summary_detistov

Summary of research work

Fulbright grantee, Dr. Oleksandr S. DetistovUkraine

2

FULBRIGHT PROGRAM

In 1945, Senator J. William Fulbright introduced a bill in the United States Congress that called for the use of surplus war property to fund the 'promotion of international good will through the exchange of students in the fields of education, culture, and science.'On August 1, 1946, President Harry S. Truman signed the bill into law, and Congress created the Fulbright Program, the flagship international educational exchange program sponsored by the U.S. Government.

THE FULBRIGHT MISSION STATEMENT

The worldwide Fulbright Program is designed to:• Increase mutual understanding between the people of the United States and the people of other countries.• Strengthen the ties that unite the United States with other nations.• Promote international cooperation for education and cultural advancement.• Assist in the development of friendly, sympathetic, and peaceful relations between the United States and other countries of the world.

3

RESEARCH WORK IN A FIELD OF COMBINATORIAL CHEMISTRY 2003 − 2008 yy

Work was done under general support of and in cooperation with Chemical Diversity company. ChemDiv is a fully integrated contract research organization headquartered in San Diego, California, with subsidiaries in Russia and Ukraine.

4

One-pot liquid-phase parallel synthesis of 1,2,4-oxadiazole libraries by approach A

OH

O

R2 + CDI +NH2

N OH

R1

1 2 3

Subsequent addition of reagents

R: Heteryl;R`: Alkyl, Aryl.

NH2

N O

R1

O

R`DMF

50-60 0C

I-1

N

NO R`

R2

DMF

110 0C

4 - 12

5

Heteryl-1,2,4-oxadiazoles synthesized by approach А

4 (approx. 700 compounds) 5 (approx. 600 compounds) 6 (approx. 300 compounds)

R1: Alkyl, Aryl, Heteryl; R2: Aryl, Heteryl.

R1: Aryl;R2: Aryl, Heteryl.

R1: Aryl, Heteryl. R2: Aryl, Heteryl.

7 (approx. 400 compounds) 8 (approx. 1000 compounds) 9 (approx. 200 compounds)

R1: H, Alkyl, Alkoxy, Halogen;R2: Aryl, Heteryl.

R1: H, Alkyl, Alkoxy, Halogen;R2: Alkyl;R3: Aryl, Heteryl.

R1: H, Alkyl, Alkoxy, Halogen;R2: Alkyl;R3: Aryl, Heteryl;n: 1-3.

10 (approx. 50 compounds) 11 (approx. 50 compounds)

12 (approx. 50 compounds)

R1: Aryl, Heteryl; n = 1-4

R1: Aryl, Heteryl. R1: Aryl, Heteryl. X = N, O

N

NO

R2

N N

R1N

ON

NO

R1

R2N

NO

R2

NS

O

O

R1

N

NOR2

O OR1

N

NO

N

OR3

R2

R1R1

N

NO

R3

N

N

O

O

R2

n

ON

N

N

N

n

R1

N

NO

N

N R1 X

NN

NO

R1

6

In-house methods for synthesis of useful functionalized building-blocks of 1,2,4-oxadiazole row

NH2

N OHR1

1

R1: Aryl, Heteryl.

NN

O

N

N

ON

NR1

14

13

O O

O

N

ON

OR1

15

16

7

NON

NR1

17

R2O

OH

O O

N

NOR1

R2

18: R1 = 4-CH3O-C6H4, 4-CH3-C6H4;R2 = 8-OH, 8-C2H5O;

14O NH

N

NOR1

R2

i-Pr-OH, piperidine

17

R2O

OH

19: R1 = 4-CH3O-C6H4, 4-CH3-C6H4; R2 = H, 8-C2H5O; 4-CH3-C6H4;

NH2

R4

O N

N

NOR2

R4

R1

CH3COOH

20

21

R4 = 4-CH3, 4-CH3CO, 4-CH3CONH.

NH2 OH

O

N

NO

NOH

R2

R1

O

O

O

R6R6

O

N

NO

NO

R2

O

R6

R1

CH3COOH

24

25

26

27

R6 = CH3, C2H5, (CH3)2CH.

SNH

O

ONH2

R5

O N

N

NO

NHS

O

O

R2

R5

R1

CH3COOH

22

23

R5 = 4-CH3, 3,4-di(CH3O), 2,5-di(CH3O).

28

N

O

OH

OH

NO O

N

NOR1

OH

29: R1 = 4-CH3O-C6H4, 4-CH3-C6H4;

H Cl1. MeOH, piperidine2. HCl, H2O

Reactions involving 5-cyanomethyl-1,2,4-oxadiazoles 14

8

NON

NR1

14

NO N

NR1

SS

1. CS2 (30), NaOH2. CH3I (31)

dioxane / H2O

32: R1 = C6H5; 4-CH3-C6H4; 4-CH3O-C6H4; 4-Cl-C6H4.

NO N

NR1

SNH

R2

33: X = N; R1 = C6H5, 4-CH3-C6H4,4-CH3O-C6H4, 4-Cl-C6H4. R2 = CH3, C6H5,C2H5

Method A

R2NH2

i- Pr-OH

34

1. R2NCS (35), NaOH2. CH3I

Method B

dioxane


9

NO N

NR1

SX

R2

33: X = N; R1 = C6H5, 4-CH3-C6H4,4-CH3O-C6H4, 4-Cl-C6H4. R2 = CH3, C6H5,C2H5

NH2 NH2

EtOH O N

NR1

XNN

NH2

R2

36, 37

32: X = S; R1 = C6H5, 4-CH3-C6H4,4-CH3O-C6H4; R2 = CH3.


ClNH

OR3

41

N

NO

NN NH2

X

NH

O

R1

R3

R2

42, 43

NOESY

K2CO3, DMF

42a: R1 = C6H5; 42b-g: R1 = 4-CH3-C6H4; 43a-g: R1 = 4-Cl-C6H4;43a-g: R2 = CH3, C2H5, CH(CH3)2, CH2CHCH2, C6H5.42: R3 = 3-CH3O-C6H4-CH2, 3-Cl-4-CH3-C6H3, 4-C2H5O-C6H4, 4-CH3-C6H4, 3-F-4-CH3-C6H3, 3-Cl-4-F-C6H3, 4-CH3O-C6H4. 43:R3 = 3,5-di-CH3-C6H3, 2-CH3O-5-CH3-C6H3, 3-C2H5-C6H4, 2-Cl-C6H4-CH2, 4-Cl-C6H4-CH2, 2,4,6-three-CH3-C6H2,2,4,6-three-CH3-C6H2.

O

O

O

R6

R5

38

CH3COOH

N

NO

N

X

NNH

O

R1

R2

R5R6

39, 40

36, 39: R1 = 4-CH3-C6H4; 37, 40: R1 = C6H4; R1 = 4-Cl-C6H4; R2 = CH3, CH2CHCH2; R5 = CH3, C2H5; R6 = H, CH3,

10

NON

NR1

14

O

O

MeOH, piperidine

ON

NR1

NH

O

45: R1 = C6H5, 4-CH3O-C6H4, 4-CH3-C6H4,4-Cl-C6H4.

44


O

R2

N

ON

NR1

R2

EtOH, piperidine

47: R1 = 3-CH3-C6H4, 4-(CH3)2CHO-C6H4, 2-C6H4N;R2 = 4-Br-C6H4, 4-(CH3)2N-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4.

N

ON

ONH2

N

NH

R1

R2

N NH

O

CH3CN

49: R1: 3-CH3-C6H4,4-(CH3)2CHO-C6H4, 2-C5H4N.R2: 4-Br-C6H4, 4-(CH3)2N-C6H4,4-CH3O-C6H4.

46

48

N3R2

N

ON

NH2

N

NN

R1

R2

50

51: R1 = C6H5, 4-CH3O-C6H4;R2 = C6H5, 4-CH3-C6H4, 3-CH3O-C6H4, 2-Cl-C6H4, F-C6H4.

MeOH, MeONa

11

N

ON

OR1

14

Reactions involving 5-acetonyl-1,2,4-oxadiazoles 16

N

ON

OR1

EtOH, HClNH2

S

NH2

+ N

ON

R1

NH

NH

S

OH

R1 = C6H5, 2-CH3-C6H4, 4-CH3O-C6H4; R2 = H, 3,4-benzo.

16 17 54 56 57

+O

OH

R2 + R2

N

O

N

R1

O

NH

NH

S

N

ON

N

NN

R1

R2

N3R2

MeOH, MeONa

R1 = 3,4-CH2O2-C6H3, 2-Cl-C6H4;R2 = 3,4-di-(CH3O)-C6H3, 2,5-di-(CH3O)-C6H3, 3-CF3-C6H4, 2,4-di-(F)-C6H3, 4-CH3OOC-C6H4.

52

53

O

R2

EtOH, HCl

NH2

S

NH2

+

N

ON

R1

NH

NH

S

R2

R1 = C6H5, 2-CH3-C6H4, 4-CH3-C6H4, 4-Cl-C6H4; 2-F-C6H4, 3,4-CH2O2-C6H3, 3,4-di-(CH3O)-C6H3; R2 = C6H5, 4-CH3O-C6H4, 4-CH3S-C6H4, 4-(CH3)2N-C6H4;

55 54

56

12

Figure 1 1H NMR spectrum of 5-methyl-13-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]-1,2,4,5-tetrahydro-3H-1,5-methanonaphtho[1,2-g][1,3,5]oxadiazocine-3-thione, 57

13

Figure 2. 13C NMR spectrum of 5-methyl-13-[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]-1,2,4,5-tetrahydro-3H-1,5-methanonaphtho[1,2-g][1,3,5]oxadiazocine-3-thione, 57

15

CUSTOM SYNTHESIS OF BUILDING BLOCKS FOR BIOMOLECULAR RESEARCH

2008 − 2009 yy

Work was done under general support of and in cooperation with InterBioScreen. IBS is a Moscow-based joint-stock company providing biologically active natural as well as synthetic organic compounds for screening at pharmaceutical, agrochemical and biotechnology companies.

16

NO

O

R2 O

O+ CDI +

NH2

N OH

R1

1 2 3 58

DMF

110 0C

NO

O

N

NO

R1

R2

1) NH2-NH2, i-Pr-OH2) HCl (gas), benzene

HCl

59

Where,

R1 = Aryl;R2 = Amino acid residue.

N

NO

R1

NH2

R2

Synthetic route for preparation of 5-aminoalkyl-1,2,4-oxadiazoles 59

17

Examples of 5-aminoalkyl-1,2,4-oxadiazoles synthesized by this method

59a 42 g 59b 40 g 59c 50 g

59d 50 g 59e 60 g 59f 40 g

59g 80 g 59h 35 g 59i 50 g

NO

NNH2

O

O

S

N

ON

NH2

N

NONH2 F F

FN

NO

O

F

F

F

NH2N

NO F

FNH2

N

NONH2

ON

NO

NH2

N

NONH2

NN

ONH2

18

CUSTOM SYNTHESIS OF BUILDING BLOCKS FOR BIOMOLECULAR RESEARCH

2010-2011 yy

Princeton BioMolecular Research is a privately held company established in 1998. Field of research work includes design of unique small molecules and development of advanced tools for drug discovery, enabling new generations of chemical entities.

19

Syntheses of commercially unavailable benzofurans and benzothiophenes by modified Stobbe method

X

O +

O

O

O

O

MeOLi

MeOH X

O

O

O

O Li+

O

O O

X

O

O

O

O

1) NaHCO3,

EtOH / H2O

2) H+

X

OH

O

O

Where X = O, S.

60 61 62

64 63

20

Syntheses of commercially unavailable benzofurans and benzothiophenes by modified Stobbe method

X

OH

O

O

R Hal

K2CO3, DMF X

O

O

O

R

X

O

OH

O

R

1) OH-, EtOH / H2O

2) H+

Where X = O, S.

64 65 66

64a 40 g 66a 25 g 66b 25 g 66c 25 g

66c 50 g 66d 30 g 66e 20 g 66f 20 g

O

OH

O

OO

O

OH

OO

O

OH

OO

O

OH

O

O

O

OH

O O

OCHF2

O

O

S

O

OH

O S

O

OH

O

Examples of benzofurans and benzothiophenes synthesized by this method

21

Dresden city, Germany

22

Synthesis and characterization of conjugated polymer nanoparticles

SS H

HHH

H

H

HH

n

23

• Conjugated (semiconductive) polymers:

Motivation

n

SS

SS

Rn

R

R

R

Polymer LED Picture from:J. Mater. Chem. 2007, 17, 3551

Color flat-panel displays

Picture from: nature.com (Seiko–Epson Corp)

Polymer solar cells Picture from:

University of Regensburg (Germany)

24

Nanoscale organization can be controlled by polymer’s architecture

Molecular brushes

“Hairy” particlesPlanar brushes

25

mono

Init.

mono

mono

mono

mono

mono

mono

Prerequisite for chain-growth polymerization mechanism:one-by-one addition of monomers to initiator points

26

Polycondensation mechanisms: chain-growth

mono Init.

mono

mono

mono

mono

mono

mono

27


mono Init.

mono

mono

mono

mono

mono

mono

28


mono Init.

mono

mono

mono

mono

mono mono

29


mono Init.

mono

mono

mono

mono

mono mono

30


mono Init.

mono

mono

mono

monomono mono

31


mono Init.

mono

mono

mono

monomono mono

32


mono Init.

mono

mono

mono

monomono mono

33


mono Init.

mono

mono

mono

monomono mono

34


mono Init.

mono

mono

mono

monomono mono

35

Init.

mono

mono

mono

mono

mono

mono Init.mono monomono mono

Grafting from surface

36

McCullough-Yokozawa mechanism of Kumada Catalyst Transfer Polycondensation (KCTP)

SClMg

Br

R

2

monomer

catalyst precursor

NiL2Cl2

- MgCl2

NiL2

SS

R R

BrBrS S

R R

Br Br

+Ni(0)L2

"real" Ni(0) catalyst

S S

R R

Br Ni(L2)Br

SClMg

Br

R

- MgBrCl

S

S S

R R

Br Ni(L2)

R

Br

intramolecular transfer

SR

Br

S S

R R

Br

.

Ni(0)L2

SR

NiL2Br

S S

R R

Br

Poly-3-alkylthiophen (P3AT)

SR

H

S S

R R

Br n

37

Commercially available Ni-based initiators and catalysts

Ni

Cl P

Cl P

Ph Ph

Ph Ph

NidpppCl2

[1,3-Bis(diphenylphosphino)propane]nickel(II) chloride

Ni

P

P

Ph

Ph

Ph

Ph

initiators (precursors) catalysts

[1,3-Bis(diphenylphosphino)propane]nickel(0)

Ni

Cl P

Cl P

Ph Ph

Ph Ph

[1,2-Bis(diphenylphosphino)ethane]nickel(II) chloride

Ni

P

P

Ph

Ph

Ph

Ph

[1,2-Bis(diphenylphosphino)ethane]nickel(0)

NidppeCl2

38

Commercially unavailable Ni-based initiators and catalysts

Ni

P

Br P

Ph Ph

Ph Ph

Ph

PhNidpppBr

Phenyl[1,3-Bis(diphenylphosphino)propane]nickel(II) bromide

Ni

P

P

Ph

Ph

Ph

Ph

initiators (precursors) catalysts

[1,3-Bis(diphenylphosphino)propane]nickel(0)

Ni

P

Br P

Ph Ph

Ph Ph

Ph

Phenyl[1,2-Bis(diphenylphosphino)ethane]nickel(II) bromide

Ni

P

P

Ph

Ph

Ph

Ph

[1,2-Bis(diphenylphosphino)ethane]nickel(0)

PhNidppeBr

39

Ligand-exchange strategy

Br

NN

Ni

Et Et NN

Ni

Br

P PPh Ph

Ph Ph

n

PP

Ni

Br

PhPhPh Ph

n

24

Where n = 0,1If n=0, PhNidppeBrIf n=1, PhNidpppBr

S

R

BrBrMgn

Initiated by PhNidppeBr or PhNidpppBr

S

R

Hn

Terminated by H+

40

SiO

O

O

.

.

.

Br

NN

Ni

Et Et

P PPh Ph

Ph Ph

2

4

SiO

O

O

.

.

.N

N

Ni

Br

ligand exchange

SiO

O

O

.

.

.P

P

Ni

Br

Ph

PhPh

Ph

S

R

BrClMgn

Kumada chain-growth polycondensation

SiO

O

O

.

.

.

S

R

Hn

organosilica

40

O

O

OBr

O

O

OBr

surface-initiated polymerization

Si

Si

“hairy” P3ATs particles

Grafting from organosilica

41

Thiophen-based precursors under investigation

S

NN

Br Br

TBP-1 TBP-2

SSBr Br

TBP-3

Si

SSBr Br

TBP-4

O

O

S

SBr Br

S

N

NO

Br Br

TBP-5

*

**

*

*

**

** commercially unavailable

* Provided by Luminescence Technology Corp. http://www.lumtec.com.tw/index.aspPrice - USD 1700 / 5 g

42

Synthesis of TBP-1

Br2

MgMgBr2

1) CuBr, LiBr

Cl

O

O

Cl2)

O

O

14 + 16

S

NN

TBP-1

S

NH3

+NH3

+ClCl

K2CO3

S

NH2NH2

NBS

DMF

S

NN

BrBr

Yield = 52 %

Yield = 38 %

Yield = 82 %

Yield = 65 %

Step 1

Step 2

Step 3 Step 4

43

1H NMR spectrum of TBP-1

8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

ns

ity

15.97 12.003.43 1.79

Chloroform-d

N

N

S

CH3

CH3

CH3

CH3

Br

Br

44

13C NMR spectrum of TBP-1


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

ns

ity

Chloroform-d

11.2

01

4.3

4

23

.25

26

.37

29

.12

33

.07

38

.20

39

.77

10

3.4

1

13

9.3

7

15

8.1

3

S

N N

CH3 CH3

BrBr

CH3 CH3

45


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

ns

ity

15.97 12.003.43 1.79

Chloroform-d

N

N

S

CH3

CH3

CH3

CH3

Br

Br

Conversion of TBP-1 into TBM-1 and polymerization of TBM-1

TBP-1

S

NN

BrBr

+ MgCl * LiCl

TBM-1

S

NN

BrClMg

THF

30 - 40 % of conversion by NMR method

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

ns

ity

16.95 12.002.88 2.120.34

Chloroform-d

S

N N

CH3CH3

CH3CH3

BrH

HCl in dioxane

46

TBP-1

S

NN

BrBr

+ MgCl * LiCl

TBM-1

S

NN

BrClMg

THF

30 - 40 % of conversion by NMR method

PhNidppeBr

S

NN

H

n

TBPol-1

GPC data of TBPol-1

Sample of PTBM-1

Mn (g/mol)

Mw (g/mol)

Mn / Mw

1 400 1200 3.00

2 400 1000 2.50

3 300 900 3.00

4 400 1000 2.50

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Inte

ns

ity

Chloroform-d

nS

NN

H

Conclusion: Polymerisation proceeds out of order - derangements occur!

NMR spectrum of TBPol-1


47


TBP-2

SSBr Br+ MgCl

THF

SSClMg Br

TBM-2

PhNidppeBr

SS Hn

TBPol-250-60 % conversion by NMR

48

Conversion of TBP-2 into TBM-2

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Inte

ns

ity

30.003.871.88

Chloroform-d

6.9

2

S

S

Br

Br

CH3

CH3

CH3

CH3

7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

Inte

ns

ity

2.000.58

Chloroform-d

6.9

2

NMR spectrum of TBP-1

50-60 % conversion by NMR

49

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Inte

ns

ity

29.564.001.390.22

Chloroform-d

7.3

7

7.5

8

nS SH

CH3

CH3

CH3

CH3

HHH

H

H

H

H

NMR spectrum of TBPol-2

50

NMR spectrum of TBPol-2, field of aromatic proton signals

n = 8

8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6Chemical Shift (ppm)

0

0.05

0.10

0.15

0.20

0.25

Inte

ns

ity

16.512.232.00 0.75

Chloroform-d

7.3

7

7.5

8

nS SH

CH3

CH3

CH3

CH3

HHH

H

H

H

H

meta- ortho-

β-thiophen protons

β-1

51

GPC data of TBPol-2

Sample of PTBM-2

Mn (g/mol)

Mw (g/mol)

Mn / Mw

1 1500 2300 1.5

2 1200 2200 1.8

Conclusion: Polymerisation proceeds by chain-growth mechanism, but process is not fully controlled.

And so on…

52

Barcelona city, Spain

56

Positive feedback fromDr. Karl Hemming.

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V.N. Karazin Kharkiv National University is one of the oldest universities in Eastern Europe. It was founded in November 1804, on the initiative of the prominent educator V.N. Karazin and in accordance with the charter of Tsar Alexander I.

Kharkiv University is the only university in Ukraine that has trained and employed three Nobel Prize laureates: the biologist I. Mechnikov, the economist S. Kuznets, and the physicist L. Landau.

The University of Kharkiv main academic building

The University of Kharkiv main academic building

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Acronym KKNUAccreditation IVStatus StateEstablished 1804Teaching staff 1300Students trained 15000+

The northern academic building

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UniversityNumber of Publications in

ScopusNumber of Citation In Scopus Hirsch index (H-index)

Taras ShevchenkoKyiv National University

10947 40807 64

Karazin Kharkiv National University

6072 22974 47

Universities of Ukraine according to Scientometrics database SciVerse Scopus

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50 Most Innovative CountriesBy Bloomberg Rankings - Feb 1, 2013 11:37 AM GMT-0500

42. UkraineUkraine ranked 42nd in Bloomberg's Global Innovation Index. Here is how the country ranked in the determining factors:

R&D intensity: 37thProductivity: 69thHigh-tech density: 47thResearcher concentration: 39thManufacturing capability: 34thTertiary efficiency: 6thPatent activity: 17th

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19th-century view of Kharkiv, with the Assumption Cathedral belltower dominating the skyline.

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Kharkiv city, airport

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Kharkiv city, railway station

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Kharkiv city, Freedom Square

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Kharkiv city, night view

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