systems chemistry mucsi zoltán servier 2 nd in france 25 th in ww 1
TRANSCRIPT
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
AromaticityAromaticity
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.
AromaticityAromaticity
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
AromaticityAromaticity
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 %
AromaticityAromaticity
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
AromaticityAromaticity
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%)
AromaticityAromaticity
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
AromaticityAromaticity
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
AromaticityAromaticity
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 %
Aromaticity 28.6 % 50.3 % 0.0 %Aromaticity = + 21.7 %
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
Test reactions 2Test reactions 2 AmidicityAmidicity
33
O
N
41
O
NNH
42 43
NH
44+ +
Amidity -30.2 % 100.2 %Amidity = +130.4 %
Aromaticity 91.1 % 99.4 % 0.0 %Aromaticity = + 8.3 %
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
Test reactions 3Test reactions 3 AmidicityAmidicity
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
Test reactions 5Test reactions 5 AmidicityAmidicity
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
HH2 ~stabilization energy
[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 %
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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
Peptide couplingPeptide coupling (3) (3)
Mixed anhydrideMixed anhydride
+25.4 %+25.4 %
+21.9 %+21.9 %
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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 %
Peptide couplingPeptide coupling (4) (4)
HBTUHBTU
BOPBOP
+10.9 %+10.9 %
+19.2 %+19.2 %
+8.1 %+8.1 %
+19.2 %+19.2 %
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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 %
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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
CarbonylicityCarbonylicityCarbonylicityCarbonylicity
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
HH2 ~stabilization energy
[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 %)
OlefinicityOlefinicityOlefinicityOlefinicity
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 %)
OlefinicityOlefinicityOlefinicityOlefinicity
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 (%)
OlefinicityOlefinicityOlefinicityOlefinicity
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
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)
COMPLEXCOMPLEXCOMPLEXCOMPLEX
SYSTEMS OF COMPONENTSSYSTEMS OF COMPONENTS
56