, 8GoC, (c) CpCo(C=8NC=8)8, %is(trimethylsilyl)5acetylene, DME, 8GoC!

13

The syntesis of e(tended circulenes, or polycyclic aromatic hydrocar%ons, ha e also gained interest o er the last decades! G! Mehta and G! $anda conducted the synthesis of a C 6D=:8 O%ucky5%owl), that represents an e(tended circulene, or a section of a &uckminsterfullerene.:40! This compound has a saddleshaped conformation! The synthesis of the compound started from 8,95dimethylphenanthrene, which is a readily a aila%le compound! This compound was transformed into the %is5ylide ia the %is(8,95%romo5 methyl)phenanthrene, %y %romination with >&C! ' wittig5reaction of the %is5ylide with p5 %romo%en-aldehyd was then carried out! 'fter o(idati e photocycli-ation, and flash accum pyrolysis, the desired compound was o%tained! The synthetic pathway is shown in figure :!:63

P
h
C
H 3
Br
P
h
P
h
Br
P
+
Br

Br
C
H 3
Br
Br

P
h
P
P
h

P
h

Br

Br

Figure 1.1!: a) >&C, CCl;, heat, ;h, %) $$h6, %en-ene, room temperature, 856 days, c) B8CV6, T=1, :/5crown57! p5%romo%en-aldehyde, :Dh, d) h (;GDE), pyre(, %en-ene, 8h, e) 1W$, ::GDoC, >8!!

14

"n efforts to utili-e the intermolecular interactions that circulenes e(hi%it, different types of alkylsu%stituted circulenes ha e %een synthesi-ed, in order in make different discotic li<uid crystals! Many of such compounds ha e %een synthesi-ed in the +! &! Christensen group! "n one pro*ect the main focus was the synthesis of different tetrao(a./0circulenes .8D0! The o erall synthesis included the following2 synthesis of 65(8,G5dimetho(y5phenyl)5propanic acid from reaction of 8,G5dimetho(y%en-aldehyde and malonic acid to yield 65(8,G5 dimetho(yphenyl) acryllic acid, and reducti e hydrogenation with hydrogen and $alladium on car%on! Transformation to the acylchloride, and intramolecular 1riedel5Crafts reaction! Di5 alkylation of this compound through the enolate and different iodoalkyl compounds! Catalytic hydrogenation in the presence of =ClV; afforded the reduced compound! V(idation of these with C'>, and reaction with &16[VEt8 resulted in the successful synthesis of the alkyl su%stituted tetrao(a./0circulenes! The synthetic route is shown in figure :!:;!
H3
C
H3
C
H3
C
H3
C
H3
C
O
O

O
R

a
O
C
H 3
R
O
C
H 3
R

O
H

%
O
C
H 3

O
H

c
O
C
H 3

d
O
C
H 3

e
O
R

H3
C
O
O
O

g
R
R
O

f
O
C
H 3

R
R

R
R

Figure 1.1": a) (=VVC)8C=8, piperidine, pyridine, %) =8, $d5C! EtV'c, c) :! CVCl8, heat, 8! 'lCl6, C=8Cl8, d) >a", ?", T=1, e) =8! $d5C! =ClV;, =V'c, f) C'>, MeC>J=8V, g) &16[VEt8, C=8Cl8!

Cynthesis of symmetrical and asymmetrical K5e(tended tetrao(a./0circulenes ha e %een successfully synthesi-ed %y M! $ittelkow et al!./0 These compounds were synthesi-ed %y treatment of a :3: mi(ture of naphto<uinone and 8,65%isundecyle5:,;5%en-o<uinone with &16[VEt8! 'fter careful separation of the formed compounds %y column chromatography on silica it was shown that these compounds are fluorescent, and could pro e to %e interesting in VHED#s! The synthesis of these compounds are shown in 1igure :!:G!

15

Figure 1.1%: Cynthesis of K5e(tended tetrao(a./0circulenes!

16

+! &! Christensen and his group has done e(tended work on different tetrao(a./0circulenes! U! Harsen successfully synthesi-ed deri ates of these types of compounds .8:0, similar to the work conducted %y C! Me*ls,e! This work inculded synthesis of ;,95dimetho(yindan585 car%o(ylic acid, %y reaction of 8,65%is(%romomethyl)5:,;5dimetho(y%en-ene, with diethylmalonate, followed %y %y o(idation to the ;,95dio(oindan analogue! This compound underwent different reactions such as hydrolysis of the ester groups, decar%o(ylation to yield the ca%o(ylic acid deri ate, reaction of these compounds with CVCl 8 and different alcohols to yield the esters, and then tetrameri-ation of these compounds to form the tetrao(a./0circulenes.8:0! The reactions are shown in 1igure :!:7!
O
O
O
O
O
O
C
H 3
O
C
H 3
O
O
R
O
O
R

f
O
C
H 3
O
Br
Br
H3
C
O
O
C
H 3
O
C
H 3
O

g
O
O
C
H 3

C
H 3
O

C
H 3
O
O
H O
H

C
H 3
O
R
O
O
R
O
C
H 3

C
H 3
O
C
H 3
O
O

O
C
H 3

d
O
O

h
R

C
H 3

e
R

C
H 3

O
O

O
O
C
H 3

O
H O
C
H 3

Figure 1.1&: Cynthesis of the %uilding %locks for tetrameri-ation to the tetrao(a./0circulenes! a) >a=, T=1, %) :! BV=, EtV=J=8V, 8! =ClJ=8V, c) CVCl8, ?V=, r!t, d) heat, e) CVCl8, ?V= f,g,h) C'>,=8V, C=6C>! These compounds were then transformed to the corresponding tetrao(a./0circulenes %y reaction with &16[Et8V! 's shown %elow in 1igure :!:93
R
1
R

O
R
1
R
R
1
R
O

R
1
R

R
1

Figure 1.1*: Tetrameri-ation of the compounds from figure :!:7! ?eaction proceeds %y reaction with &16[Et8V in C=8Cl8 !

17

+! Eskildsen, T! ?een%erg and +! &!Christensen, also synthesi-ed different alkylsu%stituted tetrao(a./0circulenes.880! This work also started out with 8,65%is(%romomethyl)5:,;5 dimetho(y%en-ene! This was reacted with different lithium acetylides, followed %y reduction of the triple %ond to yield the desired disu%stituted alkyl deri ates! These compounds were then o(idi-ed with C'> to produce the <uinones, that could %e tetrameri-ed %y reaction with &16[VEt8! The work is shown in 1igure : :/!
R
C
H 3
C
H 3
O
R
R
O
C
H 3

O
R

Br
Br

a
O
C
H 3

%
O
C
H 3

R
R

c
O

R
R

R
O
C
H 3

R
O
O

Figure 1.1+: a) ?C=C=Hi, (? N :5%u, :5pent, :5he(, :5hept, :5oct! %) = 8J$tV8 'cV=, 'cVEt, ;GoC, c) C'>, C=6C>J=8V, d) &16[VEt8, C=8Cl8, heat! 's shown circulene chemistry has gained increased interest o er the past decades, %ut mi(ed heteroatomic circulenes ha e yet to %e throughly e(plored! The most studied of these types of compounds are the tetraselenatetrathia5sunflower circulenes! The presented work in this thesis focus on synthesis of a a-atrio(a./0circulene, and the synthesis of a K5e(tended tetraa-a./0circulene!

1.": Intra)olecular interactions

Circulenes often ha e ery low solu%ility, in normal organic sol ents, due to strong intermolecular interactions! "n supramolecular chemistry, an aromatic interaction (or K5K interaction) is a non5co alent interaction %etween organic compounds containing aromatic moieties.860! 'lignment of positi e electrostatic potential on one ring with negati e electrostatic potential on another ring, forms an offset stack.860! These interactions %ecome stronger as the num%er of K5electrons increases! Vther nonco alent interactions include hydrogen %onds, an der Eaals forces, charge5transfer interactions, and dipole5dipole interactions! Circulenes ha e strong K5K interactions, due to the large K5systems in these types of compounds! This affects the solu%ility of such compounds! "n order to increase the solu%ility, the K5K interactions must somehow %e minimi-ed! K5K "nteractions are <uite strong interactions (D5GD B+Jmol)! "ntroducing large %ulky su%stituents on the circulenes will minimi-e the K5K interactions, and hopefully increase solu%ility of the compounds! K5K Ctacking can occur in

18

two different ways2 Either it occurs in a face5to5face manner, where an interaction %etween the negati ely K5system of one aromatic compound interacts with the partial positi ely charged \5%ond of another! Vr it occurs in a face5to5edge interaction, where the K5system interacts with a partial positi ely charged hydrogen5atom of another aromatic compound, in a perpendicular manner (1igure :!:6)!

#a$

#b$

Figure 1.1!: (a) 1ace5to5face K5stacking, (%) face5to5edge K5interaction! 'nother intermolecular interactions that can affect heteroatomic circulenes are hydrogen %onds.860! These are non5co alent %onds %etween a hydrogen atom connected to an electronegati e atom, to a lonepair or negati e charge in another molecule (figure :!/)! This type of intermolecular non5co alent %onding is ery common, in nature as well as in the la%oratory! "t is one of the main forces that wraps D>' in a dou%le heli(, and the cause of the high %oiling point of water! These interactions are not strong interactions (;5:8D B+Jmol), %ut there is often numerous of these present %etween compounds in solution!

O H3C O

H H

O O

CH3

Figure 1.+3 =ydrogen %onds in %utyric acid! Dipole5dipole interaction is another intermolecular interaction often seen %etween organic

19

compounds.860! These are interactions of a%out G!GD B+Jmol, and are due to the electronegati ity of different atoms! 'n e(ample is shown in 1igure :!:;!

O H3 C O O O CH 3

CH 3

H3 C

Figure 1.1": Dipole5dipole interaction in methyl%utanoate! These interactions are ery often present in circulenes! The most often o%ser ed is the K5K interaction! "n order to make circulenes solu%le these interactions must %e minimi-ed!

1.%: -here can circulenes be used.

"n 8DDD, +! &! Christensen showed that %y introducing long alkyl5chains onto the large tetrao(a./0circulenes they %ecame li<uid crystals of discogenic structure, due to the intermolecular non5co alent interactions.880! Circulenes can %e interesting for molecular electronics, for e(ample in molecular wires, photoconductors and VHEDs (organic light5 emitting diode)! 'nother e(citing use for circulenes is in D>' intercalation.8;0! "ntercalation is the re ersi%le inclusion of molecule (or group), %etween two other molecules (or groups)!
There are se eral ways molecules can interact with D>'! Higands may interact with D>' %y co alent %inding, electrostatic %inding, or %y intercalating .8;0! "ntercalation occurs when ligands of an appropriate si-e and chemical nature fit themsel es in %etween %ase pairs of D>' ! These

ligands are often polycyclic, aromatic, and planar, which is e(actly the type of molecules
circulenes are! D>' intercalation induces local structural changes to the D>' strand, such as

lengthening of the D>' strand, or twisting of the %ase pairs .8;0! These structural modifications can lead to functional changes, and often to the inhi%ition of transcription and replication, and D>' repair processes, which makes intercalators interesting from a medicinal chemical standpoint! Eith the right design, perhaps circulenes can %e used as intercalators for D>'! Especially a type of D>' with an alternati e 6D structure, the G5<uadruple(, has attracted our attention!

20

1.&: /01uadruple2 345 and circulenes

1irst disco ered in :/74 %y 1irdrich Miescher, D>' has continued to ama-e those who study chemical and %iological systems.8G0! V er /D years ago the ]5form duple( D>' was disco ered %y 1rancis Crick and co5workers, which ga e a %etter mechanistic insight .8G0, understanding of replication and the flow of genetic information! The dou%le heli( D>' has since %een regarded as the %iological rele ant structure of D>', howe er, with a ariety of nuceloprotein comple(es, and with different core particles, D>' can adopt se eral different conformations, including distorted '5, &5, ^5form of dou%le heli(es .870! "n addition to the ariety of dou%le heli( conformers, single5stranded D>' can also fold into many different conformers, such as triple( and G5<uadrople(es.870! =ere it is important to remem%er that the meta%olically acti e form of D>' is indeed single5stranded, and are important for replication, transcription and repair! Vne might actually say that the dou%le heli( is in fact the inacti e form of D>', and the single stranded is the %iologically rele ant! Vne family of structures, that originates from guanosine5rich strands, is referred to as G5<uadruple(es .890! These structures contain two or more stacked G5tetrads (1igure :!:G) and are sta%ili-ed %y potassium ions, or similar metal5ions, at ery low concentrations.890! G5<uadruple(es are either assem%led in an intramolecular fashion, or from two, or four strands in an intermolecular fashion (1igure :!:7).8/0! "ntramolecular G5<uarduple(es ha e %een implicated to play an important role in the regulation of the gene e(pression, and chromosome sta%ility!

67

Figure 1.1%: The G5<uarduple( with potassium, as it appears in D>'!The glycoside %ack%one contains negati ely charged phosphate esters! Many currently used chemotherapeutic agents %inds to D>' non5specifically! The

21

de elopment of small molecules that specifically %inds to certain D>' secondary structures may impro e cancer5specific targeting, and decrease side effects associated with chemotherapeutic treatment! G5<uadruple( D>' structures are highly attracti e targets, gi en the a%undance information a aila%le regarding their structures! Detailed structural analysis of G5<uadruple(5ligand comple(es ha e %een done %y >M? and S5ray crystallography! These studies imply at least two different %inding sites for G5<uarduple( ligands! The most common is co5facial end5stacking of the ligand onto one, or %etween two, of the terminal G5tetrads, other known ways of sta%ili-ing the G5tetrads is %y intercalating %etween two G5tetrads, or %y groo e 5%inding where the ligand sta%ili-es the formed %ack%one of the G5<uadruple( ( figure :!:9).890! G5<uadruple(es ha e %een shown to inhi%it telomerase acti ity, and therefore drugs that sta%ili-e these conformers could interfere with telomere replication.8/0! This is where circulenes might pro e to %e highly efficient ligands, and thus a ia%le anti5cancer drug! Designed in the correct manner, the strong K5K interactions that circulenes e(hi%it, com%ined with the possi%ility to add fa ora%le side5chains to interact strongly with the phosphate %ack%one of the D>'5strand, makes them interesting in a medicinal point of iew! Higands with planar aromatic systems, containing delocali-ed K5 electrons, stack on the face of guanine <uartet, whereas ligands with positi ely charged su%stituents interact with the negati ely charged phosphate %ack%one of the G5<uadruple( .890! To %e effecti e, these ligands must e(hi%it high selecti ity to <uadruple(es o er duple(es! Most of the already known G;5ligands are in fact planar aromatic systems containing heteroatoms (figure :!:/).8/0! The K5stacking refers to stacked arrangement of aromatic systems, which is mainly controlled %y hydropho%ic effects and Wan der Eaals interactions! "n addition, the ligands must e(hi%it reasona%le water solu%ility, usually achie ed %y incorporating side chains around the aromatic system which can %e protonated, or that are polar! Ce eral ligands with ammonium groups ha e %een used as ligands! The hydrogen %ond interactions %etween guanines in the <uartet ha e %een documented as 8!// _, and the distance %etween two stacked <uartets is consistently 6!6 _.8/`! The dimensions for the G5 <uadruple( is :D!/ M ::!/ _ in one direction, and :8!9 M :6!D _ in the other, shown in figure :!:4.8/0! "n order to ha e high affinity ligands, the compounds dimensions should resem%le those of the G5tetrads to ensure optimal interactions! Circulenes, with their large planar aromatic structures, and possi%le positi ely charged side chains, can pro e to %e actual ligands for G5<uadruple(es!

22

Figure 1.1&3 G5<uadruple(es are mostly assem%led in an intramolecular fashion, or from two or four strands, or in an intermolecular single strand fashion!

Figure 1.1+3 G5<uadrople( K5ligands! 13 'cridine deri ate su%stituted with pyrrolidinopropionamides, 23 &?'CV5:4, !3 TM$y$;, a tetracationic porphyrin deri ate, "3 pyridyl5su%stituted corrole isomers, %3 a %is5tria-ole deri ate, &3 telomesatin, *3 Metalloporphyrins, +3 nickel("") salphen comple(es!

23

Figure 1.1,: The <uadruple( structure and the G5<uartet surface!

Figure 1.1*: ' representation of a ligand5G; comple( with a) e(ternal stacking mode on the surface of the terminal G5<uartet, %) intercalating mode %etween the stacks of G5tetrads, c) groo e %inding mode! TM$y$;, a tetracationic porphyrin deri ate, shown in figure :!:8 is a known ligand for G5 <uadrople( %inding! Taking this into account, the dimensions of new ligands should %e similar to the ones of the TM$y;5ligand! The main focus of the work in this report was done on two different hetero./0circulenes2 a a-atrio(a./0circulene and a dia-adio(a./0circulene! Comparison of the dimensions were made %y computational calculations, to optimi-e the ligands an der Eaal %inding with G5tetrads! 1igure :!8D shows the dimensions of the TM$y$; ligand as well as the dimensions of the tetrao(a./0circulene, as measured for (5ray crystal structures! This comparison can also %e applied to the a-atrio(a./0circulene, and the dia-adio(a./0circulene, as %ond lengths are ery similar! 1or optimi-ed %inding, >5alkyl su%stituents with cationic ammonium groups should %e introduced to the a-a5ligands!

24

(a)

(%)

Figure 1.28: (a)3 The longest distance in the con*ugated system of TM$y$; (/!GG9 @), (%) The longest distance in the con*ugated system of the tetrao(a./0circulene (/!GD9 @)!

Chapter 2: Synthetic work

This chapter will descri%e the planning of the synthetic work, choice of target molecules, and e(perimentals of actual la%oratory work!

2.1: Choice o target )olecules

The aim of the pro*ect was to synthesi-e new heteroatomic ./0circulenes for %inding to G5 <uadruple( D>' ! 1our different types were chosen2 a dio(adia-a./0circulene, a a-atrio(a./0circulene, a tetraa-a./0circulene and a tetrao(a./0circulene! The main properties that was wanted was for the circulenes to %e water solu%le! >ot much work has %een done on this su%*ect to date! 'n important part of the design of these compounds, was to introduce %ulky su%stituents at positions that would minimi-e the the polymeri-ation of the compounds during the synthesis, and fa or the formation of circulenes! "ntroducing car%on chains containing tetra alent ammonium ions, would make the ./0circulenes water5solu%le! The main focus was on the dio(adia-a./0circulene and the a-atrio(a./0circulene, which pro ed challenging to synthesi-e! This work is %ased on the work that =! Erdtman and =! E! =Ig%erg did on acid cataly-ed oligomeri-ation of p5%en-o<uinones.6`! "n this work it was e ident that the 8,/5dihydro(ydi%en-ofuran was an important intermediate in the synthesis of the tetrao(a./0circulene! The idea was to su%stitute the furan compound with the nitrogen analogue, car%a-ole and from that synthesi-e the desired a-atrio(a./0circulene, and the

25

dia-adio(a./0circulene! The tetraa-a./0circulene would %e synthesi-ed from napthalene deri ates, and would therefore contain e(tra aromatic rings (a K5e(tended circulene) ! The %ulky su%stituents on the %uilding %locks for the ./0circulenes, were introduced to e(plore the idea that this, in fact, would fa ori-e circulene formation o er polymeri-ation! The desired compounds are shown in figure 8!:!
H3
C
C
H3
C
H 3
Ts
NH N N Ts

H3
C
H3
C
O

H3
C
C
H 3
H3
C
O
C
H 3
C
H 3
H3
C
H3
C

C
H 3

H3
C
H3
C
O
H3
C
C
H 3
O

C
H 3

H3
C

C
H 3
C
H 3

H3
C
H3
C

H3
C
H3
C

C
H3
C
H3
Ts
H3
C
H3
C
C
H 3

C
H 3
HN

O
C
H 3
H3
C
C
H 3

C
H 3

O
C
H 3
H3
C
C
H 3

HN

O
C
H 3
H3
C
C
H 3

H3
C

N Ts

(a)

(%)

(c)

(d)

Figure 2.1: (a) The a-atrio(a./0circulene, (%) The tetrao(a./0circulene, (c) The dia-adio(a./0circulene,(d) The tetraa-a./0circulene! The general idea for the synthesis of the dia-adio(a./0circulene, was to synthesi-e a 4 Hcar%a-ole deri ate, and dimeri-e it to the desired ./0circulene! The steps in the first proposed reaction path included2 a halogenation, a %en-ylation, a Ullmann coupling, a 1riedel5Crafts alkylation, a demethylation, dimeri-ation and de%en-ylation followed %y N5alkylation! The first proposed path is shown in figure 8!8!

26

Br

Br

H3
C

C
H 3

N H

H3
C
H3
C

C
H 3
O

H3
C

C
H 3
C
H 3

HO
H3
C
H3
C
H3
C
H3
C
N O
O
C
H 3
C
H 3
C
H 3
C
H 3
H3
C
H3
C
H3
C
N

O
H C
H 3
C
H 3
C
H 3
O
H3
C
H3
C
C
H 3
H3
C
C
H 3
C
H 3
N N

H3
C

C
H 3
C
H 3
H3
C
C
H 3
C
H 3
H3
C
C
H 3
C
H 3
H3
C
C
H 3
C
H 3
C
H 3
R
C
H 3
C
H 3
H3
C
H3
C
C
H 3
H3
C
O
NH H3
C
C
H 3
N R
N O
C
H 3
C
H 3
C
H 3

HN

C
H 3

C
H 3
C
H 3

C
H 3

HN C
H 3
C
H 3

H3
C
H3
C
H3
C
C
H 3
O
O
H3
C

C
H 3

H3
C
H3
C
C
H 3
H3
C
H3
C
C
H 3
H3
C
H3
C
C
H 3

H3
C
H3
C
C
H 3

Figure 2.23 The first proposed synthetic pathway to the dia-adio(a./0circulene and the a-atrio(a./0circulene! "t would later %ecome clear that difficulties in ol ing the demethylation step would arise! Ehere selecti ity %etween the demethylation of the metho(ygroups, and the de%en-ylation of the N5%en-yl group was sought! Many different approaches to this con ersion was tried without greater success, some of the failed attempts to demethylate included reaction with &&r6, under se eral different conditions, reaction with sodium ethanthiolate and with inorganic salts such as lithiumiodide, reaction with methylsulfonic acid, and micowa e assisted reaction with ethyleneglycol! The %romination step was also done after the %en-ylation, as this increased yield! The synthetic path to the tetraa-a./0circulene, was to start from :5amino5;5nitronapthalene, reduction to the diamino analogue, N5tosylation, o(idation to the diimine compound, and oligomeri-ation with tert5%utylhydro<uinone, to form the desired compound! The proposed path is shown in figure 8!6!

27

C
H3
O
S
NH2
NH2
HN O

NO
2

NH2

HN S
O

C
H3

H3
C
C
H 3
O
S
N O
O
H O
H C
H3
C
H3
C
H3
O
O
S
N N H3
C
C
H 3
C
H3
O
S
O

C
H3

N S
O

O
S

N S

O
H3
C
C
H 3
H3
C
H3
C
C
H3

O
C
H3

Figure 2.!: The proposed synthetic pathway to the tetraa-a./0circulene! The proposed pathway was followed to some e(tend! The formation of the actual tetraa-a./0circulene, %y reaction with tert5%utylhydro<uinone and &16[VEt8, unfortunately yielded the products from a redo(5process %etween the two compounds ( tert5 %utyl%en-o<uinone and the reduced imine5compound)! Co other reaction types was taken into consideration! These included an Ullmann aryl5aryl coupling with copper(")iodide a catalyst, as well as a Cu-uki5coupling, of the 85%romodiimincompound! The synthetic pathway to the tetrao(a./0circulene is rather simple, as it is merely a condensation of tert5 %utyl%en-o<uinone, under acidic conditions! Cimilar reactions has %een reported %y =! =Ig%erg! The reaction is shown in figure 8!;!

28

H3
C

C
H 3
C
H 3

C
H 3

C
H 3
C
H 3

H3
C

C
H 3

=P

H3
C

C
H 3
C
H 3

O
H3
C
H3
C
C
H 3

H3
C

Figure 2.": The formation of the tetrao(a./0circulene from tert5%utyl%en-o<uinone!

2.2: /eneral e2peri)ental 9rocedures

'll sol ents used were of =$HC grade standard! T=1 and DM1 were dried o er molecular ;_ sie es, prior to use! C=8Cl8, 'cV= and toluene were used without any purification, unless otherwise mentioned! THC analysis were made on aluminum silica gel sheets (Bieselgel 7D 18G;), and made isi%le under UW5light! >M? e(periments were conducted on a Warian Mercury 6DD M=- or a &ruker GDD M=-, with deuturated sol ents as standard (CDCl 6 9!87 ppm in := >M? and 99!:7 ppm in :6C >M?, and DMCV5d7 8!G ppm in := >M?, and 64!G8 in
:6

C >M?)! Mass spectra were o%tained on a =ewlett5$ackard G/44D series "" with G M!C!

(crosslinked Ga $h Me silicone) 6D m ( D,8G mm ( D,8G bm column! Melting point analysis were conducted on a HT%ke Wario from &Tchi! Column chromatography was done on columns of :cm, 8cm, ;cm, 7cm diameter, depending of the amount! The columns were packed with Bieselgel 7D (D,D:G M D,D;D mm), and the eluent was EtV'cJheptane, unless otherwise mentioned!

29

2.!: Synthetic work

"n this section the la%oratory work done for the pro*ect is descri%ed in detail! The main focus of the work was the a-atrio(a./0circulene, and the dia-adio(a./0circulene! The synthetic pathway towards these compounds, as well as the work conducted on synthesis of the tetraa-a./0circulene will %e descri%ed in the following chapter! :he dia;adio2a[+]circulene < a;atrio2a[+]circulene: The following will descri%e the work conducted on the synthesis of the dia-adio(a./0circulene! "n order to synthesis the dia-adio(a./0circulene a synthetic pathway was de eloped! This route included the following steps3

N5&en-ylation of 4H5car%a-ole %romination of 45%en-yl54H5car%a-ole Copper catalysed cross coupling of the %rominated compound with >aVMe 1riedel5Crafts alkylation with t&uCl Demethylation of the dimetho(ycompound V(idation of the phenolic compound Dimeri-ation to form the dia-adio(a./0circulene Condensation with tert5%utyl%en-<uinone, to form the a-atrio(a./0circulene

The first step in the synthesis of the dia-adio(a./0circulene was the %romination at the 6 and 7 position of 4H5car%a-ole! This was done %y reaction of 4H5ca%a-ole with 8 e<ui alents of >&C in acetonitrile! The reaction was carried out in DM1! Come of the desired product was o%tained, %ut at unsatisfying yields (G757Da)! >o effort was made to identify the %y5products of the reaction! DM1
N H Br
Br

P %y5products >&C
N H

30

'nother approach was the taken in efforts to increase the yield! The %romination was carried out under traditional method2 %y reaction of 4H5car%a-ole with %romine in acetic acid! The same o%ser ations as with the >&C attempt were made! This promoted the e(ploration of an alternati e route to the 45%en-yl56,75di%romo54 H5 car%a-ole, where the first reaction would %e the %en-ylation of 4 H5car%a-ole, and afterwards the %romination (with %romine in acetic acid)! The N5%en-ylation of 4H5car%a-ole was carried out %y C>85reaction of 4H5car%a-ole with %en-yl%romide in toluene, and alkaline solution, with a phase5transfer reagent! This transformation proceeded in almost <uantitati e yield!

n5&u;>P"5 &n&r
N H N

Br

Br

&r8 'cV=
N

toluene >aV=

The Ullmann5type copper cataly-ed coupling of 45%en-yl56,75di%romo54H5car%a-ole, was carried out %y reaction with >aVMe in MeV= in DM1, with copper(")iodide as the catalyst! The reaction was carried out with e(clusion of moisture, and under a nitrogen atmosphere! The introduction of the metho(y groups was important for direction of the following 1riedel5 Crafts alkylation, to the desired positions!

Br

Br

H3
C

C
H 3

>aVMe
N

Cu(")" DM1

The ne(t challenge was to carry out a 1riedel5Crafts alkylation with tert5%utylchloride, to yield the desired 8,95di5tert5%utyl5compound! The first attempt at this was carried out %y reaction of 45%en-yl56,75dimetho(y54H5car%a-ole, with tert5%utylchloride in dry dicholromethane with 'lCl6 as the Hewis acid, at DoC! The reaction was carried out under nitrogen atmosphere! 'fter addition of the tert5%utylchloride the reaction was kept at DoC for 8 hours, and then allowed to reach room temperature! The reaction mi(ture was stirred o ernight! This reaction

31

was later e(cluded due to formation of undesired %i5produccts, which later would %e assigned to the acid strength of 'lCl6! Vne of the o%ser ed %yproduct was the N5%en-yl deprotected compound! The formation of the tert5%uyl5cation was modified %y using anhydrous 1eCl6 as the Hewis acid, and this increased the yield of desired product! 1ormation of the 45%en-yl58,95di5 tert5 %utyl56,75dimetho(y54H5car%a-ole was also carried out %y reaction of 45%en-yl56,75 dimetho(y54H5car%a-ole with tert5%utylalcohol and T1', with tert5%utylalcohol %oth as the reagent and the sol ent! The reaction mi(ture was heated to reflu( for ;D minutes, cooled to room temperature, e aporated to half the olume, neutrali-ed with sodium hydrogen car%onate, and the product was o%tained after column chromatography! The reaction time was greatly decreased %y this method! Due to differences in yield the 1riedel5Crafts alkylation with 1eCl6, was the preferred method for alkylation!

H3
C

C
H 3

H3
C

C
H 3
C
H 3
C
H 3

&uCl

H3
C
H3
C

H3
C

C
H 3

1eCl6

The demethylation of the 45%en-yl56,75dimetho(y58,95di5tert5%utyl54H5car%a-ole pro ed to gi e rise to a lot of difficulties! Mainly due to the fact that the N5%en-yl group can %e clea ed under similar conditions! "n effort to selecti e demethylate the compound a num%er of different unsuccessful routes were tried! 1irst of the demethylation was carried out with &&r6 in dry C=8Cl8! ' solution of 45%en-yl56,75 dimetho(y58,95di5tert5%utyl54H5car%a-ole in C=8Cl8 was cooled to 59/oC, and &&r6 in C=8Cl8 was added drop wise to the stirred solution! The reaction was stirred at 59/ oC for 8 hours, and then allowed to reach room temperature! The reaction mi(ture was stirred o ernight, and the products purified %y column chromatography! ' mi(ture of compounds were collected when 8 e<ui alents of &&r6 was used, due to the fact the %en-yl5 protected aromatic anime, as well as the metho(y groups, was deprotected under these conditions! ' le el of chemoselecti ity for clea age of the metho(y5groups was e(pected, %ut unfortunately not o%ser ed!

32

"n order to e(plore this further, different procedures of deprotection of the 6,75dimetho(y5 compound was in estigated! ?eaction with freshly prepared sodiumethanethiolate in DMCV was tried, as the hard and soft nucleophile5principle would suggest increased reaction at the metho(y groups, compared to the %en-yl group.840! Unfortunately this was not the case! 'nd the procedure was a%andoned! 1rom the same perspecti e, deprotection %y reaction of the dimetho(y5compound with Hi" in DM1, was tried.840! This reaction only yielded the starting compound! 1urthermore deprotection %y reaction with TMC" (neat and with :,85dichloroethane as sol ent), at reflu(, as suggested in the literature, was tried .6D0! This reaction was also done at room temperature! 'fter workup of the reaction mi(ture, trace amounts of the desired compound was collected! Deprotection was also attempted %y reaction of the compound with methylsulphonic acid, heated to /DoC! Vnce again without satisfying products! Microwa e assisted demethylation was also tried! ?eaction of the dimetho(y5compound with BVt&u and :/5crown57 in ethyleneglycol, under microwa e radiation was carried out .6:0! The reaction tu%e was allowed to reach 88DoC and irradiated of 8 hours! Unfortunately this procedure failed as well! 'n alternati e microwa e assisted procedure, that seemed promising, was also tried! This included reaction of the dimetho(y5compound with pyridinium hydrochloride, under sol ent free conditions! The 45%en-yl56,75dimetho(y58,95di5 tert5%utyl5 4H5car%a-ole was mi(ed with 8 e<ui alents of pyridinium hydrochloride, and su%*ected to microwa e irradiation at 8:GE for :/ minutes! 'fter the period the reaction mi(ture was decomposed using ice water, and e(tracted with dichloromethane! This procedure also failed to yield the desired compound, and starting materials could %e isolated! This reaction was also carried out thermally (the mi(ture was heated to :/G5:4DoC), without microwa e irradiation, with the same result! The failed attempts of selecti e demethylation is shown in figure 8!G 3

Figure 2.%: 1ailed attempts at selecti e demethylation of 45%en-yl58,95di5 tert5%utyl56,75 dimetho(yc4H5car%a-ole!

33

'fter the numerous failed attempts at selecti e demethylation of 45%en-yl56,75dimetho(y58,95 di5tert5%utyl54H5car%a-ole, it was decided to modify the proposed synthetic pathway! To increase the yield of the demethylated product, it was decide to try stepwise deprotection of the N5%en-yl protected nitrogen, followed %y deprotection of the metho(y5groups with &&r 6! The deprotection of the N5%en-yl group was done %y o(idati e clea age of 45%en-yl56,75 dimetho(y58,95di5tert5%utyl54H5car%a-ole, with o(ygen, DMCV and Bt&uV in T=1.680! The car%a-ole deri ate was dissol ed in dry T=1, and DMCV was added to the mi(ture! Thereafter o(ygen was %u%%led through the solution for 8 hours! The clea age of the %en-yl group proceeded in high yield! DMCV BVt&u V8 T=1 ?eplacement of the %en-yl5group with a tosyl5group was suggested, as this should %e sta%le under the &&r65clea age of the metho(y groups! The tosylation was done %y reaction of 45 %en-yl56,75dimetho(y58,95di5tert5%utyl54H5car%a-ole with p5toluenesulphonyl chloride and sodiumhydride in T=1! The addition of sodiumhydride and p5toluenesulphonyl chloride was done at DoC, and then allowed to reach room temperature, followed %y continuous stirring for ; hours! The reaction mi(ture was then washed with water, e(tracted with C= 8Cl8, the sol ent was dried, and e aporated under reduced pressure! This yielded the N5tosylated compound in nearly <uantitati e yield!
H3
C
H3
C
H3
C
H3
C
H3
C
H3
C
N H O
O
C
H 3
C
H 3
C
H 3
C
H 3
H3
C
O
O
C
H 3
C
H 3
C
H 3
N S
O
O
C
H 3

H3
C
H3
C
H3
C
H3
C
N H O
O
C
H 3
C
H 3
C
H 3
C
H 3

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

C
H 3

>a= TsCl

H3
C

C
H 3

34

'fter the ma*or difficulties o%ser ed with the demethylation step, it was also decided to deprotect %oth the metho(y5groups and the 45%en-yl5group at the same time, %y reaction with 6 e<ui alents of &&r6! This reaction was carried out similar to the pre ious attempt of demethylation, descri%ed earlier! 'fter purification %y column chromatography, this reaction yielded the fully deprotected compound2 6,75dihydro(y58,95di5tert5%utyl54H5car%a-ole, in moderate yield!

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

HO

O
H C
H 3
C
H 3
N H C
H 3

&&r6 C=8Cl8

H3
C
H3
C
H3
C

C
H 3

1ormation of the dimerised compound was attempted %y o(idation of 6,75dihydro(y58,95di5 tert5%utyl54H5car%a-ole, %y reaction with $%(V'c); in acetic acid! This reaction was carried out at room temperature for :8 hours! The o(idation lead to selfcondensation of the compound, to yield the oligomers! These were identified %y M'HD"5TV15MC! The o(idation most likely yields the compound2 8,95di5tert5%utyl575hydro(y56H5car%a-ol565one, that underwent spontaneous selfcondensation (figure 8!7)! The o(idation was carried out in a ery dilute (D!: mM) solution in effort to minimi-e the formation of the undesired oligomers! 'fter identifying the formation of the oligomers, dehydration without purification was attempted, %y addition of &16[VEt8 to the reaction mi(ture! This reaction yielded a mi(ture different products, that was not successfully purified! The o(idation was also carried %y reaction with DDZ in acetonitrile, under nitrogen atmosphere! The formation of oligomers was also identified %y M'HD"5TV15MC for this reaction! These results were somewhat promising, and would %e interesting to in estigate further! .o(0
H3
C
C
H 3
H3
C
HO
H3
C
C
H 3
C
H 3
N H3
C
H3
C
C
H 3
N H H3
C
HO
O
H C
H 3
C
H 3
O
H C
H 3

H3
C
H3
C
H3
C
HO

C
H 3
C
H 3
C
H 3
O
O
H3
C
H3
C
H3
C
O

+
O

C
H 3

H3
C
C
H 3
C
H 3
H C
H 3
C
H 3
H3
C
O
H H3
C
O
H3
C
H3
C

C
H 3

H N

H3
C
C
H 3
C
H 3
H3
C

C
H 3

H N

O
C
H 3

O
H

HO
H3
C
H3
C
H3
C
N

O
C
H 3
C
H 3
C
H 3

H3
C
C
H 3
N H3
C

Figure 2.&3 ' proposed mechanism for the oliomeri-ation of 8,95di5 tert5%utyl575hydro(y56H5 car%a-ol565one! 1ormation of a a-atrio(a./0circulene was done %y reaction of 6,75dihydro(y58,95di5 tert5%utyl5

35

4H5car%a-ole with 8 e<ui alents of tert5%utyl5%en-o<uinone, with &16[VEt8 as catalyst! This reaction was carried out in dichloromethane, at room temperature! To a solution of 6,75 dihydro(y58,95di5tert5%utyl54H5car%a-ole in dry C=8Cl8, 8 e<ui alents of tert5%utyl5 %en-o<uinone, and an e(cess of &16[VEt8 was added! The reaction was stirred o ernight at room temperature, and yielded the desired compound in low yield
H3
C
C
H 3
C
H 3

HO
H3
C
H3
C

O
H C
H 3
C
H 3
N H C
H 3

C
H 3

&16[VEt8
C
H 3
C
H 3

C
H 3

C
H 3
C
H 3

C=8Cl8

H3
C
H3
C
C
H 3
O
NH

H3
C

O
H3
C
H3
C
C
H3

:he tetraa;a[+]circulene: The following will descri%e the work conducted on the synthesis of the tetraa-a./0circulene! "n order to synthesis the tetraa-a./0circulene a synthetic pathway was de eloped! This route included the following steps3 ?educti e hydrogenation of ;5nitronaphthalen5:5amine Tosylation of naphthalene5:,;5diamine to form N,N#5ditosyl5:,;5naphthalenediamine V(idation of N,N#5ditosyl5:,;5naphthalenediamine to form N,N#5ditosyl5:,;5 naphto<uinone diimide Condensation of the o(idi-ed compound with tert5%utylhydro<uinone

The first transformation in the synthesis of the tetraa-a./0circulene was a reducti e hydrogenation o er, palladium on car%on, of ;5nitronaphthalen5:5amine to yield the diamine! This reaction was carried out %y adding $dJC to a solution of ;5nitronaphthalen5:5amine in ethylacetate, and reducing the nitrogroup under ; %ar of hydrogen, The reaction essel was shaken in a mechanical shaker until consumption of hydrogen no longer occurred (ca! 8!G hours)! The reaction mi(ture was filtered through a layer of silica, and the olatile sol ent e aporated under reduced pressure! This yielded the diamine in <uantitati e yield! The product was used for further synthesis without further identification, as o(idation of the compound needed to %e a oided!

36

NH2

NH2

$dJC =8
NO
2
NH2

The N5tosylation of the diamine was done %y reaction of naphthalene5:,;5diamine and p5 toluenesulphonyl chloride, with pyridine as %ase! ' solution of naphthalene5:,;5diamine in pyridine was added p5toluenesulphonyl chloride, in a :38 molar ratio! The reaction mi(ture was stirred at room temperature o er night, poured into icewater and neutrali-ed with =Cl, e(tracted with C=8Cl8, and recrystalli-ed from acetic acid! This produced the desired N,N#5 ditosyl5:,;5naphthalenediamine in good yields (/7a)!

C
H 3
O
S
NH2
HN O

TsCl $yridine

NH2

HN S
O

C
H 3

The o(idation of N,N'-ditosyl5:,;5naphthalenediamine proceeded smoothly %y reaction with $%(V'c);! $%(V'c); was added to a solution of the ditosylated compound in acetic acid, and heated to ;G5GDoC! The reaction mi(ture was stirred at this temperature for : hour, the mi(ture was coled to room temperature, and the formed product was filtered off! The yellow crystals were recrystalli-ed from acetic acid, and yielded N,N#5ditosyl5:,;5naphto<uinone diimide in e(cellent yield (4;a)!

37

C
H 3
O
S
HN O
N O
S

C
H 3

$%(V'c); 'cV=

HN S
O

N S
O
C
H 3

C
H 3

The last step in the synthesis of the target compound, was a reaction of N,N#5ditosyl5:,;5 naphto<uinone diimide with tert5%utylhydro<uinone, with &16[VEt8 a catalyst! :M &16[VEt8 was added drop wise to a solution of N,N#5ditosyl5:,;5naphto<uinone diimide and tert5 %utylhydro<uinone in chloroform! The reaction mi(ture was heated to reflu(, and kept at this temperature for :G minutes! 'fter cooling to room temperature the formed product was filtered off, and recrystalli-ed from acetic acid! 'fter structural studies %y := >M?, it was e ident that a redo(5reaction had occurred instead of the desired condensation reaction! 'nd the o%tained product was the reduced compound2 N,N'-ditosyl5:,;5naphthalenediamine as well as tert5%utyl%en-o<uinone! $rolonged reaction time, of the condensation reaction, was also tried %ut yielded the same products!
C
H3
O
S
N O
O
H C
H3
C
H3
C
H3
HN C
H3
O
S
O
O
C
H3

C
H3
C
H3

&16[VEt8 C=Cl6
HN O
S
O
C
H3

P
N S
O
C
H3
O
O
H

P
O

'n o%ser ed %iproduct from this reaction was the tetrao(a./0circulene for condensation of the <uinone and the hydro<uinone! "n an effort to synthesi-e the desired target compound %romination of the N,N#5ditosyl5:,;5 naphthalenediamine at the 85position was attempted, as this compound afterwards would %e a%le to undergo an copper5cataly-ed aryl5aryl coupling, with the halogenated tert5

38

%utylhydro<uinone! 1irst the %romination was done %y reaction of N,N#5ditosyl5:,;5 naphthalenediamine and %romine in acetic acid! 'fter purification of the formed product, %y recrystalli-ation, it was e ident that an o(idation of the diamine had occurred, instead of the desired reaction! 'fter this o%ser ation %romination with >&C in acetonitrile was attempted instead! This reaction was carried out at room temperature, with a :3: molar ratio of >&C and N,N#5ditosyl5 :,;5naphthalenediamine! 'fter completion of the reaction, two products was identified2 the %rominated compound as well as the o(idi-ed diamine!

2.": Future perspecti(es:

' successful synthetic route to the a-atrio(a./0circulene ha e %een de eloped, %ut impro ed reaction conditions to increase yield would %e necessary to in estigate! 'n alternati e route to the desired 45%en-yl58,95di5tert5%utyl56,75dihydro(y54H5car%a-ole was thought out, to o ercome the synthetic difficulties of the deprotection of the metho(y groups in pressence of the %en-yl group! This synthesis would start from the commercially a aila%le 6,6#5dimetho(y5:,:#5%iphenyl, and the final step would %e the formation of the car%a-ole , %y palladium cataly-ed dou%le N5arylation of the primary %en-ylamine! The proposed synthetic route is shown in figure 8!9!
O
C
H 3

a
Br

C
H 3

%
H3
C
H3
C

C
H 3

C
H 3

C
H 3
C
H 3

Br

c
Br
H3
C
H3
C
C
H 3
O
H

O
H

C
H 3

C
H 3
C
H 3

HO
H3
C
H3
C
H3
C
N

O
H C
H 3
C
H 3
C
H 3

Br
O
C
H 3
O
C
H 3

Br

Br

C
H 3

O
C
H 3

Figure 2.*: 'n alternati e route to the desired 45%en-yl58,95di5tert5%utyl56,75dihydro(y54H5 car%a-ole! a) &r8, 'cV=, rt!, %) t&uCl, 1eCl6, C=8Cl8, rt! c) &&r6, C=8Cl8, d) $d8d%a6, ligand, >aVt&u, toluene, /DoC This route would ensure that the N5%en-yl group and the metho(y groups wouldn#t %e present in the molecule at the same time! Unfortunately this was not attempted! The dimeri-ation of 8,95Di5tert5%utyl54H5car%a-ole56,75diol, under o(idati e conditions, seemed promising, and tweaking the conditions for this reaction is also desired! The formation of the tetraa-a./0circulene under different conditions, perhaps %y transition metal cataly-ed aryl5aryl coupling of the halogenated analogues, with materials like $d, $%, ?u or Cu, is also a route that need further in estigation!

39

2.%: =2peri)ental section This section will pro ide a detailed plan for synthesis of the compounds descri%ed in the thesis! "ncluding the data o%tained for characteri-ation of these compounds! ,0>en;yl0,H0carba;ole: &n&r toluene
N H

>aV= &u;>P"5

4H5Car%a-ole (G!G: g, D!D66 mol) was added to toluene (GD mH), and thereafter :8M >aV= (GD mH) was added to the suspension! The mi(ture was stirred for :D minutes, and tetra%utylammoniumiodide (:!88 g, 6!6 mmol) was added while stirring, at room temperature! &en-yl%romide (::!4 mH, D!: mol) was added drop wise o er a period of one hour! The reaction mi(ture was stirred for four hours, and the organic phase was separated in a separation funnel! The organic phase was dried with MgCV ;, and the olatile su%stances were e aporated in acuum! The o%tained product was recrystalli-ed from EtV= (8DD mH), and washed repeatedly with EtV=, until the crystals where white! Yield3 /!7G g, 4/a!
:

= >M? (GDD M=-, CDCl6) X /!D7 (d, J N 9!G =-, 8=), 9!6; (d, J N 7!4 =-, 8=), 9!84 (d, J N C >M? (:87 M=-, CDCl6) X :;D!9, :69!8, :8/!/, :89!G, :87!;, :8G!4, :86!D, :8D!;, ::4!8,

9!G =-, 8=), 9!:9 (m, G=), 9!D9 (d, J N 7!4 =-, 8=), G,;G (s, 8=)!
:6

:D/!4, ;7!7! Calculated a for C:4=:G>3 C //!7/ a, = G!// a, > G!;;a, found a for C:4=:G>3 C //!69 a, = G!46 a, > G!9D a! Melting point3 literature.6602 ::85::GoC, measured2 ::;5::7oC!

40

,0>en;yl0!?&0dibro)o0,H0carba;ole:
Br
Br

'cV=
&r8
N N

To a suspension of 45%en-yl54H5car%a-ole (7!4; g, D!D89 mol) in glacial acetic acid (9G mH), was added %romine (8!97 mH, D!DG; mol) i glacial acetic acid (9G mH) drop wise, o er a period of one hour, at room temperature! 'fter addition of half the %romine, the reaction mi(ture turned clear! The reaction mi(ture was stirred for 8 hours, and the formed white crystals were collected! The crystals were dissol es in methylenechloride (8G mH), washed with water (8 ( GD mH), dried with MgCV;, and the sol ent was e aporated in acuum! The white crystals were recrystalli-ed from 'cV=! Yield3 4!/G g, /Ga! := >M? (GDD M=-, DMCV) X /!G: (s, 8=), 9!7G (d, J N /!9 =-, 8=), 9!7D (dd, J N /!9, 8!D =-, 8=), 9!659!8; (m, :=), 9!86 (d, + N 9!G =-, 8=), 9!:6 (d, + N 9!G =-, 8=), G!7/ (s, 8=)!
:6

C >M? (:87 M=-, DMCV) X :64!8, :69!8, :84!D, :8/!7, :89! ;, :87!7, :86!G, :86!:, :::!4,

:::!7, ;G!/! Calculated a for C:4=:6>&r83 C G;!49 a, = 6!:7 a, > 6!69 a, &r 6/!GD a, found a for C:4=:6>&r83 G;!/G a, = 6!:8 a, > 6!;G a! Melting point3 literature.6;02 :785:76oC, measured2 :G/5:7:oC!

41

,0>en;yl0!?&0di)etho2y0,H0carba;ole:
Br
Br

>aVMe J MeV= Cu(")" DM1

H3
C

C
H 3

To a 8GD mH round %ottomed flask, 45%en-yl56,75di%romo54 H5car%a-ole (G!74 g, D!D:69 mol) was added to dry DM1 (:DD mH), under nitrogen atmosphere! >aVMe (:8G mH, 8Ga >aVMe in MeV=) was added, and Cu(")" (8Dmola) in small portions o er :D minutes! The reaction was kept under nitrogen, and reflu(ed o ernight! The reaction mi(ture was e(tracted with C=8Cl8 (8 ( GD mH), and washed with water (8 ( 8G mH)! The com%ined organic phase was e aporated to dryness, and the white crystals was recrystalli-ed from MeV= (GD mH)! Yield3 ;!:6 g, 4G a!
:

= >M? (GDD M=-, DMCV) X 9!9G (d, J N 8!G =-, 8=), 9!;/ (d, + N /!/ =-, 8=), 9!8; (d, + N

9!; =-, 8=), 9!8D ( d, + N 9!; =-, 8=), 9!:; M 9!D/ (m, :=), 9!D6 (dd, + N /!/, 8!G =-, 8=), G!G9 (s, 8=), 6!/G (s, 7=)!
:6

C >M? (:87 M=-, DMCV) X :G6!D, :6/!:, :6G!7, :8/!G, :89!:, :87!7, :88!G, ::;!4, ::D!6,

:D6!8, GG!7, ;G!9! Calculated a for C8:=:4>V83 C 94!;9 a, = 7!D6a, > ;!;: a, V :D!D/ a, found a for C8:=:4>V83 C 94!6/ a, = 7!DG a, > ;!;7 a! Melting point3 :8/5:6DoC!

42

,0>en;yl02?*0di0tert0butyl0!?&0di)etho2y0,H0carba;ole:

H3
C

C
H 3

&uCl

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

1eCl6
N

C=8Cl8

C
H 3

45&en-yl56,75dimetho(y54H5car%a-ole (D!6D g, D!4; mol was added to a GD mH round %ottomed flask, containing dry methylenechloride (:D mH)! 1eCl6 (D!: g, D!7: mmol) was added to the mi(ture! t&uCl (7 mH, G;!; mmol) in dry methylenechloride (7D mH), was added drop wise to the solution at DoC, under nitrogen atmosphere, while stirring! The reaction mi(ture was allowed to reach room temperatue o er a period of 8 hours! The mi(ture was stirred o er night, and the reaction mi(ture was e aporated to a thick %rown oil! The product was purified %y column chromatography (EtV'c J =eptane )! Yield2 D!87 g, 7G a!
:

= >M? (GDD M=-, DMCV) X 9!9: (s, 8=), 9!6G (s, 8=), 9!6: M 9!:/ (m, G=), G!G9 (s, 8=), C >M? (:87 M=-, DMCV) X :G8!;, :6/!;, :67!6, :6G!:, :8/!G, :89!:, :87!4, ::8!D, :D9!D,

6!48 (s, 7=), :!;D (s, 4=)!

:6

:D6!D, GG!/, ;G!7, 6G!:, 6D!D! Calculated a for C84=6G>V83 C /:!D/ a, = /!8: a, > 6!87 a, V 9!;G a, found a for C84=6G>V8 3 C /:!88 a, = /!:/ a, > 6!84 a! Melting point3 :765:7GoC!

43

2?*03i0tert0butyl0!?&0di)etho2y0,H0carba;ole:

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

BtV&u DMCV V8 T=1

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

C
H 3

N H

C
H 3

45&en-yl58,95di5tert5%utyl56,75dimetho(y54H5car%a-ole (:!G g, 6!66 mmol) was added to dry T=1 (6G mH) in a :DD mH flamedried round %ottomed flask under nitrogen atmosphere! DMCV (G!8G mH, D,D96 mol) was added, and BVt&u (6!D6 g, D!D89 mol)! The nitrogen flow was stopped, and o(ygen was %u%%led through the solution for 8 hours! The reaction mi(ture was e aporated in acuum, and purified %y column chromatography(tolueneJheptane)! Yield2 :!D9 g, 4Ga!
:

= >M? (6DD M=-, DMCV) X :D!G: (s, :=), 9!G4 (s, 8=), 9!8; (s, 8=), 6!// (s, 7=), :!64 (s, C >M? (:87 M=-, DMCV) X :G8!D, :67!D, :6;!4, :8D!6, :D/!;, :D8!9, GG!9, 6G!D, 6D!D!

:/=)!
:6

Calculated a for C88=84>V8 3 C 99!/; a, = /!7: a, > ;!:6 a, V 4!;6 a, found a for C88=84>V8 3 C 99!/8 a, = /!78 a, > ;!:7 a! !roposed mechanism"

44

2?*03i0tert0butyl0,H0carba;ole0!?&0diol:

H3
C
H3
C
H3
C
H3
C

C
H 3
C
H 3
C
H 3

HO

O
H C
H 3
C
H 3
N H C
H 3

&&r6 C=8Cl8

H3
C
H3
C
H3
C

C
H 3

45&en-yl56,75dimetho(y58,95di5tert5%utyl54H5car%a-ole (:!D g, 8!66 mmol) was addded to dry C=8Cl8 (6G mH), in a :DD mH flamedried round %ottomed flask, under nitrogen atmosphere, and cooled to M 9/oC! :M &&r6 (;!9 ml, ;!9 mmol) in dry C=8Cl8 (6G mH) was added drop wise to the solution o er a period of 6D minuttes, while stirring! The reaction mi(ture was stirred for 8D minuttes, and more :M &&r6 in C=8Cl8 (8!6 ml, 8!6 mmol) in dry C=8Cl8 (:8 mH) was added dropwise! The reaction mi(ture was kept at 59/oC for a duration of 8 hours, and then allow to reach room temperature! The reaction was stirred o ernight, and the product was purified %y dry column chromatography (EtV'cJ=eptane)! Yield3 /6a, D!7D g!
:

= >M? (GDD M=-, DMCV) X :D!88 (s, :=), /!97 (s, 8=), 9!:/ (s, 8=), 9!:7 (s, 8=), :!;6 (s,

:/=)! Calculated a for C8D=8G>V8 3C 99!:; a, = /!D4 a, > ;!GD a, V :D!8/ a, found a for C8D=8G>V8 3 C 99!88 a, = /!:8 a, > ;!;6 a! !roposed mechanism
Br
H3
C
H3
C
H3
C
H3
C
N O
O
C
H3
C
H3
C
H3
C
H3

Br
B

Br

Br

Br
B O
C
H3
C
H3

&&r6

H3
C
H3
C
H3
C
H3
C

O
+

C
H3
C
H3

5 Me&r

H3
C
H3
C
H3
C
H3
C

C
H 3
N C
H3

C
H3

=8V 5 =6&V6

H3
C
H3
C
H3
C
H3
C

H C
H3
C
H3

H3
C

H C
H3
C
H3

&&r 6

H3
C
H3
C
H3
C

+
N

5 &n&r

C
H3

B Br

Br
Br

C
H3

=8V
H3
C
H3
C
H3
C
H3
C
Br
N B Br
O
O
H C
H3
C
H3
C
H3

?epeat
H3
C
H3
C
H3
C
H3
C
N H O
O
H C
H3
C
H3
C
H3

5 =6&V6

demethylatyion
H3
C
H3
C

H C
H3
C
H3

H3
C

N H

C
H3

45

2?*03i0tert0butyl0!?&0di)etho2y0,0tosyl0,H0carba;ole:
H3
C
H3
C
H3
C
H3
C
H3
C
H3
C
N H O
O
C
H 3
C
H 3
C
H 3
C
H 3
O
O
C
H 3
C
H 3
C
H 3
N S
O
O
C
H 3

>a= TsCl DM1

H3
C
H3
C

C
H 3

6,75Dimetho(y58,95di5tert5%utyl54H5car%a-ole ( D!: g, D!6 mmol ) was dissol ed in dry DM1 (:D mH), in a flamedried GD mH round %ottomed flask! The solution was cooled to D oC, and >a= (D!DG g, D!6 mmol) was added while stirring! 'fter stirring for :D minutes, p5 toluenesulphonyl chloride (D!D/ g, D!6 mmol) was added to the stirring solution! 'fter stirring for ; hours, the reaction mi(ture was washed with water (GD mH), and C= 8Cl8 (GD mH)! The organic phase was separated in a separation funnel, and e aporated to yield the desired product! Yield3 48a!
:

= >M? (6DD M=-, DMCV) X /!D4 (s, 8=), 9!7G (s, 8=), 9!;4 (d, J N /!8 =-, 8=), 9!86 (d, J N C >M? (:87 M=-, DMCV) X :GG!4, :;G!:, :69!;, :66!6, :68!D, :84!4, :87!D, :8G!8, ::8!4,

/!8 =-, 8=), 6,/4 (s, 7= ), 8!8: (s, 6=), :!;8 (s, :/=)!
:6

:D6!D, GG!7, 6G!8, 84!9, 8D!4! Calculated a for C84=6G>V;C 3 C 9D!G7 a, = 9!:G a, > 8!/; a, V :8!47 a, C 7!GD a, found a for C84=6G>V;C 3 C 9D!G8 a, = 9!:7 a, > 8!/7 a! Melting point3 8:4588:oC!

46

5;atrio2a[+]circulene:

H3
C

C
H 3
C
H 3

O
HO
H3
C
H3
C
H3
C
N H O
H C
H 3
C
H 3
C
H 3
O
C
H 3
C
H 3
C
H 3

C
H 3

P
H3
C
H3
C
C
H 3
O
NH

C
H3
C
H3

P 8
O

H3
C
H3
C
C
H3

8,95Di5tert5%utyl54H5car%a-ole56,75diol (D!G g, :!7 mmol), was dissol ed in dry C= 8Cl8 (8D mH), in a flamedried GD mH round %ottomed flask! Tert5&utyl%en-o<uinone (:!DG g, 7!; mmol) was added to the solution, and :M &16[VEt8 "n C=8Cl8 (7!7 mH, 7!7 mmol ) was added drop wise at room temperature, while stirring! The reaction mi(ture was stirred o er night, and washed with water ( 8 ( 8G mH)! The organic phase was dired with MgCV;, and the olatile components was e aporated under reduced pressure! The product was purified %y column chromatography (EtV'cJ=eptane)! Yield3 D!D;9 g, G!D: a!
:

= >M? (6DD M=-, CDCl6) X /!8G (s, :=), 9!79 (s, 8=), 9!;; (s, 8=), :!9D (s, :/=), :!77 (s, C >M? (:87 M=-, CDCl6) X (not o%tained)

:/=)!
:6

Calculated a for C;D=;:>V63 C /8!6a, = 9!D/a, > 8!;a, V /!88a, found a for C ;D=;:>V63 (not o%tained)! Melting point3 (not o%tained) !roposed mechanism"

47

4apthalene01?"0dia)ine:

NH2

NH2

=8 $dJC
NO
2
NH2

:5'mino5;5nitronaphthalene ( 8!D: g, :D!7/ mmol ) and $dJC (D!G g, :Da $d), was added to EtV'c (8DD mH), and hydrogenated for 8 hours at ; %ar =8! 'fter the consumption of =8 stopped, monitored %y pressure (d 8 hours), the reaction mi(ture was filtered through a layer of celite, and the sol ent was e aporated under reduced pressure, to yield yellow crystals! Yield3 4/a!
:

= >M? (GDD M=-, DMCV) X 9!4; (dd, J N 7!G, 6!6 =-, 8=), 9!6; (dd, J N 7!G, 6!6 =-, 8=), C >M? (:87 M=-, DMCV) X :6G!:, :8;!8, :86!G, :88!7, :D4!G!

7!G; (s, 8=), ;!99 (s, ;=)!

16

Calculated a for C:D=:D>8 3 C 9G!48 a, = 7!69 a, > :9!9:a, found a for C:D=:D>83 C 9G!4: a, = 7!67 a, > :9!46 a! Melting point3 literature.6G02 ::;5::7oC, measured2 ::G5::9oC!

48

N?N@0#4aphthalene01?"0diyl$bis#"0)ethylben;enesul ona)ide$:
C
H 3
O
S
NH2
HN O

TsCl $yridine
NH2
HN S
O
C
H 3
O

>aphtalene5:,;5diamine (:!7D g, :D,:7 mmol) was added to pyridine (:GD mH), in a 8GD mH round %ottomed flask! p5Toluenesulphonyl chloride (;!DG g, 8D!68 mmol) was added to the soultion while stirring! The reaction mi(ture was stirred o er night, and poured into ice5water (8DD mH ), and :8M =Cl (GD mH) was added while stirring! 'fter G minutes, stirring was stopped and transferred to a separation funnel! E(traction was done with C= 8Cl8 (8DD mH), the organic phase was dried with MgCV;, e aporation under reduced pressure, and recrystalli-ation from acetic acid! The reaction yielded orange crystals! Yield2 /7!G a (;!:D g)!
:

= >M? (GDD M=-, CDCl6) X 9!/8 (dd, J N 7!G, 6!6 =-, 8=), 9!G/ (d, J N /!: =-, 8=), 9!;; C >M? (:87 M=-, DMCV) X :;6, :69, :6:, :6D, :84!G, :87!7, :87!::, :86!6, :88!7, 8D!4

(dd, J N 7!G, 6!6 =-, 8=), 9!:4 (s, 8=), 9!:9 (d, J N /!: =-, 8=), 7!7D (s, 8=), 8!69 (s, 7=)!
:6

Calculated a for C8;=88>8V;C8 3 C 7:!9/ a, = ;!9Ga, > 7!DD a, V :6!98 a, C :6!9; a, found a for C8;=88>8V;C83 C 7:!98 a, = ;,97 a, > 7!D/ a! Melting point3 literature.6702 8;8oC, measured2 8;:58;8oC!

49

N?N@0#naphthalene01?"0diylidene$bis#"0)ethylben;enesul ona)ide$:

C
H 3
O
S
HN O
N O
S
O

C
H 3

$%(V'c); 'cV=

HN S
O

N S
O

C
H 3

C
H 3

N,N#5(>aphthalene5:,;5diyl)%is(;5methyl%en-enesulfonamide) ( 8!G g, G!6G mmol) was added to 'cV= (GD mH) in a :DD mH round %ottomed flask! $%(V'c) ; (8!Gg, G!76 mmol) was added to the stirred solution, and the mi(ture was heated to ;G5GDoC! 'fter : hour the solution was allowed to cool to room temperature, and yellow crystals precipitated! The crystals were filtered off, and recrystalli-ed from acetic acid (GD mH)!Yield2 46a
:

= >M? (6DD M=-, CDCl6) X /!66 (s, 8=), /!:/ (dd, + N 7!D, 6!6 =-, 8=), 9!47 (d, J N /!: =-, C >M? (:87 M=-, CDCl6) X :7:!7, :;;!G, :69!7, :66!8, :68!9, :6D!9, :84!/, :89!G, :87!4,

8=), 9!7D (dd, + N 7!D, 6!6 =-, 8=), 9!64 (d, J N /!: =-, 8=), 8!;/ (s, 7=)!
:6

8:!9! Calculated a for C8;=8D>8V;C8 3 C 78!DG a, = ;!6; a, > 7!D6 a, V, :6,9/ a, C :6!/D a, found a for C8;=8D>8V;C83 C 78!D/ a, = ;!68 a, > 7!D; a! Melting point3 literature.6702 88DoC, measured2 8885886oC! !roposed mechanism"
H3
C
O
S
O
NH O
H3
C
O
S
N AcO
P
b
O
Ac O
O
H3
C
O
S
N O
O
H

H3
C
AcO
P
b

O
O
Ac O
S
N AcO

AcO

P
O
S
O
H3
C
H3
C
NH O
S
O
NH

H3
C

C
H 3
O
N S
O
H3
C

P
b
AcO

O
S
O
H3
C

N H

50

:errao2a[+]circulene

H3
C

C
H3
C
H3

H3
C
H3
C

C
H 3

H3
C

C
H3

&16[VEt8 C=8Cl8
O

H3
C
C
H3
O
O
C
H 3
C
H3

H3
C
H3
C
C
H3

tert5&utyl%en-o<uinone (:!D: g, 7!:G mmol ) was added to dry C= 8Cl8 ( :G mH ), in a GD mH round %ottomed flask! :M &16[VEt8 ( :G mH ) in dry C=8Cl8 ( :D mH ), was added drop wise to the stirred solution! 'fter addition of &16[VEt8, the reaction mi(ture was heated to reflu(, and was kept at this temperature o ernight! 'fter cooling of the reaction mi(ture, 8 M =Cl (:DD mH) was added while stirring! The organic phase was separated in a separation funnel, and the olatile components e aporated under reduced pressure! The collected product was purified %y column chromatography (=eptaneJEtV'c)! Yield3 88a, D!8D g!
:

= >M? (GDD M=-, CDCl6) X3 Came as literature.67`! C >M? (:87 M=-, CDCl6) X3 Came as literature.670!

:6

51

2.&: Spectral

data #1A 4B'$:

52

53

54

55

56

57

58

59

60

61

2.*: Spectral

data #1!C 4B'$:

62

63

64

65

66

67

68

69

70

2.+: /C0BS:

71

72

73

74

75

76

'e erences: .:0 He%ermann, C! #er$ :/ (1++%) p!477547/ .80 Erdtman, =! $roc! %o&$ 'oc$ ( :;6 (1,!!) p!88/ .60 Erdtman, =!, =Ig%erg =! E! )hem$ )omm! 8 (1,&+) p!996599; .;0 Erdtman, =!, =Ig%erg =! E! Tetrahedron 6G (1,*,) p!G6G5G;D .G0 Cy in, C! +!, &rendsdal, E!, &run oll, +!, Ckaret, M! J$ *ol$ 'tr+c! 8;9 (1,,1) p!::45:89 .70 Yamamoto, B!, =arada, T!, >aka-aki, M!, >akao!, T!, Bai, Y!, =arada, C!, Basai, >!, J$ (m$ )hem$ 'oc$ :DG (1,+!) p!9:9: .90 Dopper, +! =!, Eyn%erg, =!, J$ Org$ )hem$ ;D (1,*%) p!:4G95:477 ./0 >ielsen, C! &!, &rock5>annestad, T!, ?een%erg, T! B!, =ammersh,*, $!, Christensen, +! &!, Ctouwdam, +! E!, $ittelkow, M! )hem$ ,+r$ J$ :7 (2818) p!:6D6D5:6D6; .40 Clar, E! Eiley Hondon (1,*2) .:D0 Wi*ayalakshmi, B! $!, Curesh!, C! =!, New J$ )hem$ 6; (2818) p!8:6858:6/ .::0 Broto, =! E! et al! Nat+re 6:/ (1,+%) p!:785:76 .:80 Ccholl, ?!, Meyer, B! #er$ 7G (1,!2) p!4D8 .:60 >ewman, M! C! J$ (m$ )hem$ 'oc$ 78 (1,"8) p! :7/65:7/9 .:;0 Chen, =! C!, Tang, +! M!, Chang, =! B!, Yang, C! E!, Hu, ?! C! J$ Org$ )hem$ 9D (288%) p!:D::65:D::7 .:G0 &arth, E! E, Hawton, ?! G! J$ (m$ )hem$ 'oc$ // (1,&&) p!6/D56/: .:70 Groen, =! C, Eyn%erg, =! J$ Org$ )hem$ 'oc! 4G (1,*!) p!6748 .:90 Cherichenko, B! Y, Cumerin, W! W!, Chpanchenko, ?! W!, &alenko a, E! C!, >ena*denko, W! G! (ngew$ )hem$ ::/ (288&) p!9G8959G6D .:/0 Bing, &! T!, &harat, &hola, ?!, &ally, T!, Walente, '!, Cyraeski, H! D!, Cpain, C! M!, ?empala, $!, Chin, M! ?!, (ngew$ )hem$ ;4 (2818) p!6445;D8 .:40 Mehta, G!, $anda, G! )hem$ )omm$ (1,,*) p!8D/:58D/8 .8D0 Me*ls,e, C! *asters thesis (288&) .8:0 Harsen, U! *asters thesis (2881) .880 Christensen, +! &!, ?een%erg, T!, Eskildsen, +! ,+r$ J$ Org$ )hem$ (2888) p!:7695:7;D .860 Cteed, +! E!, 'rtwood, +! H!, f'+pramolec+lar )hemistr&f (2888) Eiley .8;0 Hi, C! et al! J$ !h&s$ )hem$ ::6 (288,) p!:::775:::98 .8G0 Dahm, ?! -evel$ #io$ 89/ (288%) p!89;58// .870 Huedtke, >! E! )hima 76 (288,) p! :6;5:64 .890 Murat, $!, Cingh, Y!, Defranc<, E! )hem$ 'oc$ %ev$ article DV"3 :D!:D64Jc:cs:G::9g .8/0 Tian5Miao, V!, et al! )hemmedchem, article DV"3:D!:DD8Jcmdc!8DD9DD6DD

77

.840 1leming, "! f*olec+lar or.itals and organic chemical reactions f (2818) Eiley .6D0 +ung, M! E!, Hyster, M! '! Org$ '&n$ )oll! 7 (1,++) p!6G .6:0 Bulkarni, $! $!, Badam, '! +!, Maine, ?! &!, Desai, U! W! J$ )hem$ %esearch (1,,,) p!64;5 64G .680 =addach, '! '!, Belleman, '!, Deaton5?ewolinski, M! W! Tet$ /ett$ ;6 (2882) p!6445;D8 .660 He y, &!, )hem$ *onth$ 8 (1,12) p!:94 .6;0 Sing, +! 1! et al!, %$ '$ J$ )hem$ Org$ :9 (288*) p!:;66 .6G0 &langey, H!, Helv$ )hem$ (cta 8: (1,!+) p!:G94 .670 Mate osyan, B! ?!, Hokmane, g! Ya!, 1reimanis, Ya! 1!, 0h+r$ Org$ 1him! 84 (1,,!) p!:D:85:D:/ .690 &rock5>annestad, T!, >ielsen, C! &, Cchau5Magnussen, M!, =ammersh,*, $!, ?een%erg, T! B!, $etersen, '! &!, Trpce ski, D!, $ittelkow, M!, ,+r$ J$ Org$ )hem$ 6: (2811) p!768D5768G

78