1
MSU, Laboratory of Macrocyclic Receptors
Carboxylated Adamantylcalixarenes
Moscow State University
Chemistry Department
V. Kovalev
2
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
ADAMANTYLCALIX[4]ARENES CARBOXYLATED ADAMANTYLCALIX[4]ARENES CARBOXYLATED
AT THE LOWER RIMAT THE LOWER RIM
4
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
ADAMANTYLCALIX[4,6]ARENES ADAMANTYLCALIX[4,6]ARENES
CARBOXYLATED AT THE UPPER RIMCARBOXYLATED AT THE UPPER RIM
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MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
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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
MSU, Laboratory of Macrocyclic Receptors
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 -
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MSU, Laboratory of Macrocyclic Receptors
2.7. 1H NMR SPECTRUM of p-(3-CARBOXYMETHYL-1-ADAMANTYL)CALIX[6]ARENE in CDCl3 at 298 K.
22
MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
CONJUGATES OF CARBOXYLATED CONJUGATES OF CARBOXYLATED ADAMANTYLCALIX[4,6]ARENES ADAMANTYLCALIX[4,6]ARENES
WITH AMINO ACIDSWITH AMINO ACIDS
25
MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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,
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MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
ADAMANTYLADAMANTYLTHIATHIACALIX[4]ARENES CALIX[4]ARENES
CARBOXYLATED AT THE UPPER RIMCARBOXYLATED AT THE UPPER RIM
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MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
MSU, Laboratory of Macrocyclic Receptors
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
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MSU, Laboratory of Macrocyclic Receptors
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