A.E.Arbuzov Institute of Organic & Physical Chemistry, Kazan A.M.Butlerov Chemistry Institute of Kazan Federal University, Kazan

Supramolecular chemistry of (thia)calix[4]arenes

Lviv, 6-10 September 2010

I.S.Antipin, S.E.Solovieva, I.I.Stoikov, A.I.Konovalov

Moscow

Kazan

Novosibirsk

St.Petersbourg

V International symposium “Design and Synthesis of Supramolecular Architectures”

12-16 October 2009

VI International symposium “Design and Synthesis of Supramolecular Architectures”

September 18-23, 2011

http://iopc.ru/butlerov/Index-e.html

Basic principle of supramolecular chemistry

Jonathan Swift

Macrocycles– molecular platform for multipoint interactions realization and multivalent ligands design.

Macrocyclic platforms

O

OH

OO

OH

OH

OHOH

O

OH

OOH

OHOH

R

OH

X n

HOOH HO

OH

OHHOOH

HO

R RR

R

Calixarenes

CalyxCalyx CPK-CPK-ModelModel

XXX X

H H H H

SSS S

XXX X

H H H H

X=O, S, NH

OOO O

H H H H

Calix[4]arenes

SSS S

OOO O

H H H H

The characteristic advantages of calix[4]arenes for the constructing of receptors are followed: the low cost and accessibility of parent macrocycles by one-pot synthesis; calixarenes can incorporate the small hydrophobic organic molecules into their molecular cavities with the formation of the stable host-guest complexes;the existence of variety of calixarene conformations: cone, partial cone, 1,2-alternate, 1,3-alternate etc.; calix[4]arene conformations are rather rigid and are able to fix the required spatial orientation of binding centers; nontoxicity of calixarene platforms.calixarene platform gives an unique possibility to decorate the upper and lower rim of macrocycle by the suitable heteroatom groups and to form the molecular system possessing the several binding centers;

1997 – S.Miyano et al

Thiacalix[4]arene

O OOO

H HH H

OH

HO

H

O

OH

OO

H H

HO

H

O

OO

H H

HO

H

O

Cone Partial Cone

V≈10A3

1,3-Alternate 1,2-Alternate

Background of Calixarene Chemistry

Main Problem:

Stereo and Regio Selective Functionalization of Lower and Upper Rim

SSS

S

OHOHOH OH

Upper Rim

Lower Rim

Mono, Di, Tri and Tetra Substituted Derivatives

O OOO

R RR R

OR

RO

R

O

OR

OO

R R

RO

R

O

Cone Partial Cone 1,3-Alternate 1,2-Alternate

OO

R R

RO

R

O

1. Covalent assembly: towards nanosized molecules

2. Noncovalent assembly: towards “soft” nanosystems

2

n + nFunctionsReceptor - signalPhototransforming – accumalation

hν “guestquenching

Outline

Y= B, Ge, Sn, Sb, Mn+= Fe2+, Co2+, Co1+, Ru2+

R = Hal, Ar, Alk, XAr, XAlk, Z =F, Alk, PhYO

OO

NN

NR

R N

OY

OO

N N

R

R

R

R

Mn+

Z

Z

Clathrochelates – tris-dioximates

The characteristic advantages of macrobicyclic tris-dioximates:

accessibility by one or two-step synthesis;

stability in acidic and alkaline media;

metal ability to redox processes inside of the ligand cavity;

the possibility of side and apical position functionalization.

Mn + Cl

Cl

SS

SH O S

SHO S

HS

HS

O

OS

S

S O S

SO S

S

S

O

OMn +Mn +

Guest

1,3-Alternate

Mn + Cl

Cl

SH SH

OOSSSS

S

S OO

S

S S

S

Mn +

Guest

Design of new types of cavitands: conjugates of clathrochelate and thiacalixarenes

Route b

Route a

Cone

Where we are going?

S

O

O

O

O

S

S

S

(C H 2)nSH

(C H 2)n

(C H 2)n

(C H 2)n

HS

HS

SH

F

Cl

BOO

O

N N N

N

OB

OO

N N

Fe 2+

F

Cl+

S

O

O

O

O

S

S

S

B OO

O

NNN

N

OBOO

NN

Fe

F

F

(CH2)nS

(CH2)n

(CH2)n

(CH2)n

S

SS

BOO

O

N N N

N

OBO O

N NFe

F

F

n=3, 4, 5

2+ 2+Yield:n=3: 0%n=4: 58%n=5: 2%

Synthesis calixarene/clathrochelate conjugates:effect of methylene spacer length

Synthesis calixarene/clathrochelate conjugates:effect of methylene spacer length

N=3, Yield 20%

S

O

O

O

O

S

S

S S

S

HS

HS

B OO

ONNN

NO

BOONN

Fe

F

F

B O

O

O

NN

N

N

O

B

OO

NN

F e

S

O

O

O

O

S

S

S

S

S

S

SBO

O

O

NN

N

N

O

B

OO

N N

Fe F

F

F

BO

O

O

NN

N

N

O

B

OO

N N

F e

F

C l

C l

N=5, Yield 65%

Nanoparticles size (nm) /Polydispersity

Free ligand Li+ Ag+

Cone-5 - - 84 / 0.18

Cone-6 - 143 / 0.19 153 / 0.08

Paco-5 - - 134 / 0.16

Paco-6 - - 131 / 0.17

Alternate -5 - - 140 / 0.19

Alternate -6 - - 141 / 0.23

Extraction data C (Меn+) = 0,1M, C(L) =10-4 - 2.5*10-3 M, С(Pic-) = 2.3*10-4 M

Li+ Ag+

n LogKex E% n LogKex E%

Cone-5 0.8 3.3 61 0.7 4.1 79

Cone-6 1.9 8.4 100 1.1 6.1 99

Paco-5 0.6 2.0 22 1.5 8.4 68

Paco-6 1.0 4.5 81 1.6 8.2 100

Alternate -5 0.6 2.0 16 2.0 9.9 98

Alternate -60.8 3.3 53 1.9 9.8 100

15

R

O

OO

O

RRR

S SOOO O

S S

RR O

O

O

O

R

R

SO

S SO OOS

RR

O O

OO

O

RR

S SO

O

OS

S

R= N O

R= N

5

6

Cone Paco

1,3-Alternate

Noncovalent assembly of nanoaggregates

16

3 hours

28 hours+ Ag+HNHN O

O

O

O

HN

NH

SO

S SO OO

S

Nanoparticles size distribution of Ag complex in CH2Cl2

Paco-7

C OHN

C

S SO

O

OSS

O

CONH

C OHN NH

O

CH2 H2C

CH2H2C

SEM nanoparticles image of Ag(I) complex in CH2Cl2

17

1,3-alt - 10

The size of the aggregates formed thiacalix[4]arenes, functionalized with hydrazide groups, with metal cations

HN

O

OO

O

NHHN

NH

S SOOO O

S S

H2NNH2 NH2

NH2

6a

HNHNO

O

O

O

HN

NH

SO

S SO OO

S

NH2

NH2 NH2NH2

6b

NHNH

O O

OO

O

HNHN

S SO

O

OS

S

H2N H2N

NH2NH2

6c

220.0 240 260 280 300 320 340 360 380 400 420 440 460 480 500 520 540.0

0.002

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.623

nm

A

220 240 260 280 300 320 340 360 380 400 420 440 460 480 500 520 540

nm

0.60

0.55

0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

А

1

2

UV spectra (5•10–6 mol L–1, 1cm cell) of p-tert butyl thiacalix[4]arene in the trans (1) and cis (2) forms in

dichloromethane

NHNH

O O

OO

O

HN

S SO

O

OS

S

HN

N

N

N

NN

N

N

N

NHNH

O O

OO

O

HN

S SO

O

OS

S

HN

N

N

N

NN

N

N

N

hv (365 nm)

1

2

Photo-switching of thiacalix[4]arene derivative 1 containing azobenzene moieties

NH

NH

O

O

O

O

O

HN

S

S

OO

O

S

S

HN

N

NN

N

N

N N

N

NH

NH

O

O

O

O

O

HN

S

S

OO

O

S

S

HN

N NNN

NNNN

Ag+

Cu2+

Fe3+

Ag+

Fe3+

aggregates(61.1 nm)

aggregates(188.9 nm)

aggregates(125.7 nm)

aggregates(41.7 nm)

aggregates(65.2 nm)

synt

hezi

s

hv (254 nm)

Photo-switchable self-assembly of nanosized aggregates

Mn+

Mn+

Mn+Mn+

Mn+

Mn+

Mn+

Mn+

Mn+Mn+

Mn+

Mn+

Mn+

Mn+

Mn+Mn+

Mn+

Mn+

Mn+

Mn+

Mn+Mn+

Mn+

Mn+

Mn+

Mn+

Mn+Mn+

Mn+

Mn+

Mn+

Mn+

Mn+

Mn+

Mn+ Mn+

Mn+

Mn+

hν (2

54 n

m)

Model of photo-switchable self-assembly:first step from the inanimate to living matter

Magnetic Resonance Imaging (MRI)

Relaxivity R1p ~ 3000-5000 M-1s-1,

lgβ ~ 19-26

Commercial contrast agents

Main approaches to relaxivity enhancement:

- the induction of steric hindrance around the water binding site;

- the rise of the complex molecular mass due to aggregation.

Effect of macrocycle conformation on Gd(III) relaxivity

0

20000

40000

60000

80000

100000

120000

0 0.1 0.2 0.3 0.4 0.5

C TC[4]Ac, мM

R 1, M-1с-1 конус

част.кон.альт.

cone

paco

1,3-alt

TC[4] Ac

Acknowledgment

Scientific team in KFU

Prof. I.I.StoikovDr.O.A.Mostovaya A.Yu.ZhykovE.A.Yushkova E.A. Zaikov

GrantsRussian Foundation for Basic ResearchRussian Academy of Sciences Ministry of Education and Sciences RF CRDF

Academician A.I.Konovalov

Collaborators

Prof. Ya.Z.VoloshinProf. M.W.HosseiniProf. R.R.AmirovProf. A.R.MustafinaProf. G.A.EvtyuginDr. E.E.StoikovaDr. A.T.Gubaidullin

Scientific team in IOPC

Dr. S.E.SolovievaDr. E.A.PopovaDr. S.R.KleshninaDr. M.N.KozlovaDr.A.A.Tuyftin