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

Synthesis and applications of functionalized (thia)calixarenes

Moscow, 26-30 October 2009

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

Macrocyclic platforms

O

OH

OO

OH

OH

OH OH

O

OH

OOH

OHOH

R

O HX n

HOOH HO

OHOH

HOOHHO

R RR

R

Calixarenes

CalyxCalyx CPKCPK--ModelModel

XXX XH H H H

SSS S

XXX XH H H H

X=O, S, NH

OOO OH H H H

Calix[4]arenes

SSS S

OOO OH 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

HO

OH

OOH H

HO

HO

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

RO

OR

OOR R

RO

RO

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

OO

R R

RO

R

O

1.Design of new types of cavitands2.Design of hosts molecules3.Design of tectons for MOFs

Main topics

O OOOH H

X

OO O OHH

X

OO O OHHH H

Br-X-BrK2CO3

O

2 X=

3 X=

1 X=

OO

OO

HH

O

O

O

O

OO

HH

O OOO

O OOO

HH

HH

OO O OHH

OO

OO H

H OO

OOH

H

O OOO

OO O OHH

HH

3 (45%) 4(23%)2 (33%)1 (30%)

Design of new types of cavitands

X

O N-H

RO

XS

X XXSS S

XRRX

RX+

O NHR

SXX XX

SS S

O NH HN OHN OR R R

-

Lower rim complexes: recognition of the charged species and surfaces

SS

SS

-O3S

-O3S SO3-

SO3-

OOHO

n+M

-O

A.I.Konovalov, I.S.Antipin Mendeleev Commun., 2008, 18, 229-237.

Low selectivity

High selectivity

SOH

4 4

SO

(CH2)nY

Hal(CH2)nY

M2CO3, CH3CN

Stereoselective synthesis using template effect

Y = group capable to bind cations:–C(O)NEt2, -C(O)-Ph , n = 1

S SO

RO

OSS

RO

RR

SOO O O

S SS

H H HH

M2CO3, RY

SOO O O

S SS

R R RR

SO

OO

SS

OS

RR

R

R

+ +

R Base

Reagentsratio

TCA:XR : M2CO3

Products distribution, %

Cone Partial cone 1,3-Alternate K+- 1,3-Alternate

Na2CO3 1 : 8 : 4 - - -

K2CO3 1 : 8 : 4 - 58 10 24K2CO3 1 : 8 : 6 - 11 -

79Сs2CO3 1 : 8 : 4 - 11 62

-

CH2C(O)Ph

Na2CO3 1 : 6 : 6 86 7 -

K2CO3 1 : 6 : 6 - 75 -

Сs2CO3 1 : 6 : 6 7 40

88

CH2C(O)NEt2

OO

R R

R

O

R

O

1,2-AlternateNot found

Stereoselective synthesis using template effect

O H O H

SS SS

O H O H

1

OS S

O

O

S

OPCl

PCl

2 δ(31P): 170.2 ppmm/z = 848[M+H+]

2 PCl3 ( N Et3) S

OS S

O

O

S

OP

Et2N

PN Et2

S

OS S

O

O

S

OPCl

O

PClO

S

4 δ (31P): 134.3, 140.4 ppmm/z = 924[M+H+]

3 δ (31P): -4.2 ppmm/z = 880[M+H+]

[O2]

HNEt22h, 90oC

Organophosphorus Derivatives of Thiacalix[4]arenes

SOO O O

S SS

H HHH

OP

OCl

PO

S

O

O

S

O SS

P

O

OO O OH HHH O

PO O

OO

H

POH

OP

OCl

OHO

PO

Cl OP

O

H

OCl

Кормачев В. В. Препаративная химияфосфора. / В. В. Кормачев, М. С.

Федосеев.- Пермь: УрО РАН, 1992. - C. 457.

(95%)

(56%)

Organophosphorus Derivatives of Thiacalix[4]arenes

Stabilization of monosubstituted derivative

1 2

H

SS

S S

O

O

O

O

HH

H

NH

NO2

H

SS

S SO

O

O

OHO

H

Base Solvent Time, h Yield, % 1 2 3 4 5

Na2CO3 CH3C(O)CH3 72 37 - - 11 26 -

K2CO3 CH3C(O)CH3 72 60 54 6 - - -

Cs2CO3 CH3C(O)CH3 72 52 10 42 - - -

Na2CO3 CH3CN 20 56 - - 51 - 5

K2CO3 CH3CN 20 51 44 7 - - -

Cs2CO3 CH3CN 20 73 20 53 - - -

NH

SOO O O

S SS

H2C

CO

H

NO2

CONH

CH2

NO2

H

NH

SOO O O

S SS

H2C

CO

H

NO2

CONH

CH2

NO2

CONH

CH2

NO2

SOO O O

S SS

HCONH

CH2

NO2

H H SO

H

NH

SO O

S

H2C

CO

H

NO2

O

H2C

NH

NO2

O C

S O OS

H

CONH

CH2

NO2

NH

OH2C

CO

NO2

SO

CONH

CH2

NO2

SS

Reaction of BrCH2C(O)NHC6H4NO2 with p- tertbulylthiacalix[4]arene

1 2 3 4 5

Effect of binding sites preorganizationon calixarene platform

0

20

40

60

80

100E, %

S

OCH2CNEt2

O 4

Cone, paco, 1,3-alternate;Li, Na, K, Cs

Δ lg K ≈ 6-10S

OCH2C(O)NEt2 OCH2C(O)NEt2

2

1

cone-1paco-11,3-alt-1

Li+Na+

K+ Cs +

0

1

2

3

4

5

6

Macrocycle conformation effect

The extraction constants of alkali metal ions by conformers I and II.

Cone

SOO O O

S SS

O RO ROROR

SO

OOSS

OS

ORO R

O

O

R

R

Partial Cone

R R

R

O

O

O

OS S

O

O

OSS

R O

1,3-Alternate

I – R= Ph; II – R= NEt2

O

O

PhCs+

O

Ph O

O

PhO

O

Ph O

Cs+

O

PhO

O

PhO

O

Ph O

O

PhO

O

PhO

O

PhO

O

OPh

O

Ph O

Li+Li+

O

PhO

O

PhO

O

Ph O

O

Ph OLi+

O

PhO

O

PhO

O

O

PhPh

O

OLi+

Li+Li+

Li+

O

PhO

O

PhO

O

OPh

O

Ph O

Li+Li+

O

PhO

O

PhO

O

Ph O

O

Ph OLi+

O

PhO

O

PhO

O

O

PhPh

O

OLi+

Li+Li+

Li+

O

O

PhCs+

O

Ph O

O

PhO

O

Ph O

Cs+

O

PhO

O

PhO

O

Ph O

O

PhO

O

PhO

O

PhO

O

OPh

O

Ph O

Li+Li+

O

PhO

O

PhO

O

Ph O

O

Ph OLi+

O

PhO

O

PhO

O

O

PhPh

O

OLi+

Li+Li+

Li+

O

PhO

O

PhO

O

OPh

O

Ph O

Li+Li+

O

PhO

O

PhO

O

Ph O

O

Ph OLi+

O

PhO

O

PhO

O

O

PhPh

O

OLi+

Li+Li+

Li+

Complexes stoichiometry of I (R= CH2COPh)

Log Kex

1

2

3

4

Р 1

Р 2

Р 3

cone-2paco-21,3-alt-2

Li+ Na+K+ Cs +

0

2

4

6

8

10

12Log Kex

NH

3a3b3c

HNNH

HN

NHHN

HNNH HN

HN

NHNH

3 4 0 3 6 0 3 8 0 4 0 0 4 2 0 4 4 0 4 6 0 4 8 0 5 0 00

2 0

4 0

6 0

8 0

1 0 0

1 2 0 3 b 3 b + F -

3 b + C l-

3 b + B r-

3 b + J -

Fluo

resc

ence

Inte

nsity

, r.u

.

W a v e le n g th , n m

340 360 380 400 420 440 460 480 5000

50

100

150

200

3c 3c +F-

3c + Cl-

3c + Br-

3c + J-Fl

uore

scen

ce In

tens

ity, r

.u.

Wavelength, nm

340 360 380 400 420 440 460 480 5000

20

40

60

80

100

3a 3a +F -

3a + C l-

3a + B r-

3a + J-

Fluo

resc

ence

inte

nsity

, r.u

.

W ave length , nm- C(O)Naphtyl

F- Cl- Br- I-

350 420 350 420 350 420 350 420

3a ↑ ↑ ↑ ↑ - - ↓ ↓3b ↑ ↓ ↑ ↓ - ↓ ↓ ↓3c ↓ - - ↓

Array of fluorescent chemosensors for molecular recognition of halide anions

TransfectionTransfection DNADNA into theinto the cells by synthetic receptorscells by synthetic receptors

DNA

Calixarenes

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 dataC (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 -6 0.8 3.3 53 1.9 9.8 100

29

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

SR= N O

R= N

5

6

Cone Paco

1,3-Alternate

Aggregation effects at the complex formation with tetra-amides (DLS method)

30

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

31

1,3-alt - 10

cone 1,3-alternate partial cone 1,2-alternate

- Binding sites: -COOH; -C(O)NR2; -CN; -Pyr; etc...

ORS SS

ROOR

OR

SS

OROR

ORORS SS S

OR

OR

ORSS

ORS

ROSS

OR OR

ORS S

Design of tectons for MOFs

1D

3D

2D

M/L=1/1 (nontubularsystem)

M/L=2/1 (tubular system)

M/L=1/1

M/L=2/1

Collaboration with M.W.Hosseini

Strategies of MOFs formation on the basis of 1,3-alternate

Preorganized calixarene ligands (1,3-alternate)

R

Y

* S*

4

R = t-Bu; H

R

* S*

O

C

N

n4

R

* S*

O4

C

N

R

* S*

O

NH2

n4

R

* S*

O4

O NR2

R

* S*

O

n4

O OH

X-Ray structure of the synthesized

calixarene ligands

2 31

X – non coordinating anion PF6

-, SbF6-, BF4

-

(C56H68N4O4S4Ag)(PF6)·2(CH2Cl2)

1D structure of (3-cyanopropoxy)-p-tert-butylthiacalix[4]arene with silver ion

Infinite linear 1D- structure, M/L=1/1

2

S

O(CH2)3CN 4

·AgX

Space group P2, Z = 1

Distorted tetrahedron

25,77 Å

Structure of decanuclear cluster of AgNO3 with (p-cyanobenzyloxy)-p-tert-butyl-thiacalix[4]arene

Space group P42/n, Z = 4The 1D arrangement along the c axis

The solid-state structure of clusters Ag10

Distance (Å)

Ag1-Ag2 3.568

Ag1-Ag3 3.854

Ag2-Ag3 5.380

Ag1-S 2.527

Ag2-S 2.654

Ag1 - pentacoordinated with a NSO3 environment

Ag2 – heptacoordinated with a SO6 environment

Ag3 - tetracoordinated with O4 environment

vertices of a tetrahedron

summits of the basal plane of the octahedron

apicalpositions

1,3 nm

1,3 nm

ТСА

The arrangement of the decanuclear cluster in the (001) plane

Acknowledgment

Scientific teamin KSU

Prof. I.I.StoikovDr.O.A.MostovayaDr. L.S.YakimovaA.Yu.ZhykovS.A.ZhykovaE.A.YushkovaE.A. Zaikov

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

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. L.M.PilishkinaA.A.Tuyftin

Academician A.I.Konovalov