part i general characteristics of calixarenes · 1.1 functionalization of the narrow rim 11 r a h b...

Part I

General Characteristics of Calixarenes

Calixarenes and Resorcinarenes: Synthesis, Properties and Applications. W. Sliwa and C. KozlowskiCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32263-3

7

1Reactivity of Calixarenes

Numerous reactions of calixarenes have been reported [1–14]; some examples ofthese are described here. To improve the properties of calixarenes, functionalizationof the narrow [15–17] as well as of the wide rim is carried out [18–20]. In the firstpart, functionalization of the narrow rim of calixarenes is described, followed byfunctionalization of the wide rim. Then some examples of calixarene bridging arepresented.

1.1Functionalization of the Narrow Rim

A series of calixarenes bearing azo chromophores on the narrow rim were synthe-sized using two routes. The first one was a direct reaction of calixarenes 1a–c with4-chloroacetoaminoazobenzene 2 in the presence of K2CO3 and KI. In the second,indirect approach calixarenes reacted with ethyl chloroacetate affording esters 3hydrolyzed to give acids 4, which were treated with thionyl chloride, followed byp-aminoazobenzenes ArNH2. Both procedures led to the formation of calixarenes5 containing azo chromophores [21].

2

ClO

NHAr

na 4b 6c 8

Arna–cd–f 4, 6, 8 Ar2

4, 6, 8 Ar1

nO NHAr

O

5

43

1

Cl COOEtn 1. SOCl22. ArNH2

nO COOH

NaOH/

EtOH

nO COOEt

K2CO3 / KI / acetone

OH

N N , Ar2 = N N

Me

Me

Ar1 =

Calixarenes and Resorcinarenes: Synthesis, Properties and Applications. W. Sliwa and C. KozlowskiCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32263-3

8 1 Reactivity of Calixarenes

In order to introduce the ferrocenyl unit into calixarenes, the reaction of 1a–c withethyl chloroacetate affording esters 3 was performed. These compounds reactedwith hydrazine to give hydrazides 6, which upon treatment with ferrocenecarbox-aldehyde yielded derivatives 7 [22].

H2N–NH2K2CO3 / KI /

acetoneOH

n nO

OEtO

COOEtCl

na 4b 61c 8

na 4b 63c 8

n nO

NH O

CHO/AcOH

Fe

NH2 NH–N=CH fc

OO

na 4b 66c 8

na 4b 67c 8

The reaction of calix[6]arene 8a with (+)-camphor-10-sulfonyl chloride RCl 9affords either the mono-O-sulfonylated product 8b or the hexa-O-sulfonylatedproduct 8c, depending on the stoichiometry [23]. This rather unexpected result, i.e.the absence of di- to pentasubstituted products, is due to the structure of 8b inwhich the camphor-sulfonyl unit covers the narrow rim of calixarene, thus forminga steric hindrance for substitution of the second hydroxyl group.

However, if the second hydroxyl group is sulfonylated, the two substituentsrepulse one another; therefore, other hydroxyl groups are exposed to reaction withexcess sulfonyl chloride to give 8c.

It was established that 1,3,5-trimethoxy-t-butylcalix[6]arene 10 reacts with phenyl-pyridines 11 and 12 and with fluorenylpyridine 13 to give calix[6]arenes 14, 15,and 16 respectively, functionalized at alternate rings on the narrow rim [24]. The1H NMR measurements show that 14–16 exist predominantly in the C3v coneconformation and have unusually deep cavities.

1.1 Functionalization of the Narrow Rim 9

OSO2Cl

RCl

XOOZ

XO

OX

OXOX

9

Xa Hb H8c R

ZHRR

13

R

R

N

Br

N

Br

N

O

NN

OMeO OMe

N

O

NN

OMeO OMe

HO OMeOH OMe

11

10

12

14 15

N

Br

HOMeO

OMeO OMeO

O OMe

N N N

R

R

R

R

R

R

R = n-C6H1316

OMeO O OMe


The restriction of the conformational flexibility of calix[6]arenes may be achievedby using the Ritter reaction. This procedure involves the reaction of calix[6]arenesbearing one, three, and six cyanomethoxy groups on the narrow rim i.e. 17, 18,and 19 respectively, with tertiary alcohols [25]. Functionalization of 17 and 18 with1-adamantanol 20a (RDH) or 3-substituted 1-adamantanol 20b (RDCH2COOH)yielded monoamides 21a,b and triamides 22a,b respectively, existing in rigid coneconformations.

6

X

O

N

5OHO

N

3O

N

OMe

Xa t-Bu

b

19

17 18

c COOMe

R

20

R

OH

HOHO OHO

O

OH OH

TFA

H

17R

20ab

HCH2COOH

R

21ab

HCH2COOH

N

1.1 Functionalization of the Narrow Rim 11

R

a Hb CH2COOH

R

TFA

O O O

O

NH

OMe

OOMe

R

OH

R

O

NH

O

HN

R

22

2018 Me

ROH / TFA2

X

O

N

X

O

O

HN

R

X

O

O

NH

R

19a–c

R X

a t-Bu

b t-Bu t-Bu

c t-Bu23

d t-Bu COOMe

The reaction of 19a–c bearing six cyanomethoxy groups showed an unexpectedregioselectivity, since with adamantanol or t-butyl alcohol they afford tetramides23, adopting a flattened 1,2,3-alt conformation. This result, i.e. the selectivefunctionalization of the narrow rim of calixarenes bearing exhaustively modifiedhydroxyl groups is rather surprising, because usually selective reactions occur incalixarenes with free hydroxyl groups.


1.2Functionalization of the Wide Rim

In order to obtain anion binding derivatives of calixarenes, syntheses of poly-Lewis-acid-based calixarenes have been studied. For this purpose, calix[4]arene 1a wassubjected to the removal of the t-butyl groups, followed by O-methylation to give24; its bromination afforded tetrabromocalix[4]arene 25. The reaction of 25 witht-butyllithium gave the tetralithium salt, which without isolation was silylatedwith chlorotrimethylsilane affording tetrasilylated derivative 26 and the trisilylatedderivative 27 [26]. However, the use of boron electrophiles after lithiation, e.g.boron trifluoride or boron trichloride instead of Me3SiCl, resulted in only partialboronation.

OMe

Br

4

NBS2-butanone

OMe 4

1. AlCl3 / phenol / toluene

2. NaH / MeI / DMF/ THF

OH4

1. t -BuLi / THF2. Me3SiCl

3OMe

SiMe3

OMe+

SiMe3

OMe4

1a

25

26 27

24

In the next experiment, calix[8]arene 1c was used. The removal of t-butylgroups from 1c afforded 28a, which was methylated to give 28b. The subsequentbromination yielded 29, which was lithiated, forming the octalithium salt; thiswithout isolation was treated with Me3SiCl, yielding 30. It was shown that onlypartial silylation occurs, since only disilylated compound 30 was obtained [26].

Tetraiodocalixarene 31 was subjected to the Wurtz–Fittig reaction with the useof Na/Me3SiCl in 1,2-dimethoxyethane (DME), affording the mixture of tetrakis-and tris-silylated calixarenes cone 32 and flattened cone 33, separated by chro-matography. However, the reaction of tetrabromocalixarene 34 with Na/Me3SiClin toluene gave 35, both C-silylated and O-silylated, which upon hydrolysis yieldedtetrakis-silylated calixarene 36 [27].

1.2 Functionalization of the Wide Rim 13

OMe2 6

88OROH

OMe

1. AlCl3 / phenoltoluene

2. NaH / MeI / DMF/ THF

NBS / toluene2- butanone

1. t-BuLi / THF2. Me3SiCl

8OMe

Br

SiMe3

1c R

HMe

ab28

29

30

OPr

Me3Si

PrO

SiMe3

OPr

SiMe3

+

Na / Me3SiClDME

OPr

Me3Si

PrO

SiMe3

OPr

SiMe3

OPr

I

PrO

I

OPr

31 Cone 32

Flattened cone 33

I

PrO

I

PrO

Me3Si

PrO

36

OH

SiMe3SiMe3Me3Si

HO OHHO

Me3Si

NaOMe / MeOHNa / Me3SiCl

toluene

34

O

Br

Ph

BrBr

O

Ph

O

Ph

O

Br

Ph

35

R

OR

R

R

OR OROR

R

R = SiMe3

It should be noted that the above Wurtz–Fittig reactions are promising, sincesuch large-scale processes are safer, cheaper, and easier to perform than thoseusing t-butyllithium.


A series of calix[4]arenes with azo moieties containing four, three, two, andone free phenol groups, as well as those without free phenol groups, have beeninvestigated in view of their conformational properties. Calixarenes with azomoieties, containing one to four free phenol groups were synthesized eitherby coupling calixarenes with corresponding diazonium salts or by reaction ofcalixarene diquinones with nitrosubstituted phenylhydrazines [28].

The coupling of calixarene 37a with diazonium salt 38 [29] affords azosubstitutedcalixarenes containing four free phenol groups 39; similarly, reactions of 40 with 38and 41 yield azosubstituted calixarenes containing three phenol groups 42. Similarreactions of calixarenes 43 with 38, 41, or 44 afford 45 containing two phenol groups.An alternative procedure, i.e. oxidation of 46 with ClO2 leading to calix[4]arenediquinones 47, subsequently treated with 4-nitro- and 2,4-dinitrophenylhydrazine,also gives rise to azosubstituted calixarenes containing two phenol groups 48. Thecoupling of calixarenes 49 with diazonium salts 38 or 41 yields calixarenes 50a,b,containing only one free phenol group.

R3R2R4

R1

R1 R2 R3 R4

OHHO OHOHHO OH

N

N2Cl−

DMF MeOH

HO HO

37a

38

AN

NN

a A H H HA A H HA H A HA A A HA A A A

bc39de

+

OH

RR

OMe OH

OHOMe OH

N

N2Cl−

or

O2N

+

N2Cl−+

DMF / MeOH

HOHO

R

N N NO2

R

A

N

a

b42

40

41

38

N


DMF / MeOH

+

O2N

or

N

R1O R1O OR1OR1HO OH HO

R2 R3

OH

or

N

N2Cl−

+N2Cl−

+N2Cl−

38 41

44

R1R1 R2

a CH2COOEt

b Mec COPh

43

d CH2Ph

a CH2COOEt H

H

A

H

A

N

N

R3

B

A

A

A

A

N

N

b CH2COOEt

c CH2COOEt

Me

Me

COPh

CH2Ph

d

e

f

45

gNN

N

B

OHHO

O

O

ClO2

NO2

R1O

R1O OR2OHOH

OR1

O2N NH NH2

R2

H2SO4

N NNN

NO2

R2 R2

O

R2R1O

R1

R1 R2

a COPh46

b CH2Ph

a COPh HHNO2

NO2

b CH2Phc COPh

48

d CH2Ph

R1

a COPh47

b CH2Ph


R

OMeHO

R

OMeOMeHO OMe

N

N2Cl−O2N

DMF / MeOH

49

+

N2Cl−+

or

50a

b

A

N

38

41

MeO MeO

Acetylation and benzoylation of calixarenes bearing azo moieties were carriedout for investigation of conformational changes that occur during these processes.In the study of calixarenes with four phenol groups, it was found that acetylationof cone 39a affords 1,3-alt 51, and benzoylation of 39b gives rise to paco 52.Acetylation of tetrasubstituted 39e containing four phenol groups yields 1,3-alt 53and acetylation of 42a,b with three phenol groups leads to paco 54a,b. Acetylationof 48a–d containing two phenol groups affords calixarenes 1,3-alt 55.

Ac2O / pyridine

N

O

Me

O O

Me

O

O

Me

OO

Me

OOHHO

N

OH

N

N

N

N

HO

39a 1,3-alt 51

PhCOCl / pyridine

OO

ON

O

O

N

N

OOOH

OH

NN

NN

NN

N

NN

HOHO O

39b Paco 52


Ac2O / pyridine

N

N

N

N

OHHO

NN

OH

N

N

N

N

NO

Me

OO

Me

O

N

N

N

N

N

N

NN

N

N

N

O

Me

O O

Me

O

HO

N

N

39e 1,3-alt 53

OHHO

RR

OH

R

Ac2O / pyridine

O

OMe

RO

R

O

R

MeO

Me

O

Me

OMeO

R

a A42

b N

R

a APaco 54

b N

Ac2O / pyridine

N

NO2 NO2

R2

R2

OH

N

OR1

N

N

NO2

R2

O

Me

OO

Me

O

NN

NN

NO2

HO

R2

R1O

R1O OR1

R1 R2

a COPh HHNO2

NO2

b CH2Phc COPh

48

d CH2Ph

R1 R2

a COPh HHNO2

NO2

b CH2Phc COPh

1,3-alt 55

d CH2Ph


The conformational flexibility of calixarenes is usually explained by the presenceof intramolecular hydrogen bonds, which is related to the number of free phenolgroups. Accordingly, calixarenes containing four phenol groups 39a–e exist as coneconformers.

It could be expected that the conformational properties will be influenced bythe decrease in the number of phenolic groups. However, it was shown that 42a,bcontaining three phenol groups and 45a–g containing two phenol groups also existas cone conformers. One should note that calixarenes with two phenol groups,obtained by an alternate route via calix[4]arene diquinones 47a,b present in theircone and paco conformations being in equilibrium with each other, afford 48a–das cone conformers. The results of single-crystal X-diffraction analysis of 50a,bcontaining one phenol group indicate that they are present in a flattened coneconformation [28].

An efficient synthesis of oligothiophene-substituted calix[4]arenes was per-formed. The process begins with the stabilization of the cone conformation ofcone 37a, which involves the alkylation of calix[4]arene with bromopropane orbromodecane, followed by bromination with N-bromosuccinimide (NBS). Thetetrabromoderivative 56 obtained was submitted to palladium-catalyzed Kumadacross coupling with thienylmagnesium bromide, prepared in situ, in the presenceof PdCl2(dppf) to give tetrathienyl calixarene 57. The bromination of 57 with NBSyielded 58, which, upon cross-coupling with thienylmagnesium bromide, affordedbisthienylcalixarene 59. By repetition of such a sequence of bromination withNBS and cross-coupling reactions, tris(thienyl)- and tetra(thienyl)calixarenes 60and 61 were obtained respectively [30]. The electrochemical and optical propertiesof synthesized oligothiophene-substituted calix[4]arenes 59–61 were determined.It should be noted that they show high thermal stability (Td > 400ŽC).

5857

56Cone 37a

NBS /CHCl3

PdCl2(dppf)

/ Mg / THFS

Br1. NaH / RPr / DMF2. NBS / CHCl3

O

HO

H

OH

OH

OR

BrBr

O

R

Br

OR

OR

Br

O

RO

R

OR

OR

SS

SS

O

RO

R

OR

OR

S

Br

S

BrS

Br

S

Br


m

mm

m

59

PdCl2(dppf)S

Br / Mg / THF

OR

OR

OR

OR

SS

SS

SS S

S

m = 1

60 61

m = 2 m = 3R = C3H7 or C10H21

dppf = 1,1′-bis(diphenylphosphino)ferrocene

The heteroarylation of calix[4]arene 37a at the wide rim was performed in aone-step procedure as an example of the direct C–C coupling of calixarene withelectron-poor 1,2,4-triazinone 62 via the SN

H methodology. The reaction can beperformed in trifluoroacetic acid (TFA) in the presence of acylating agents, such asacetic or trifluoroacetic anhydrides. Treatment of 62 with acetic or trifluoroaceticanhydride in TFA yields a protonated form of 2-acyl-1,2,4-triazinone. The processis accompanied by the rearrangement of the N(2)-acyl derivatives to those bearingthe acyl group at the N(1) atom, adjacent to the reaction center [31].

O

B

CF3

O

B

OO

B

HN

N

N

OPh(CF3CO)2O /

TFA

Ac2O / TFA

OHHO OH

OAc

A

OAc

AOAc

A

+

MeOH

OH

BB

HO

B

OH

N

N

N

OPh Ph

Ac

A

HNH

CF3CF3

O

O

37a 62

63

64

65

B

NN

O

CF3O

HO

AcO

A

O

B

CF3O

HO

B

Organic anhydrides acylate hydroxyl groups of calixarene 37a and change itsconformation from cone into 1,3-alternate. The nature of the acylating agentinfluences the stereochemistry of the reaction of 37a with 62. Thus, in the presenceof Ac2O, the 1,3-alt calixarene 63 is formed, whereas reaction with (CF3CO)2O andthe subsequent recrystallization from MeOH gives, via the 1,3-alt intermediate 64,the cone calixarene 65. It is noteworthy that 63 and 65 effectively transport La3+ ions.


R

aC

H2P

hb

Ac

cH

70

R

aC

H2P

hb

Ac

cH

71

R

aC

H2P

hb

Ac

OO

OO

N3

N3

N3

N3

N3

N3

OO

OO

OR

O RO

OR

OR

69

OO

OO

O

RO

RO

OR

RO

NNN

O

OR

OR

OR

RO

NNN

OO

OO

O

RO

RO

OR

RO

NNN

O

RO

RO

OR

RO

NNN

6667

O

OR

OR

RO

OR

NNN

O

OR O

R

RO

OR

NNN

CuI

/ i-P

r 2N

Et

tolu

ene

CuI

/ i-P

r 2N

Et

tolu

ene


The glycoside cluster effect exists in the carbohydrate–protein interaction, animportant process in intercellular communication and in the adhesion of bacteriaand viruses to the cell surface. For a better understanding of this effect, theglycocluster assemblies on calix[4]arene scaffold were synthesized.

The 1,2,3-triazole linkers have been formed via click chemistry, i.e. the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of azides to alkynes [32]. Calixarenes66 and 67 bearing azido units, as well as calixarene 68 containing ethynyl groups,were used as starting materials. The reaction of 66 and 67 with ethynyl glycoside 69afforded glycoclusters 70 and 71. The reaction of 68 with azidomethylglucoside 72yielded glycocluster 73. It should be noted that the formation of 1,4-disubstitutedtriazole rings resulted in very high yield [33].

68

R

a CH2Ph

b Ac72

R

a CH2Ph

b Ac73

OOO

O

ORO

RO

OR

ORN3

OOO

O

ORO

RO

OR

RO N NN

O

RO

RO OR

RO

NN

N

+

CuI / i-Pr2NEttoluene

N

NO

OR

OR

RO

RONNN

O

OR

ORRO

OR

N


Cholic acid is being used as a building block for the construction of confor-mationally controllable foldamers [34] and nonfoldamers [35]. It was establishedthat calixarene 74 can reversibly switch between a micelle-like conformation (withthe hydrophilic faces of cholates pointing outward) in polar environments and areversed-micelle-like conformation in nonpolar environments [36]. As a result ofthe conformational change, 74 can act as a tunable supramolecular host to bindpolar guests in nonpolar solvents and nonpolar guests in polar solvents.

The amphiphilic calixarene 75 containing cholate units linked by azobenzenespacers was synthesized. It was sensitive both to solvent changes (due to cholateunits) and ultraviolet (UV) irradiation (due to azobenzene units). In nonpolarsolvents, 75 turns its polar faces inward to bind polar guests, e.g. sugar derivatives.In polar solvents, 75 turns its nonpolar faces inward to bind hydrophobic guests,e.g. pyrene. Calixarene 75 can also respond to UV irradiation, resulting in thetrans – cis isomerization of azobenzene units; it should be noted that the responsetoward both kinds of solvents and UV light is fully reversible [37].

Many calixarenes bearing azobenzene units on the wide rim are known [38]. Thesynthesis of 75 begins with the diazotization of calixarene 76 followed by couplingwith phenol to give calixarene 77, which upon reaction with brominated cholate 78affords 75.

In the study of guest-binding properties of 75, it was observed that, in 5%CD3OD/CCl4, i.e. a mostly nonpolar mixture, 75 binds phenyl β-d-glucopyranoside79. The binding of polar guests in a nonpolar mixture shows that 75 can adoptreversed-micelle-like conformations similar to that of 74.

O

R

O

R

O NH

OHNO NH

HO

HO

HO

HO

HO

HO

HN O

OH

OH

OH

OH

OH

OH

O

RO

RR = n-C6H13

74


OO

N

O

O

O

R

O

R

NN

N

HO

HO

HO

HO

HO

O

RO

R

NN

N N

HO

OH

OH

OH

OH

OH

OH

R = n-C6H13 75

78

OR

O

R

H2NH2N NH2 NH2

O

RO

R

1. NaNO2 / HCl2. Phenol / pyridine

OR

O

R

NN

NN N

N

NN

O

RO

R

OH

OHOH OH

Br

OHOH

OH

75

76 77R = n-C6H13

OOHO

OH

HOOH

79 80


It was found that pyrene 80 is a suitable guest for the micelle-like conformer. Inmethanol, 74 and 75 bind with pyrene through the hydrophobic faces of cholates,supporting the formation of micelle-like conformations in polar solvents. Theabove experiments combining the solvent-induced conformational changes andphotoisomerization of 75 show their dual responsive properties.

The palladium-catalyzed Buchwald–Hartwig procedure was used for the syn-thesis of cyclenylcalixarenes [39]. Monobromo- and dibromocalixarenes 81 and 82reacted with threefold Boc-protected cyclen 83b in the presence of catalytic amountof Pd(OAc)2 and tris(t-butyl)phosphine affording mono- and biscyclenylcalixarenes84 and 85 respectively. It should be mentioned that cyclen 83a was Boc-protected togive 83b in order to avoid the connection of more calixarene units on its molecule.The Boc-protective groups were removed from 84 and 85 in the presence of TFA togive N-protonated mono- and biscyclenylcalixarenes 86 and 87. They were basifiedwith a basic anion exchanger affording mono- and biscyclenylcalixarenes 88 and89, which upon treatment with Zn(ClO4)2ž6H2O yielded metallated compounds 90and 91 [39].

N

N N

N

Boc

Boc

Boc

O

Pr

O

PrO

PrO

Pr

N

N N

N

Boc

Boc

Boc

O

Pr

O

Pr

O

PrOPr

O

Pr

OPr

Br

O

PrO

Pr

Br

O

Pr

O

Pr

Br

O

PrO

Pr

N

N N

N

Boc

Boc

Boc

Pd(OAc)2 / P(t -Bu)3 /t -BuONa toluene

81

84

82

85

83b

N

RN NR

N

R

R

R

a H83

b Boc


Bas

ic io

nex

chan

ger

IIIM

eOH

/ H

2O

O Pr

O Pr

O Pr

O Pr

N

NH

NN

O Pr

O Pr

O Pr

O Pr

++

+

+

O Pr

N

NN

N

HH

H HH H

O Pr

O Pr

O Pr

O Pr

N

NN

N

HH

H HH H

O Pr

O Pr

O Pr

N

NH

NH

HN

HNH

HN

NH

HN

91

O Pr

O Pr

O Pr

O Pr

O Pr

O Pr

O Pr

O Pr

N

NH

NZnH

HN

N

NH

NZnH

HN

N

NH

NZn

H

Zn(

ClO

4)2

/M

eOH

84

85

86

87

88

89

90

HN

++

+

+H

H

++

+

+H

N

NN

N

HH

H HH H

TF

A


In order to investigate the influence of conformation of starting materials onthe Buchwald–Hartwig process, cone dibromocalixarene 92 was alkylated with1-iodopropane in tetrahydrofuran (THF) using Me3SiOK as a base to give 1,3-alt 93,which was treated with 83b. This reaction afforded mono- and biscyclenylcalixarenes94 and 95, both as 1,3-alt conformers.

+

PrI / THFMe3ISiOK

Pd(OAc)2/P(t-Bu)3/ t -BuONa

Cone 92 1,3-alt 93

83b

OPr

BrBr

HO OPrOH

N

N N

N

Boc

Boc Boc

94

OPr

Br·

OPr

OPrPrO

N

N N

N

Boc

Boc Boc

N

NN

N

Boc

BocBoc

OPr

95

OPrOPrPrO

PrO

Br·

OPr OPr

Br·

OPr

Pd(OAc)2 / P(t-Bu)3/ t-BuONa

Toluene

83b

N

N N

N

Boc

Boc Boc

BrBr

Br

OPrOPr OPr

OPr

OPrOPrPrO PrO

Br·

Br

Br·

Br

1,3-alt 96 1,3-alt 97

It is worth noting that the 1,3-alt tetrabromocalixarene 96 does not form calixarenecontaining four cyclen units, but the reaction of 96 with 83b leads to 1,3-altmonocyclenylcalixarene 97. This fact results from the increased steric hindranceof the 1,3-alt system, since the presence of one bulky tri(Boc)cyclen unit at thewide rim of calixarene molecule causes the outstretching of two of its neighboringpropoxy groups. As a consequence, two bromine atoms present at the narrowrim are located closer to each other, making their substitution impossible. This

1.3 Functionalization of Both Rims 27

behavior resembles a complexation-induced negative allosteric effect observed insome 1,3-alt calixarenes. It should be noted that calixarene 90 shows binding affinityto chloride, acetate, and benzoate anions, forming 1:1 complexes with them.

1.3Functionalization of Both Rims

Calixarenes bearing isoxazole or isoxazoline substituents undergo Mo(CO)6-media-ted opening of the heterocyclic ring to give calixarene derivatives containing α,β-unsaturated β-aminoketone or β-hydroxyketone units respectively [40, 41].

Calixarenes 98 bearing isoxazole units at the narrow rim afford compounds 99.Calixarenes 100 and 101 bearing isoxazoline units at the narrow rim yield products102 and 103 respectively; in the former case also, the cleaved calixarene 37a isobtained. Calixarenes 104a–c bearing isoxazoline moiety at the wide rim undergoa similar reaction, leading to 105a–c. The 1H NMR results have shown the coneconformation for all calixarenes studied.

Mo(CO)6MeCN / H2O

O

N

O

R

OH OHOHO

O

OH OHOH

R

NH2

R

aS

Cl98

bO

Cl

99a,b

OH OHOHO

N

O

R

Mo(CO)6MeCN / H2O

OH OHOHO

OH

R

O

OH OHOHHO

+

37a

R

aS

Me

bS

Cl100

cO

Cl

R

aS

Me

bS

Cl102

cO

Cl


O

S

Me

OH O

O

NH2

OHO

OH

S

Me

OH O

O

NH2

OHO

N

O

Mo(CO)6MeCN / H2O

Mo(CO)6MeCN / H2O

101 103

R

OOH

OHOHOHHOOHOHOH

HO

NOR

R

a Ph

b SMe104

cO

Cl

105a–c

By investigating models of metalloenzymes, it was found that calixarene 106treated with imidazole 107 affords derivative 108 containing three imidazolyl armsat the narrow rim, which mimics the coordination core encountered in enzymes.Upon binding a transition-metal ion, such calixarenes are constrained to a coneconformation, thus mimicking the enzyme funnel that controls the access to themetal center [42].

In the search for supramolecular models of metalloenzyme sites, the replacementof t-butyl groups by electrophilic substituents has been performed on the basis of anexample of ipso-chlorosulfonylation [42]. When aromatic rings were O-substitutedby a protonable imidazole units, they became deactivated toward an electrophilicattack, and therefore the anisole rings could be selectively ipso-chlorosulfonylatedunder mild conditions at room temperature. The regioselectivity was controlledby the presence of protonable imidazole units at the narrow rim. The process isselective and highly efficient.


OHOMe 3

NMeN

Cl

OMe 3

NMeN

O

107

106 108

It was established that treatment of 108 with chlorosulfonyl acid at roomtemperature leads to the formation of the intermediate 109, which upon hydrolysisyields the sulfonate derivative 110, and gives sulfonamide derivatives 111a–dwith amines. The reactions of 109 were performed with NH3, NHMe2, andt-butyldimethylsilyl (TBDMS)-protected diethanolamine; in the latter case, thedeprotection with TFA was necessary to obtain 111d [42]. The above reactions of108 are useful for the synthesis of calixarenes selectively functionalized at the widerim, and cause water solubilization of obtained products.

110

109

3 HSO4−

3 HSO4−

3OMe

SO2NR2

SO2NR2 SO2NR2

3OMe

SO3−

SO3− SO3

−

N

OH

3OMe

SO2Cl

Base / DMSO /H2O

Base / DMSO /H2O

R2NH / base /CH2Cl2

R2NH / base /CH2Cl2

NMeN

O

NMeN

O

HSO3ClCH2Cl2

+

3 Na+

6 Na+

+NHMeN

O 3OMe

SO2Cl SO2Cl

108

rt

Reflux

112

3

3OMe

NMeN

O

NMeN

O

113

114

Rabcd

HMeCH2CH2OTBDMSCH2CH2OH

TFA

ab

CH2CH2OTBDMSCH2CH2OH

TFA

MeN

R

111


When reaction of 108 with chlorosulfonyl acid is carried out at a higher tem-perature (reflux of CH2Cl2), perchlorosulfonylation, leading to hexachlorosulfonylcalixarene 112, takes place. Similarly, hydrolysis of 112 affords the hexaanion 113,and reaction with TBDMS-protected diethanolamine leads to 114a, deprotected to114b.

It should be noted that hexaanion 113 cannot be constrained to the desiredcone conformation due to the strong repulsion at the wide rim. In order to avoidperchlorosulfonation, in the synthesis of 110 and 111 only three benzene ringswere sulfonated by carrying out the reaction at room temperature.

The reaction of 108 with HNO3 in the presence of AcOH yields the productof ipso-nitration 115. This process may be combined with chlorosulfonylationof 115, leading to the ipso-chlorosulfonylation product 116. Hydrolysis of 116afforded tris-sulfonate derivative 117, and the reaction of 116 with NHMe2 andTBDMS-protected diethanolamine gave tris-sulfonamides 118 [42].

108

NMeN

OOMe

NO2

3 Reflux

HSO3Cl / CH2Cl2HNO3 / AcOH

115

116

3 HSO4−

SO3−

NHMeN

O

SO2Cl

OMe

NO2

SO2NR2NO2

NO2

3

NMeN

O

O

R2NH /base /CH2Cl2

Base /DMSO /

H2OOMe 3

OMe 3

117

118

ab

+

NHMeN+

c

R

MeCH2CH2OTBDMSCH2CH2OH

TFA


SnC

l 2 /

EtO

HH

NO

3 / A

cOH

DC

M

PhC

H2C

lor

n-C

4H9B

ror

BrC

H2C

OO

Et

OH

HO

OH

HO

OH

RO

OR

HO

OH

NO

2

NH

2H

2N

RO

OR

HO

O2N

1a

N

NM

e

CO

OH

OH

RO

OR

HO

OH

NH

RO

HN

OR

HO

N

N

Me

O

N

N

Me

O

122

DM

T-M

M

N

N

N

OM

e

OM

e

ON

Me

Cl−

+R

aC

H2P

hb

n-C

4H9

119

cC

H2C

OO

Et

R

aC

H2P

hb

n-C

4H9

121

cC

H2C

OO

Et

R

aC

H2P

hb

n-C

4H9

123

cC

H2C

OO

Et

R

aC

H2P

hb

n-C

4H9

120

cC

H2C

OO

Et

DM

T-M

M


The functionalization of narrow and wide rims of calixarene 1a has been per-formed. Reaction of 1a with benzyl chloride, 1-bromobutane, or ethyl bromoacetateaffords calixarenes 119, substituted on the narrow rim, which upon nitration yielddinitro calixarenes 120.

Reduction of 120 with SnCl2 leads to the formation of diaminocalixarenes121. These compounds were treated with 2,20-bipyridine 122 in the presence of4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) ascondensing agent to give calixarenes 123 substituted on the wide rim [43].

1.4Bridging of Calixarenes

In the study of photochemical reactions of calixarenes [44, 45], the photochemi-cal cycloisomerizations of calixarenes containing phenylethynyl groups have beeninvestigated. Calixarenes 124 serve as an example. they undergo photochemicalcycloisomerization to give 125. It was found that the attempted second photochem-ical reaction, which should have led to 126a,b, did not occur; instead 127a,b wasformed [46]. One should mention that molecular mechanics modeling has shownthat 126a,b are highly strained.

It was observed that the presence of hydroxyl groups in starting compoundsis necessary for the above photocyclization/rearrangement reactions. This wasconfirmed by the fact that the photoirradiation of 124c,d containing O-propylgroups instead of hydroxyl groups did not result in the formation of desiredproducts.

The above reactions are assisted by the templating effect of the calixarenescaffold; their mechanism is proposed. It should be noted that these reactionsare rare examples of intramolecular cyclizations of calixarenes containing alkynylgroups.

OR1

OR1

R1

R R

ab

Ph;4-C6H4-CF3

124

cd

Ph4-C6H4-CF3;

Hn-Pr

H

n-Pr

For a,bhv

R

1.4 Bridging of Calixarenes 33

R

OR

H

OH

OR

O

H

R

hv

OR

H

H

RO

125a,b

126a,b

127a,b

Na2CO3 / toluene4

OH

TsO OTsZ

For Z =

or

For Z =

OO

OO

OOOH

Z

Z

O

O

OH

O

O

HO

Z

OO

130 OO

Z

a

b

OO

OO

Z

129

1a

128

HO

OH HO


Calixarene 1a reacts with bis(tosylethoxy)benzenes 128 to give intramolecularlybridged calixcrowns 129a,b, and intermolecularly bridged biscalixcrown 130. Cal-ixcrowns 129a and 129b of 1:1 stoichiometry are formed from ortho and metaisomers of 128, while 130 of 2:2 stoichiometry is obtained from the para isomer of128 [47].

The bridging of calixarenes bearing allyl substituents on narrow or wide rimshas been reported. This process occurs by 1,3-dipolar cycloaddition reactions,with benzodinitrile oxides 131 serving as bis-1,3-dipoles; benzodinitrile oxides areformed in situ from benzodihydroximoyl chlorides e.g. 132 [48].

In the study of diallylcalixarenes, it was observed that the reaction of 133 withisophthaldinitrile oxide (in the form of 132) affords calixarene 134 bridged at thenarrow rim; a similar reaction of 135 with 132 yields calixarene 136, bridged at thewide rim. When 135 reacted with terephthaldinitrile oxide (in the form of 137), thediastereomers 138 and 139 were obtained.

MeOHO

N

O

N

CCl=NOH

CCl=NOH+

OHO O

OHO OHO

HO

133 132 134

139138136

135

ON

NO

OHHOOH OH

ONNO

OHHOOH OH

OH

ONNO

HOOH OH

OHHO OH OH

+

MeOHMeOH

137132

CCl NOH

CCl NOH

CCl NOH

CCl NOH


140

OH

HO

OH

OH

141

142

137

OH

OH OHOH

ON

ON

HO

HO

HO

HO

Et 3

N /

EtO

H

+

OH

OH

HON

O

OH

NO

H

CC

lN

OH

CC

lN

OH


S14

0

S

OH

NO

H

+

SH

O

ON

OH

OH OHOH

ON

HO

HO

HO

Et 3

N /

EtO

H

Et 3

N /

TH

F

+

OH

OH

HON

O

NO

ON

143

144

145

OH

HO

HOO

HO

OH

OHO

+

O

OH

OH

OH 14

613

714

7

CC

lN

OH

CC

lN

OH

CC

lN

OH

CC

lN

OH


TBAF / THF

1. t-BuLi / THF2. (Allyl)Me2SiCl / Et3N

O

Br

O OO

Br

148

Me2Si SiMe2

OO OO

149

Me2Si SiMe2

OO OO

O

150


By investigating monoallylcalixarenes, it was found that the reaction of 140bearing the allyl group at the wide rim with terephthaldinitrile oxide 137 did notgive the expected biscalixarene 141; instead the asymmetric calixarene 142 bearingisoxazoline and oxime moiety was formed.

However, the reaction of 140 with thiophene-2,5-dinitrile oxide (in the form of143) afforded the desired biscalixarene 144 along with isoxazoline-oxime compound145. The reaction of monoallylcalixarene 146, bearing the allyl group at the narrowrim yielded biscalixarene 147, as expected.

Bridging of allyldimethylsilylated calixarenes, which leads to the formation ofa Si–O–Si siloxane link, was investigated [49]. The reaction of 148 with t-BuLi,followed by (allyl)Me2SiCl, afforded calixarene 149 bearing two allyldimethylsilylgroups; 149 upon treatment with tetrabutylammonium fluoride (TBAF) in THFyielded bridged calixarene 150. Calixarene 151 containing four allyldimethylsilylgroups afforded the bridged compound 152 via a similar reaction with TBAF. Bothbridged products 150 and 152 have the flattened cone conformation.

OO OO

Me2Si

Me2Si SiMe2

SiMe2

SiMe2Me2Si

SiMe2OHSiMe2OHTBAF/ THF

OOOO

O

151 152

The reaction of calixarene 153 with TBAF gave rise to bridged compounds 154obtained as a mixture of cone and paco conformers. Removal of benzyl groupsby hydrogenation in the presence of Pd/C yielded dihydroxycalixarenes 155, alsoas a mixture of cone and paco conformers. This result was unexpected becauseusually the presence of hydroxyl groups, allowing the hydrogen bonding, favors theformation of the cone conformer exclusively; in this case, however, presumably thepresence of the siloxane bridge increased the barrier of the conformational change.Both cone and paco 155 were separated by chromatography [49].


Con

e 15

4

Pac

o 15

5

Con

e 15

5

OR

OM

eM

eO

Me 2

Si

Me 2

Si

Me 2

Si

SiM

e 2

OR

OM

e

MeO

OH

HOO

TB

AF

/ T

HF

OM

eM

eOO

HH

O

+

OM

eM

eOO

Ph

OO Ph

Me 2

Si

SiM

e 2

Me 2

Si

SiM

e 2

Me 2

Si

SiM

e 2

O

H2

Pd

/ C

153

OM

eO

Ph

MeO

O

O Ph

Pac

o 15

4

+

R =

CH

2Ph


1.5Other Reactions of Calixarenes

Contrary to many modifications of narrow and wide rims of calixarenes, themonofunctionalization of four methylene bridges of calixarenes is rather rare[50]; the following reactions of 156a,b may serve as examples. For this purpose,calixarenes 156a,b were brominated with NBS to give 156c,d, respectively, whichwere used as starting materials for functionalization.

The solvolysis of 156d in trifluoroethanol (TFE) under SN1 conditions yieldedcalixarene 156e containing four trifluoroethyl groups. In order to obtain thetetraethoxy-substituted product 156f , the solvolysis of 156d in EtOH/TFE (1:1)mixture was carried out. The reaction of 156d with NaN3 in TFE leads to 156gof paco conformation. The above reactions gave rise to products containing C–Obonds in the case of TFE and EtOH, and C–N bonds in the case of azide [51].

X X

R

OMe

X

RR

R

OMeOMe MeO

R Xa H Hb t-Bu Hc H Brd t-Bu Bre t-Bu OCH2CF3f t-Bu OEt

156

g t-Bu N3

X

In order to synthesize products with C–C bonds, the solvolytic Friedel–Craftsreaction of 156c with 2-methylfuran was performed in TFE using 1,2-butyleneoxide as a scavenger of HBr; calixarene 157 was obtained as the sole product. TheX-ray analysis results have shown its pinched cone conformation with all furanylsubstituents situated at equatorial positions of the macrocycle and the furanyloxygen atoms pointing toward the narrow rim [51].

156c

O Me

O

Me

O

Me

O

Me

O

Me

OMe

OMe MeO

OMe

TFE

O

Me

157

1.5 Other Reactions of Calixarenes 41

6

Me

OH

6HC

HO

conc

ente

rate

d H

Cl /

ben

zene

Me

OH

OH

OH

Me

OH

Me

Me

OH

Me

NaO

H /

TE

BA

acet

one

Cl

Cl

OM

e

HO

Me

Me

O

Me

OO

Me

Me

OO

H

OH

OH

O O

Me

OHM

eM

e

Me

OO

Me

HO

O O

Me

H

Me

158

159


Synthesis of biscalixarenes joined tail to tail via ether linkages was carried out.Biscalixarenes have interesting recognition abilities; they are promising in thedesign of redox active chromophores, ditopic receptors, and ion selective electrodes[52]. The acid-catalyzed condensation of p-cresol with formaldehyde leads tocalix[6]arene 158 in a single step. The reaction of 158 with bis(2-chloroethyl)etherin the presence of NaOH and triethylbenzylammonium chloride (TEBA) as aphase-transfer catalyst (PTC) affords biscalix[6]arene 159.

O

Me

COOH

MeMe Me

O

COOH

O

COOH

MeMe

OH

COOH / NaOHBr

158NaOH / TEBA

acetone

Cl ClO

160

COOH

OHO

Me

OR

MeMe

O

Me

O

O

O

O

Me

HO O

O

O

OO

O

O

O

Me

O OH

O

Me

OR

MeMe

O

Me

O

Me

O

O

O

Me

O OH

HO

Ra

CH2(CO)ClCH2N(OH)Ph

bc

SOCl2PhNHOH161

CH2(CO)OH

In order to obtain other biscalixarenes, 158 was treated with bromoacetic acid togive calixarene 160, which reacted with bis(2-chloroethyl)ether in the presence ofNaOH and TEBA, yielding biscalix[6]arene 161a. The reaction of 161a with thionylchloride gives rise to 161b, which upon condensation with N-phenylhydroxylamineaffords biscalixarene 161c bearing hydroxamic acid moieties.

In the above syntheses, a phase-transfer catalyst was used; a large amount ofsolvents and a longer reaction time would have been required without the use ofthe catalyst [52].

part i general characteristics of calixarenes · 1.1 functionalization of the narrow rim 11 r a h b...

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