1 MSU, Laboratory of Macrocyclic Receptors Carboxylated Adamantylcalixarenes Moscow State University Chemistry Department V. Kovalev.

1

MSU, Laboratory of Macrocyclic Receptors

Carboxylated Adamantylcalixarenes

Moscow State University

Chemistry Department

V. Kovalev

2


MAIN TOPICS:

ADAMANTYLCALIX[4]ARENES CARBOXYLATED ADAMANTYLCALIX[4]ARENES CARBOXYLATED

AT THE LOWER RIMAT THE LOWER RIM ADAMANTYLCALIX[4,6]ARENES CARBOXYLATED AT THE ADAMANTYLCALIX[4,6]ARENES CARBOXYLATED AT THE

UPPER RIMUPPER RIM CONJUGATES OF CARBOXYLATED CONJUGATES OF CARBOXYLATED

ADAMANTYLCALIX[4,6]ARENES WITH AMINO ACIDSADAMANTYLCALIX[4,6]ARENES WITH AMINO ACIDS ADAMANTYLTHIACALIX[4]ARENES CARBOXYLATED AT ADAMANTYLTHIACALIX[4]ARENES CARBOXYLATED AT

THE UPPER RIMTHE UPPER RIM

3


ADAMANTYLCALIX[4]ARENES CARBOXYLATED ADAMANTYLCALIX[4]ARENES CARBOXYLATED

AT THE LOWER RIMAT THE LOWER RIM

4


1.1. CALIX[4]ARENES CARBOXYLATED AT THE LOWER.

4: X = H, t-Bu; R = CH3, CH2CONEt2, R+R = (CH2CH2O)3CH2CH2

X

O

X

O

X X

O

R ROO

OH OH

O

1, X = OEt2, X = OH3, X = NEt2

OOOO

O

X

OX O X X

O

7, R = H, tert-Bu6, R = H, tert-Bu; X = H, C5H11

5

R

O

CH2 4

(CH2)4

NH+ C5H11

CO2-

R

O

CH2

(CH2)n

4

O NX

OH

O NH

OH

O

R

O

CH2 4

5


1.2. COMMON STRATEGY OF THE LOWER RIM

CARBOXYLATION OF CALIX[4]ARENES .

X = OEt, NR2

Y = CH2COOEt, CH2CONEt2

OH

R

OH

R

HO

R

HO

R

R = H, t-Bu

4

O

CH2

XO

R

2

X

R

O OH

R

O

4

O

CH2

OHO

R

4O

CH2

YO

R

X = OEt, NR2

HO-

for X = OEt

Y = NR2

2

X

R

O OY

R

O

HO-

for X = OEt Y = CH2COOEt2

2

OH

R

O OY

R

O

1. Activation2. Y-

for X = OEt

6


1.3. ADAMANTYLCALIX[4]ARENES CARBOXYLATED AT THE

LOWER RIM .

OHOH

HOHO

L1, X = OEt, OH, NEt2

L2, X = Alkyl, 1-adamantyl 3-Y-1-adamantyl, Y - functional groups

OH

R

OH

R

HO

R

HO

R

R = H, t-Bu, Ad

4

O

CH2

XO

NH

R

O OH

R

OX

22

N

R

O OH

R

7


1.4. p-(1-ADAMANTYL)CALIX[4]ARENE TETRACARBOXYLIC

ACID AND ITS DERIVATIVES. .

8, 77%

1. NaOH,

2. HCl

10, X = NEt2, 88% N(CH2)5, 90%

NHR'R''

O

CH2

R

O Cl

4

9, 93%

BrCH2CO2Et,K2CO3, aceton

4OH

CH2

Ad

O

CH2

Ad

O OEt

4 O

CH2

Ad

O OH

4

O

CH2

Ad

O X

4

SOCl2, C6H6

8


R = Ad tert-Bucomplex free ligand complex free ligand

7.18 (6.84) 7.19 (6.81)

3.36 (3.23) 3.32 (3.23)

4.20 (5.32) 4.21 (5.34)

3.50 (3.36) 3.50 (3.36)

R

O

R

O O

R

O

OEt2N N

OO

Et2N NEt2O

Hax

Heq

CH3

CH2

CH3

RH

Some characteristic signals of 1H NMR spectraof complexated and free ligands

Sr2+

1.5. COMPLEXATION OF TETRADIETHYLAMIDE OF

AdC4A CARBOXILIC ACID WITH Sr(Pic)2.

Sr(Pic)2+

n-C3H7OH/CHCl3

Sr(Pic)2

.O

CH2

Ad

O NEt2

4O

CH2

Ad

O NEt2

4

O

CH2

O NEt2

4

11 10

9


1.6. AdC4A SELECTIVELY CARBOXYLATED

AT THE LOWER RIM.

R12, t-Bu, 71%13, H, 74%14, Ad, 81%

ClCH2CN, K2CO3,NaI, aceton

OH

CH2

R

4 O

CH2

RR

OH

N

2

CF3COOH (5-10 equiv)

20-80oC, 7-15h+

40-90%

OH

X

R N NHCOR

X

10


1.7. AdC4A SELECTIVELY CARBOXYLATED

AT THE LOWER RIM

OH

X

CF3CO2H20-70oC

12, R = tert-Bu13, R = 1-adamantyl

+

X = HX = 4-MeC6H4

X = iso-PrX = CH2COOH

15, X = H, R = tert-Bu16, X = 4-MeC6H4, R = tert-Bu17, X = CH2COOH, R = tert-Bu18, X = H, R = 1-Ad19, X = iso-Pr, R = 1-Ad

44-76%

O

R

OHO

R

HO

RR

CNNC

O

NH

X

O

NH

X

O

R

OHO

R

HO

RR

11


1.8. THE ALKYLATION OF CALIXARENE NITRILES IN

TRIFLUOROACETIC ACID (TFA).

2

OH O

CH2

N

OH O

CH2

NH O

CH

Ph2CHOH, TFA 2

12 20

12


1.9. ADAMANTYLATION OF 1,3-DICYANOMETHOXY-p-H-CALIX[4]ARENE IN TFA

1-AdOH (4.1 equiv.) CF3COOH

21, 69%

2

Ad H

O

CH2

NH O

OH

Ad

CF3COOH

22, 19%

2

NH

OH O

CH2

O

H H

O OH

OH

COOH

1-Ad+1-Ad+

1-Ad+

O

CH2

HH

OH

N

2

B C

A

13


1.10. X-RAY STRUCTURE OF 5,17-DI(1-Ad)-26,28-DI[N-(1‑Ad)

CARBOMOYLMETHOXY]CALIX[4]ARENE.

Empirical formula C96 H116 N2 O6 Formula weight 1393.91 Temperature 110(2) K Crystal system, space group MONOCLINIC, C2/C Unit cell dimensions a = 60.018(8)A b = 10.9904(14)A c = 24.777(3) A Volume 15698(3) A3 Z, Calculated density 8, 1.180 Mg/m^3

Analysis of Potential Hydrogen Bonds:

Donor – H… Acceptor distances angles

N(1) – H(1A) … O(3) 3.024(3) 164.03

N(1) – H(1A) … O(4) 2.663(3) 110.84

O(3) – H(3A) … O(6) 2.715(3) 178(3)

O(5) – H(5A) … O(4) 2.768(2) 173(3)

14


ADAMANTYLCALIX[4,6]ARENES ADAMANTYLCALIX[4,6]ARENES

CARBOXYLATED AT THE UPPER RIMCARBOXYLATED AT THE UPPER RIM

15


2.1. FULL ADAMANTYLATION OF p-H-CALIX[4, 6]ARENES BY CARBOXYLATED ADAMANTANOLS

n = 4, 6

OH

CH2 n

OH

CH2

O

OH

n

n

O OH

OH

CH2

OH

OH

CH2

O

OH

n

R

OH

+ + CF3COOH

Yields 90-100%

16


2.2. SELECTIVE ADAMANTYLATION OF p-H-CALIX[4, 6]ARE-NES WITH CARBOXYLATED ADAMANTANOLS

OHOH OHOHOHOH OHOH

COOH HOOC

OHO O

OO

OH NO2

NO2

O2N

O2N

i i

i: 3-R-1-AdOH, CF3COOH, reflux; ii: NaOH / EtOH / H2O

ii

OH

COOH

CH2COOHR =

OH2

OH OHOH

2OH OH

R

i

17


2.3. UPPER and LOWER RIM METHYLATION OF CARBOXY LATED DAMANTYLCALIX[6]ARENES

O6

OHO

O2

O O

OHO

OH6

OHO

OH2

OH OH

OHO

(MeO)2SO2 / NaH NaOH/EtOH/H2O 1a

2a

O6

OO

3a

4a

5a

6a

O2

O O

OO

18


2.4. UPPER RIM MODIFICATIONS OF CARBOXYLATED ADAMANTYLCALIX[6]ARENES.

1a, R = H5a, R = Me

2a, R = H6a, R = Me

OR2

OR OR

OHO

OR6

OHO

ClO

NH2O C N

5f5g

O OMe

NR1R2O

OH

N

NH

O

O

N O

NR1R2 = Et2N

19

2.5. CONFORMATIONAL PROPERTIES OF ADAMANTYLCALIX[4]ARENES

OH 4

SO2Me

OH 4OH 4

OHO

OH 4

O OMe

OH 4

O

OH

R n SOLVENT TC, C G*, KCAL/MOL

1-Adamantyl 4 Chloroform 53 15.7

3-MeSO2Ph-1-Ad 4 Chloroform 60 15.9

3-HOOCCH2-1-Ad 4 Tetrachloroethane 95 17.5

3-MeOOCCH2-1-Ad 4 Chloroform 57 15.8

3-HOOC-1-Ad 4 DMSO 30 -

20


OH 6OH 6

SO2Me

OH 6

OHO

OH 6

O OMe

2.6. CONFORMATIONAL PROPERTIES OF ADAMANTYLCALIX[6]ARENES

Coalescence Temperatures For The Conformational Inversion Of The Adamantylcalix[6]arenes.

R n SOLVENT TC, C G*, KCAL/MOL

tert-Butyl 6 Chloroform 11 13.3

tert-Octyl 6 Chloroform 13 13.6

1-Adamantyl 6 Chloroform 12 -

3-MeSO2Ph-1-Ad 6 Chloroform 25 -

3-HOOCCH2-1-Ad 6 Chloroform 60 -

21


2.7. 1H NMR SPECTRUM of p-(3-CARBOXYMETHYL-1-ADAMANTYL)CALIX[6]ARENE in CDCl3 at 298 K.

22


2.8. METHYLENE PARTS OF 1H NMR SPECTRA of MONBENZYLATED P-TERT-BUTYL- (A) and ADAMANTYL-

(B) CALIX[6]ARENE IN CDCl3

Ha,bHc,d

He,f

23


2.9. METYLENE PARTS OF 1H NMR SPECTRA OF CARBOXYLATED CALIX[6]ARENES 1a, 2a, 2f, 4a and 6a (RT, CDCl3)

OH 6

OHO

1a

2a, X = Y = H

2f, X = CH3, Y = H

4a, X = Y = CH3

6a, X = H, Y = CH3

OY2

OY OY

OXO

1a

2f4a 6a

2a

24


CONJUGATES OF CARBOXYLATED CONJUGATES OF CARBOXYLATED ADAMANTYLCALIX[4,6]ARENES ADAMANTYLCALIX[4,6]ARENES

WITH AMINO ACIDSWITH AMINO ACIDS

25


3.1. PRINCIPAL STRATEGIES OF PEPTIDOCALIX[N]ARENE SYNTHESES. UPPER AND LOWER RIM DERIVATIVES.

a) N-linked peptidocalixarenes b) C-linked peptidocalixarenes

ZHN-CHRCOOH

HNCO

R

NHZ

NH2

NH2

NHOC

RZHN

H2N-CHRCOOX

OCNH

R

COOX

COOH

COOH

COHN

RXOOC

26


3.2. CONJUGATES OF CALIX[4,6]ARENES WITH AMINO ACIDS.

O O O O

NHNH

NH NH

OOH

H

OO

NH NH

NH

HH

O O

NH

OH

O

O

H

NH

NH

OH

O H

O H

O

4

O

NH O

NH

NH

NH

NH

NH O

R1

O

R2

OR3

O

R4

O

O O OMeMeO

NHAA1

AA2

O

NH

8

O

O

NHAA3

O

AA4O

27


3.4. CONJUGATES OF ADAMANTYLCALIX[4,6]ARENES WITH AMINO ACIDS. SYNTHESIS

OH

O

OHHO

O

HO

OHOHOH

OO

OH

OH

O

OHHO

O

HO

NHNHNH

OO

NH

OO O

O

RR R

R

OMeOMe

MeOMeO

1. SOCl22. HCl NH2CHRCOOMe, Et3N THF - H2O

R = H;R = CH2Ph

1a,1b,

28


3.5. CONJUGATES OF AdC[4,6]A WITH AMINO ACIDS. POTENTIOMETRIC MEASUREMENTS.

Membrane 1

0

30

60

90

120

150

-5 -4 -3 -2 -1 0

lg a (МE Phe)

Em

f, m

V

Membrane 2

-100

-50

0

50

100

150

200

-5 -4 -3 -2 -1 0

lg a (МE X)

Em

f, m

V

МЭ Ile МЭ Tyr МЭ Phe

For linear section of the calibration curvesSlope (mV decade-1) 43±5 (Phe) 57±2 (Phe) 46±1 (Ile)

59±1 (Tyr)

Membrane composition for carrier-based ISEs in wt %.Membrane 1 Membrane 2

Sensor agent, calixarene 1 1 1Polymer matrix, PVC 66.0 65.7Plastizer, o-NPOE 33.0 32.9Ionoc additive, NaTPB - 0.4

29


3.6. CONJUGATES OF AdC[4,6]A WITH AMINO ACIDS. WORKING CHARACTERISTICS OF THE MEMBRANE 2.

-3,9

-1,1-0,8

-0,6 -0,5

-3,6

-5

-4

-3

-2

-1

0

Mg2+ Ca2+ ME Tyr ME Val ME Leu ME Ile

lg K

po

t (M

E P

he/

X)

-4,4 -4,3

-3,2-2,9

-2,4 -2,3

-5

-4

-3

-2

-1

0

Li+ Na+ NH4+ K+ Cs+ Rb+

lg K

po

t (M

E Il

e/X

)

-80

-60

-40

-20

0

20

40

60

0 2 4 6 8 10

pH

E, мВ

Effect of pH of the test solution on the potential response of the ME Phe.H+ ion-selective electrode

Potentiometric selectivity coefficients (log KPot) of the ISE 2 for ME Phe and Ile in the presence of various interfering ions

30


ADAMANTYLADAMANTYLTHIATHIACALIX[4]ARENES CALIX[4]ARENES

CARBOXYLATED AT THE UPPER RIMCARBOXYLATED AT THE UPPER RIM

31


4.1. THE WAYS OF TC4A TRANSFORMATIONS.

OH

SS

OH

S

OH

SHO

NH2

SS

NH2

S

NH2

SNH2

C-S 1.76 A

O

SOSO

O

SO

O

SOO

CH3CH3CH3 CH3

SO3Na

OH

SS

SO3Na

OH

S

NaO3S

OH

S

Na3SO3

HO

The high complexation ability toward organohalogenes

OH

SOsO

OH

SO

OH

SOHOOH

SOnSOn

OH

SOn

OH

SOn

OH

A

B C

B + C

D

n = 1, 2

32


4.2. TC[4]A MODIFIED AT THE UPPER RIM. LIT. DATA

S

SS

S

R

R

R

ROHOH

OHOH

1, R = t-Bu; 2, R = 1,1,3,3-tetramethylbutyl3, R = H; 4, R = SO3Na

S

SS

S

Br

R

R

BrOHOPr

OHOPr

5, R = H6, R = Br

H

OH

SS

H

OHS

H

OHS

H

HO

+

E = NO2+, Br+, RCO+, CO+

E+

33


4.3. THE BROMINATION 0F 1,3-DIPROPYLOXY-TC[4]A. LIT. DATA

H

OH

SS

H

OHS

H

OHS

H

HO

H

OH

SS

H

OPrS

H

PrOS

H

HO

Br

OH

SS

H

OPrS

H

PrOS

Br

HO

Br

OH

SS

Br

OPrS

Br

PrOS

Br

HO

34


4.4. FIRST SYNTHESIS OF ADAMANTYLATED TC[4]A

OH

SS

OH

S

HO

S

HO

R

RR

R

R = H, COOH

OH

7, 28%

S8, NaOH,

MeO(CH2O)4Me,

OH

S

4

35


4.5. X-RAY STRUCTURE OF p-(1-ADAMANTYL)-TC4A.

i) AdTC4A crystallized in the orthorhombic crystal system. ii) the unit cell contained both AdTC4A and four CHCl3 molecules, one of which was localized within the cavity of the host molecule; iii) AdTC4A adopted a cone conformation; iv) the average distance between two adjacent oxygen atoms

was 2.77 Ǻ as and in the case of t-BuTC4A.

36


4.6. ADAMANTYLATION OF p-H-TC[4]A .

96%

CF3COOH, LiClO4

reflux, 72 h

+

iii

i, AlCl3, toluene, phenol, ii, CF3COOH/CF3SO3H/,

CH2Cl2, phenol,

OH

S

4

OH

S

4

OH

S

4

OH

S

4

OH

OH

S

4

37


4.7. SYNTHESIS OF THE AdTC[4]A CARBOXYLATED AT THE UPPER RIM .

8, 96% 9, 58%

OH

OH

O+

CF3COOH, CF3SO3H,reflux, 24h

THF/MeOH/H2SO4

reflux, 10h

O

OH

OH

S

4

OH

S

4

O

OMe

OH

S

4

38


O

OH

OR

Participants: E. Shokova, A. Motornay, I. Vatsuoro,

A. Matveev, I. Podolsky,

M. Kashapov

FUNDS: RFBR, Grant - 03-02-33353,

RFBR, Grant - 03-02-06254,

RFBR, Grant - 03-02-06252

ACKNOWLEDGEMENTS

1 MSU, Laboratory of Macrocyclic Receptors Carboxylated Adamantylcalixarenes Moscow State University Chemistry Department V. Kovalev.

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