SYSTEMS CHEMISTRY Mucsi Zoltán SERVIER 2 nd in France 25 th in WW 1

SYSTEMS CHEMISTRYSYSTEMS CHEMISTRY

Mucsi ZoltánSERVIER

2nd in France25th in WW

1

AB

C PED …

… E

?

Sideproducts

Synthetic plan:

R1 O

O

R2 R1 O

OR2

NR3

HHH H

O OH

H

O

O

SOL SOL SOL

SOL

B

R3N

H

HH O

SOL

R1 O

OR2

NR3

H

HH

H

O

O

SOL

SOL

B

R1 O

OR2

NR3

HH H O

SOL

BH

O

SOL

R1 O

OR2

NR3

HH H OSOL

BH

O

SOL

R1 O

OR2

NR3

HH H OSOL

BH

O

SOL

H A

R1 O

OR2

NR3

HH H OSOL

BH

O

SOL

HA

R1

O

OR2

NR3

HH H OSOL

BH

O

SOL

HA

R1

ONR3

HHH O

SOL

BH O

SOL

OR2

HA

R1

O

NR3

H

R1 O

O

R2R3

NH

H

+ HO

R2+

On paper:

In reality:

MOLECULAR ENGINEERINGMOLECULAR ENGINEERING

??4

Newton equations rules, equations

rules, equationsSchrödinger equations

Chemical reactionChemical reaction

Enthalpy Enthalpy ddeconvolutioneconvolution

H-bond

HH2

Solvent

Steric

AromaticityAmidicity

Carbonylicity

Olefinicity

Internal energy

Reactant Product

SYSTEMS CHEMISTRYSYSTEMS CHEMISTRY

5

CN

O

R1R3

R2

CY

O

R1

CY

S

R1C

Y

NH

R1C

Y

CH2

R1

amidicitycarbonyicity

tiocarbonylicityiminicityolefinicity

aromaticity

N

XX

CONJUGATICVICITYCONJUGATICVICITY

Quantitative ChemistryQuantitative Chemistry

6

CR2

Z

R1C

R2

Z

R1

Z

CR2R1

H

HHH2(1)

H2

[conj%](A) = 0% = m HH2(A) + [conj%]0 1. eq[conj%](B) = 100% = m HH2(B) + [conj%]0 2. eq[conj%](1) = m HH2(1) + [conj%]0 3. eqHRE(1) = [conj%](1) / m 4. eq

[conj%](A) = 0% = m HH2(A) + [conj%]0 1. eq[conj%](B) = 100% = m HH2(B) + [conj%]0 2. eq[conj%](1) = m HH2(1) + [conj%]0 3. eqHRE(1) = [conj%](1) / m 4. eq

CH

Z

HC

H

Z

HC

X

Z

HC

X

Z

H

0 % 100 %

HH2(A) HH2(B)

1 2

A B

X = ZNo conjugationNo conjugation Equal conjugationEqual conjugation

7

R(1) + R(2)R(1) + R(2) II(1,2)(1,2) P(1) + P(2)P(1) + P(2)

Conj. = Conj.[P(i)] - Conj.[R(j)]

Positive = advantageous; negative = disadvantageous

Thermodinamic:Thermodinamic:

Kinetic:Kinetic:

Conj. ≈ Conj. ≈ HH(RE)(RE)

Small difference = reactive; large = unreactive

8

Conj.[P(i)]

1. Aromaticitya. Phospholeb. Heterophosphete

2. Amidicitya. Transamidiationb. Selectivityc. Bio example

3. Carbonylicitya. Peptide couplingb. Reactivity

4. Olefinicitya. Cross-couplingb. Indole reaction

5. Complex approachesa. 1. exampleb. NAD, FADc. Penicillin

10

Aromaticity/AntiaromaticityAromaticity/Antiaromaticity

Aromaticity likes to beauty, easy to recognise, but hard to quantify. (P. V. R. Schleyer)

1. molecular stability2. reactionway3. Activation energy4. Spectroscopical property

-aromaticity (1979) [pl. Li cluster],

antiaromaticity (1965)

-(2D)aromaticity (1920)

-aromaticity (2004) [pl. Au cluster],

3D aromaticity (1978)

Determine …

AromaticityAromaticity

10

11

Geometrical based

Magnetic shillding based

Aromaticity/Antiaromaticity Aromaticity/Antiaromaticity „measure”„measure”

HOMA, Bird, BDSHRT index

Pl. cbutadiene [27-29] benzene [(-8)-(-9)] pirrole [(-12)-(-13)]

reference reference

Smell based Good or bad smell

??

antiaromatic

Nuclear Independent Chemical Shift: NICSNICS


11

H2

HH2(2)

( )n

( )n

( )n

( )n

( )n

( )n

( )n

( )n

HH2(1)

H2

HH2(1)

H2

HH2(2)

H2

MÓDSZER:MÓDSZER:

30.28 kJ/mol

Reference reactionReference reactionStudied reactionStudied reaction

141.24 kJ/mol141.24 kJ/mol-110.96 kJ/mol

-258.63 kJ/mol -127.60 kJ/mol -131.04 kJ/mol-131.04 kJ/mol

-104.68 kJ/mol -110.96 kJ/mol -6.28 kJ/mol-6.28 kJ/mol

AROMATICAROMATIC

ANTIAROMATICANTIAROMATIC

NON-NON-AROMATICAROMATIC

HH2(1)

H2

HH2(2)

H2

H2 H2

HH2(1) HH2(2)

G3MP2B3

X kJ/molX kJ/mol

11

22

33

[1] J. Phys. Chem A. 2007, 111, 1123–1132.

LINEAR AROMATICITY SCALELINEAR AROMATICITY SCALE AromaticityAromaticity

HH2 = HH2(1) - HH2(2)

12

X X HHH2H2 (kJ/mol) (kJ/mol)

Y =

aro

mat

icity

par

amet

er (

%)

H2

H2

HH2(1)

HH2(2)

HH2(1)

H2

HH2(2)

H2HH2(1)

H2

HH2(2)

H2

100 %

-100 %

0 %

Fitting(G3MP2B3):Y = m.X + b

m = 0.7342b = -2.4962

11

22

33

140-140 0

[1] J. Phys. Chem A. 2007, 111, 1123.

LINEAR AROMATICITY SCALELINEAR AROMATICITY SCALE AromaticityAromaticity

13

AROMATIC SCALEAROMATIC SCALE

0-100 100 %-80 -60 -40 -20 80604020t-Bu

t-Bu t-Bu

t-Bu

N O

O

N

OH

S

O

P

OH

N

N

N

O

S

HN

HP

Mucsi, Z.; Viskolcz, B.; Csizmadia, I. G. J. Phys. Chem A. 2007, 111, 1123–1132.Mucsi, Z.; Csizmadia, I. G. Cur. Org. Chem. 2008, 12, 83–96.Mucsi, Z.; Körtvélyesi, T.; Viskolcz, B.; Csizmadia, I. G.; Novák, T.; Keglevich, G. Eur. J. Org. Chem. 2007, 1759–1767.Mucsi, Z.; Viskolcz, B.; Hermecz, I.; Csizmadia, I. G.; Keglevich, G. Tetrahedron 2008, 64, 1868–1878.Mucsi, Z.; Keglevich, G. Eur. J. Org. Chem. 2007, 4765–4771.


14

P

Y

'O'

PY

r.t.

RR

O

P

P

Y O

R R

YO

HH

P

Y

'O' or S8

PYZ

Z = O or S

PYZ

PHOSPHOLE OXIDE

15

P

H

PHO

aromatic antiaromatic?phosphole phosphole oxid


16

P

Me

P

Me

P

Me

P

Me

H2 H2

PMe

PMe

PMe

PMe

H2 H2

O O O O

HH2[I] HH2[II]

Reference reactionReference reactionStudied reactionStudied reaction

HH2 aromaticity

-93.8 -115.722.0 12.3 %12.3 %

-132.6 -116.2-16.4 -12.6 %-12.6 %


17

P

Me

6

PMeO

4

PMeO

N

Me

6

B

Me

4


18

Y P

R R

X

XX Y P

R R

X X

X

1B1ARR

Y P X

X X

3R R

Y P

X

XX

+150 oC

X = O, S, NH

HETEROPHOSPHETEHETEROPHOSPHETEY ekvatoriális Y axiális

-OXO, TIO-, IMINO--OXO, TIO-, IMINO-FOSZFFOSZFORORÁÁNN

Y P

R R

X

XX Y P

R R

X X

X

2B2A RR

Y P X

X X

4

HETEROPHOSPHETANEHETEROPHOSPHETANE

INSTABLEINSTABLE

STABLESTABLE

Heterophosphates exist as two comformers (1A és 1B), they are instable and results stabile -oxo, tio-, iminophosphoranes (3) [2].

Saturated version of them are quite stable, known as the intermediates of Wittig reaction (2A and 2B) and analogues ring opening is not possible.

[2] Current Org. Chem. 2004, 8, 1245.

AromaticityAromaticityY = O, N, S

dxzpz

pzpz

Y2

C3C4

P1

emptydxz2 elektron a pz-nPY

44 systemsystemInstability of these compounds can be explained by their antiaromaticity.

ANTIAROMANTIAROMATICATIC

OVERLAPPINGbetween P atom dxz and Y atom pz orbitals

What is the reason of the sharp difference between the stability.What is the reason of the sharp difference between the stability.

[3] Eur. J. Org. Chem. 2007, 1759.

ELECTRONIC ELECTRONIC STRUCTURESTRUCTURE


19

Y = O, N, S

20

Strucutre 1A (equatorial Y) exhibits larger antiaromaticity, than structure 1B (axial Y), they are rather non-aromatic

ANTIAROMATICITANTIAROMATICITYY

Y P

1A(Y,X)

X

X

X

Y P

1B(Y,X)

X

XX

Y P

2A(Y,X)

X

X

X

Y P

2B(Y,X)

X

XX

P

1A(CH2,X)

X

X

X

P

2A(CH2,X)

X

X

X

P

1B(CH2,X)

X

XX

H2

H2

H2

H2

Measuring by the linar aromaticity scale.[3]

X = F, Cl, CN és Y = NH, O, S = 9 strucutre.

(–40%) – (–15%)

(–10%) – (15%)


20

Y P

X

XX Y P

X X

X Y P X

X X

1B1A 3

2

3

1

4

Y P

X

XX

1B-TS

Y P X

X X

Turnstile pseudorotation

3-TSH H

Y P

X

XX

+

THERMODYNAMIC AND KINETICTHERMODYNAMIC AND KINETIC

Mechanism of the 1A 1B 3 transformation

1.82.0

2.22.4

2.6120140

160180

200220

2400

20

40

60

80

100

3TS

1BTS

3

1A

1B3rela

tive

ener

gy (

kJ/m

ol)

torsion angle P1-Y2 distance (A)

X = X = F, Cl, CNF, Cl, CNY = O, NH, SY = O, NH, S

1A

1B33TS

1BTS

3-5 kJ/mol

TS

SM

40-60 kJ/mol

140-160 kJ/mol

3-12 kJ/mol

Decreasing antiaromaticity


21

22

ANTIAROMATICITANTIAROMATICITY SURFACEY SURFACE

Strucutre 1A is in a very negative, antiaromatic hole.

PESPES

AromaticitAromaticity surfacey surface

Structure 1B is in a non-aromatic valley.

Strucutre 3 is on an aromatic downhill


22

N

O

N

O

N

O

=

N

O

N

O

R3

R1

R2

N

O

N

O~100 years

seconds

minutes

Stability in aqueous media (pH = 7)

Strong or weak conjugation

AmidicityAmidicity

23

H2

O

NR1

R2

R3

B

HH2[I]N

O

R1R2

R3

A

H

H+

HH2[I] = 34.88 kJ mol-1

H2

O

N

OH

N

1

+

Quantitative measure of AmidicityQuantitative measure of Amidicity

B3LYP/6-31G(d,p)

Conjugation stopped

100 % 0 %

MEASURE:MEASURE:

SCALE(%):SCALE(%):

~full conjugation Noconjugation

N NO HO

H2

HH2[I] = -44.62 kJ mol-12

+

HH2 ~stabilization energy

[Amidicity %] = m HH2[I] + [Amidicity %]0

AmidicityAmidicity

24

25

O

NH2

O

NH

O

N

O

N

O

N

O

N

O

N

O

N

NHO

NHO

NHO

NON

ON

ON

O

NMPNMP

O

N

O

NH2 DMFDMF

+ ring strainH2

( )n ( )n

n = 1 : -137.50 kJ mol-1

2 : -111.85 kJ mol-1

3 : -118.44 kJ mol-1

HH2[II]

H2

HH2[III]

-117.40 kJ mol-1

Test set 1Test set 1

93 % 95 % 97 % 101 % 100 % 97 %

82 % 58 % 87 % 95 %

79 % 117 % 91 %

81 %122 %

90 %13 %

AmidicityAmidicity

25

26

NH

O

NHO

O

N

O

N

O

NH

O

NH

O

NH

NO2 N

O O

HN

HN

O

N N

O

N

O

NO

Aromatic (6) Antiaromatic (4)

Conjugated

Test set 2Test set 2

123 % 131 % 25 % 27 %

competingcompeting

-30 % 53 % 89 % 88 % 61 % 57 %

128 % 108 %

assisitingassisiting

competingcompetingassisitingassisiting

AmidicityAmidicity

26

-40 -20 0 20 40 60 80 100 120 140

65

16

3915

257

2412

112623

827212017 4 29 13

1418

2819

1

1022

2

Amidity (%)

Amidicity scaleAmidicity scale

O

N

O

N

N

O

O

N

O

N

O

N

NO

NO

NO

O

NH

NO2

AmidicityAmidicity

27

4 5 670

80

90

100

110

120

130

20

30

40

50

60

70

Models with NH Models with NMe

Am

idity

%

15

16

13

14

11

12

Ring size

Rel

ativ

e A

mid

ity %

NHO

NHO

NHO

NO

NO

NO

NMP

AmidicityAmidicity

28

-20 0 20 40 60 80 100 120 140-320

-280

-240

-200

-160

16

15

413

6

27

8

Y = 0.906 X + (-292.81)

(R2 = 0.884)

References (1,2) Models (3-29)

7

9

3

1112

21

10

5

29

14 28

1819

20

17

1

2

HR

eact (

kJ m

ol-1)

Amidity %

N

O

R1R2

R3

A

N

O

R1R2

R3

OH

OH

+

N

O

R1R2

R3

OH

N

O

R1R2

R3

OH

OH

O

R1

+N

R2

R3

TS-A TS-HH J

ReactivityReactivity AmidicityAmidicity

29

morereactive

lessreactive

Aromaticity = Aromaticity (T) – Aromaticity(R)

N

O

R1R2

R3

+ N

O

R1R4

R5

NR4

R5

NR2

R3

+H H

O

N

O

NNH

NH

+ +

Amidicity = Amidicity(T) – Amidicity(R)

Transamidiation reactionTransamidiation reaction

- Soft acylation- Selectivity

Pl.:

If Amidicity is positive, then the reaction is allowedIf Amidicity is negative, then the reaction is forbidden

Rule:

AmidicityAmidicity

30

O

N

26

NH2

O

23

NH

25

NH3

24

+ +

Amidity 93.4 % 96.8 %

Amidity = 3.4 %

R-I

O

N

1

NH2

O

27

NH

25

NH3

24

+ +

Amidity 96.1 % 100.0 %

R-II

Amidity = 3.9 %

Test reactions 1Test reactions 1 AmidicityAmidicity

31

O

NH

3231

NH

24

+

O

NN

57.3 % 101.6 %

R-IV

NH

24

+

30.3 % 99.4 %

R-III

N

O

HNH2

N

O

28 29

Amidity

Aromaticity

Amidity

Aromaticity

100 % 102.4 %-17.3 %

-13.7 % 0.0 %

AmidicityAmidicity

32

O

N

O

N

33 36

NH

NH

34 35

+ +

Amidity 59.0 % 106.3 %Amidity = + 47.3 %

Aromaticity 39.5 % 56.9 % 0.0 %Aromaticity = + 17.4 %

0.0 %

O

N

O

N

37

N36

NH

N NH

34 38

+ +

Amidity 46.6 % 106.3 %Amidity = + 59.7 %


0.0 %

O

NN

O

NN

39

NN

HN N

H

34 38

+ +

Amidity 44.9 % 128.4 %Amidity = + 83.5 %

Aromaticity2 x 20.6 % 2 x 50.3 % 2 x 0.0 %Aromaticity = + 59.4 %

2 x 0.0 %

N

R-V

R-VI

R-VII

402 2


33

O

N

41

O

NNH

42 43

NH

44+ +

Amidity -30.2 % 100.2 %Amidity = +130.4 %


0.0 %

R-VIII

O

N

41 38 43

NH

37+ +

Amidity -30.2 % 46.6 %Amidity = + 76.8 %

Aromaticity 91.1 % 99.4 % 28.6 %Aromaticity = - 13.4 %

50.3 %

R-IX

N NH

O

N N

O

N

O

NH

45 1

NH

24

+ +

Amidity 81.7 % 100.0 %Amidity = + 18.3 %

Aromaticity 104.0 % 100.8 % 0.0 %Aromaticity = -3.2 %

0.0 %

R-X

NH

H

46


34

O

N

4847

NH

42

+

O

N

97.0 % 95.6 %Amidity = -1.4 %

R-XI

HN

24

+

O

N

5049

NH

24

+ N

H

120.3 % 104.0 %

Amidity = -16.3 %

R-XII

N

O

Test reactions 4Test reactions 4

No reaction !!

NMPNMP

DMFDMF

AmidicityAmidicity

35

36

O

N1

NH

O

51

NH

53N

H

24

+ +

61.5 % 100.0 %Amidity = 38.5 %

R-XIII

N

ONO NO

N2O4

O

N1

NH

57N

H

24

+ +

28.5 % 100.0 %Amidity = 71.5 %

N

OSO2 SO2

CF3 CF3

O

N1

N

O O

60

NH

51

N

O

H24

+ +

53.7 % 101.6 % 100.0 %Amidity = 147.9 %

R-XVII

O

N1

NH

55

NH

24

+ +

20.3 % 100.0 %Amidity = 79.7 %

R-XIV

N

ONO2 NO2

R-XV

N2O5

CF3SO2X

MeCOX

O

N1

NH

59N

H

24

+ +

62.0 % 100.0 %Amidity = 38.0 %

N

OSO2 SO2

PhMe PhMe

R-XVI

MePhSO2X101.6 %

52

54

56

58


36

O

N

78 79

N

R-XXI

HN77X

O

NH

X

NH2

X

HN

XO

+

- 80

47NaOMe sav

Test reactions 8Test reactions 8

161.0 %161.0 % 71.9 %71.9 %

97.0 %97.0 %

reversibleorreversible

AmidicityAmidicity

37

R-XXIII

23 (93.4 %) 88

+

O

NH2

NH2

H2N

NH2

HN

O

HN

H2N

O

89 (100.4 %) 91 (80.4 %)

+

HN

HN

O

O

+

93

80-100 oC

2-4 óra

88

+

O

NH2

27 (96.1 %)

NH2

H2N

NH2

HN

O

HN

H2N

O

90 (101.2 %) 92 (82.2 %)

+

HN

HN

O

O

+

94

80-100 oC

0.2 eq. AlCl315 óra

Selectivity 2Selectivity 2 AmidicityAmidicity

38

Biological exampleBiological exampleBlood clottingBlood clotting

AANH

HN AA

O

O

OH2N

AA

HN

NH

AA

O

O

NH2

AANH

HN AA

O

O

O

AA

HN

NH

AA

O

O

HN NH3+ +

XIIIa

Transamidinaze

96.0%

101.1%

SPONTANOUSSPONTANOUS

AmidicityAmidicity

39

+4.1%+4.1%

H2

O

R2R1

B

H H2[A]R2

O

R1

A

H

H+

H H2[I] = 121.81 kJ mol-1

H2

O

O-H

OH

O-H

1

+

QUANTITATIVE MEASUREMENT OF QUANTITATIVE MEASUREMENT OF CARBONYLICITYCARBONYLICITY

B3LYP/6-31G(d,p)

Delocalisation stopped

100 % 0 %

MEASURE:MEASURE:

SCALE (%):SCALE (%):

~full conjugation No conjugation


[Carbonylicity%] = m HH2[A] + [Carbonylicity %]0 40

CarbonylicityCarbonylicityCarbonylicityCarbonylicity

H H2[II] = -80.21 kJ mol-1

H2

O

HH

OH

HH

2

+

-40 -20 0 20 40 60 80 100 120 140

O

HH 1

O

OH

13

O

C

H

HH14

1658615

O

SH

O

C

H

HH

H

O

ClH

O

N

H

HH

O

N

H

HH

HO

NH

H

2

[B]

Carbonylicity (%)

41

CarbonylicityCarbonylicityCarbonylicityCarbonylicityCarbonylicity scaleCarbonylicity scale

Peptide coupling Peptide coupling (1)(1)

O

NO

O

51.7 % 55.6 %

H HN ++ H2O

O

NO

O

54.4 % 55.6 %

Me HN ++ OMeH

O

NX

O

X % 55.6 %

HN

+ XH

O

O

HX

51.7 %

ActivationActivation

O

NO

O

102 % 55.6 %

HN ++ OH

+3.9 %+3.9 %

-46.4 %-46.4 %

+1.2 %+1.2 %

+X %+X %


42

Peptide couplingPeptide coupling (2) (2)

O

NO

O

51.7 % 55.6 %

O

O

H

HN

38.7 %

C NNc-Hex

c-Hex

N

NH

N

O

N

H H

c-Hexc-Hex-

O

NO

O

44.3 % 55.6 %

HNNO2

OH

NO2

OH

O

51.7 %

+11.3 %+11.3 %

+16.9 %+16.9 %

DCCDCC

Active esterActive ester


43

O

NO

O

51.7 % 55.6 %

H

HN

57.0 %

O

O Cli-Bu

O

O

O

Oi-Bu O

O

Oi-BuH

H2O CO2+ +

29.8 % 56.6 %

44.9 %

- HCl

+

O

OH

51.7 %

N

O

Oi-BuH

57.0 %

+

H MINOR PRODUCTS

MAJOR PRODUCTS


Mixed anhydrideMixed anhydride

+25.4 %+25.4 %

+21.9 %+21.9 %


44

O

NO

O

51.7 % 55.6 %

NN

N

O

O

O

P

PN

NN

N

N

NN

N

OH N

NN

OH O

HN

25.5 % 36.4 %

NN

N

OH

- NN

N

OH

-

O

NO

O

51.7 %

NN

N

O

O

O

NN

N

OH N

NN

OH O

HN

36.4 %28.3 %

NN

N

OH

- NN

N

OH

-

N

NN

N

NH

55.6 %


HBTUHBTU

BOPBOP

+10.9 %+10.9 %

+19.2 %+19.2 %

+8.1 %+8.1 %

+19.2 %+19.2 %


45

51.7 %22.6 %

C NNc-Hex

c-Hex

N

NH

N

O

N

H H

c-Hexc-Hex

-

N

S

OOH

O

HNR

N

S

O

OHO

HN

R

HOH

N

S

O

OHO

HN

R

H

36.0 %

Penicillin Penicillin synthesissynthesis

51.7 %37.1 %

C NNc-Hex

c-Hex

N

NH

N

O

N

H H

c-Hexc-Hex

-

N

S

OO

O

HNR

N

S

O

OO

HN

R

HOH

N

S

O

OO

HN

R

H

36.0 %

+1.1 %+1.1 %

-13.4 %-13.4 %


46

Lactame, LactoneLactame, Lactone(Amidicity, Carbonylicity)(Amidicity, Carbonylicity)

Ring-openingRing-opening

N

O

OH

O

NH( )n

( )n

n = 1, 2, 3, 4

O

O

OH

O

HO( )n( )n

H2O

H2O

O

ON

O


47

H2

R2R1

B

H H2[A]R2R1

A

R4

H+

HR3

R4 R3

H H2[I] = -2.46 kJ mol-1

H2

CH2-H CH2

-H

1

+

H H H H

Quantitative measurement of OlefinicityQuantitative measurement of Olefinicity

B3LYP/6-31G(d,p)

Delocalisation stopped

100 % 0 %

MEASURE:MEASURE:

SCALE (%):SCALE (%):

~full conjugation No conjugation


[Olefinicity%] = m HH2[A] + [Olefinicity%]0 48

H H2[II] = -145.96 kJ mol-1

H2

HH HH

2

+

H H H H

OlefinicityOlefinicityOlefinicityOlefinicity

H2

CH2

X

CH2

X

4

CH2

O

H

5

CH2

N

3

CH2

F

6

CH2

C

7

CH2

BH

H

H

HH

H

HH

HH

H H H H H

9

CH2

S

10

CH2

P

8

CH2

Cl

11

CH2

Si

12

CH2

AlH

H

H

HH

H

HH H H H H

13

CH2

N

14

CH2

C

2

CH2

O

15

CH2

NH

H

H

H

HH

H H H H

17

CH2

P

18

CH2

Si

16

CH2

S

19

CH2

PH H

H

H

HH

H H H H

21

CH2

S

22

CH2

20

CH2

O

23

CH2

24

CH2

Me

H

H H H H

28

CH2

25

CH2

26

CH2

NO2H HH

Me

NH

O

OH

O

O

O

CONJUGATIVE EFFECTS OF MONOSUSTITUTED ETHENE (Group 1)

5.9 % 20.3 % 31.1 % 12.1 % 19.6 %

2.7 % 11.9 % 8.9 % 8.8 % 19.2 %

97.4 % 110.7 % 100.0 % -14.6 % 49.0 % 27.3 %

17.3 % 7.1 % 18.8 % 9.0 % 18.9 % 1.7 % 19.1 %

57.4 % 29.7 % -5.3 %

H

H

29

CH2

H

34.7 %

27

CH2

H

25.4 %

(11.5 %) (20.4 %) (29.2 %) (11.4 %) (22.4 %)

(4.4 %) (10.3 %) (7.4 %) (10.4 %) (20.4 %)

(87.2 %) (100.7 %) (100.0 %) (-10.0 %) (46.0 %) (26.4 %)(47.2 %) (27.8 %) (-0.3 %)

(15.5 %) (10.1 %) (19.6 %) (11.6 %) (19.5 %) (5.1 %) (19.4 %) (32.4 %)(24.8 %)


49

RING EFFECTS (Group 2) AROMATIC EFFECTS (Group 3)

CONJUGATIVE EFFECTS (Group 4)

H2C

( )n( )n

n = 0 : 30 1 : 31 2 : 32 3 : 33 4 : 34

n = 0 : 35 1 : 36 2 : 37 3 : 38 4 : 39

-124.3 %2.6 %

37.1 %

-46.9 % X %17.8 %

40 41(129.2 %) (-98.0 %)

CH2

NH

H

42

CH2

NH

H

44

CH2

NH

H

46

NO2

HNH

NH

HH2C

H NH

H

CH2 O

48

50

CH2

OH

43

CH2

OH

45

CH2

OH

47

NO2H O H

CH2 O

49

31.1 % 18.9 % 33.0 % 16.2 %

46.4 %

9.4 % 9.3 %24.4 %5.1 %

26.2 % X %

CH2

NH2O2N

54 26.7 %

NH2

55 55.2 %

O2N

H

NH2

51 37.5 %

H2N

H NO2

53 -8.3 %

O2N

H

NH2

56 64.0 %

H

NO2

31.8 % 25.8 %

O2N

H2C

52 -15.3 %

OH

58 22.5 %

HO

H

NO2

OHHO

CH2

57 16.0 %

147.4 % -126.2 %

(-46.9 %)( X %)(17.8 %)(X %)(25.8 %)

(-124.3 %)(2.6 %)

(37.1 %)(26.2 %)(31.8 %)

(28.8 %) (18.7 %) (31.6 %) (15.9 %)

(43.6 %)

(12.0 %) (11.7 %)(24.0 %)(3.3 %)

(29.6 %) (56.6 %)

(38.4 %) (0.6 %)

(62.5 %)

(-7.5 %)

(27.3 %)(22.9 %)


50

-140 -120 -100 -80 -60 -40 -20 0 20 40 60 80 100 120 140

222120

32

32

5119 1617

5556

13

6715 52

14 403541 30

[B] 21

olefinicity (%)


51

H2C CH2

N

H

HH

H

CH2

SMe

H

CH2

SH

CH2

OH

CH2

CH2H

CH2

HH

CH2

NH

H

Olefinicity scaleOlefinicity scale

Pd(PMe3)2Br

+ RR

R = H, COOMe2, NO2, OMe

-HBr

olefinicity (2) (3) olefinicity

H 0.0 19.42 19.4

COOMe 12.5 37.1 24.6

NO2 5.1 31.1 26.0

OMe 26.4 35.8 9.4

(1) (2) (3)

Heck coupling (Olefinicity)Heck coupling (Olefinicity)OlefinicityOlefinicityOlefinicityOlefinicity

52

Redox reaction in biochemistry

53

COMPLEXCOMPLEXCOMPLEXCOMPLEX

54


55


PENICILLINPENICILLIN

1. Proper 3D-geometry (DESIGN)2. Internal ring strain (SPRING)3. Sensitive sensor (BAIT)4. Acylation property (MORTAL TOOL)

1. Proper 3D-geometry (DESIGN)2. Internal ring strain (SPRING)3. Sensitive sensor (BAIT)4. Acylation property (MORTAL TOOL)


SYSTEMS OF COMPONENTSSYSTEMS OF COMPONENTS

56

57

AMIDICITY OF PENICILLINAMIDICITY OF PENICILLIN

inactiveactive3 superactive


MORE ACTIVEMORE ACTIVE57

Documents

SYSTEMS CHEMISTRY Mucsi Zoltán SERVIER 2 nd in France 25 th in WW 1