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

A B C P E D… … E ? Sideproducts Synthetic plan:

On paper: In reality:

MOLECULAR ENGINEERING ? 4 Newton equationsrules, equations Schrödinger equations

Chemical reaction Enthalpy deconvolution H-bond  H H2 Solvent Steric Aromaticity Amidicity Carbonylicity Olefinicity Internal energy ReactantProduct SYSTEMS CHEMISTRY 5

amidicity carbonyicity tiocarbonylicity iminicityolefinicity aromaticity CONJUGATICVICITY Quantitative Chemistry 6

 H H2 (1) H2H2 [conj%](A) = 0% = m  H H2 (A) + [conj%] 0 1. eq [conj%](B) = 100% = m  H H2 (B) + [conj%] 0 2. eq [conj%](1) = m  H H2 (1) + [conj%] 0 3. eq  H RE (1) = [conj%](1) / m4. eq [conj%](A) = 0% = m  H H2 (A) + [conj%] 0 1. eq [conj%](B) = 100% = m  H H2 (B) + [conj%] 0 2. eq [conj%](1) = m  H H2 (1) + [conj%] 0 3. eq  H RE (1) = [conj%](1) / m4. eq 0 %100 %  H H2 (A)  H H2 (B) 12 AB X = Z No conjugation Equal conjugation 7

R(1) + R(2) I (1,2) P(1) + P(2)  Conj. =  Conj.[P(i)] -  Conj.[R(j)] Positive = advantageous; negative = disadvantageous Thermodinamic: Kinetic:  Conj. ≈  H(RE) Small difference = reactive; large = unreactive 8 Conj.[P(i)]

1.Aromaticity a.Phosphole b.Heterophosphete 2. Amidicity a.Transamidiation b.Selectivity c.Bio example 3. Carbonylicity a. Peptide coupling b. Reactivity 4. Olefinicity a. Cross-coupling b. Indole reaction 5. Complex approaches a. 1. example b.NAD, FAD c.Penicillin

10Aromaticity/Antiaromaticity Aromaticity likes to beauty, easy to recognise, but hard to quantify. (P. V. R. Schleyer) 1.molecular stability 2.reactionway 3.Activation energy 4.Spectroscopical property  -aromaticity (1979) [pl. Li cluster], antiaromaticity (1965)  -(2D)aromaticity (1920)  -aromaticity (2004) [pl. Au cluster], 3D aromaticity (1978) Determine … Aromaticity 10

11 Geometrical based Magnetic shillding based Aromaticity/Antiaromaticity „measure” HOMA, Bird, BDSHRT index Pl. cbutadiene [27-29] benzene [(-8)-(-9)] pirrole [(-12)-(-13)] reference Smell based Good or bad smell ? antiaromatic NICS Nuclear Independent Chemical Shift: NICS Aromaticity 11

MÓDSZER: kJ/mol Reference reaction Studied reaction kJ/mol kJ/mol kJ/mol kJ/mol kJ/mol kJ/mol kJ/mol kJ/mol AROMATIC ANTIAROMATIC NON-AROMATIC G3MP2B3 X kJ/mol [1] J. Phys. Chem A. 2007, 111, 1123–1132. LINEAR AROMATICITY SCALE Aromaticity  H H2 =  H H2 (1) -  H H2 (2) 12

X  H H2 (kJ/mol) Y = aromaticity parameter (%) 100 % -100 % 0 % Fitting(G3MP2B3): Y = m.X + b m = b = [1] J. Phys. Chem A. 2007, 111, LINEAR AROMATICITY SCALE Aromaticity 13

AROMATIC SCALE % 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. Aromaticity 14

PHOSPHOLE OXIDE 15 aromaticantiaromatic? phospholephosphole oxid Aromaticity

16 Reference reaction Studied reaction  H H2 aromaticity % % Aromaticity

17 Aromaticity

18 HETEROPHOSPHETE Y ekvatoriálisY axiális  -OXO, TIO-, IMINO- FOSZFORÁN HETEROPHOSPHETANE INSTABLE STABLE 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, Aromaticity Y = O, N, S

emptyd xz 2 elektron a p z -n PY 4  system Instability of these compounds can be explained by their antiaromaticity. ANTIAROMATIC OVERLAPPING between P atom d xz and Y atom p z orbitals What is the reason of the sharp difference between the stability. [3] Eur. J. Org. Chem. 2007, ELECTRONICSTRUCTURE Aromaticity 19 Y = O, N, S

20 Strucutre 1A (equatorial Y) exhibits larger antiaromaticity, than structure 1B (axial Y), they are rather non-aromatic ANTIAROMATICITY Measuring by the linar aromaticity scale.[3] X = F, Cl, CN és Y = NH, O, S = 9 strucutre. (–40%) – (–15%) (–10%) – (15%) Aromaticity 20

THERMODYNAMIC AND KINETIC Mechanism of the 1A  1B  3 transformation X = F, Cl, CN Y = O, NH, S 1A 1B 3 3TS 1BTS 3-5 kJ/mol TS SM kJ/mol kJ/mol 3-12 kJ/mol Decreasing antiaromaticity Aromaticity 21

22 ANTIAROMATICITY SURFACE Strucutre 1A is in a very negative, antiaromatic hole. PES Aromaticity surface Structure 1B is in a non-aromatic valley. Strucutre 3 is on an aromatic downhill Aromaticity 22

~100 years seconds minutes Stability in aqueous media (pH = 7) Strong or weak conjugation Amidicity 23

Quantitative measure of Amidicity B3LYP/6-31G(d,p) Conjugation stopped 100 % 0 % MEASURE: SCALE(%): ~full conjugationNoconjugation  H H2 ~stabilization energy [Amidicity %] = m  H H2 [I] + [Amidicity %] 0 Amidicity 24

25 NMP DMF + ring strain Test set 1 93 % 95 % 97 %101 %100 %97 % 82 %58 %87 %95 % 79 %117 %91 % 81 % 122 % 90 % 13 % Amidicity 25

26 Aromatic (6  )Antiaromatic (4  ) Conjugated Test set % 131 % 25 % 27 % competing -30 % 53 %89 %88 %61 %57 % 128 %108 % assisiting competingassisiting Amidicity 26

Amidicity scale Amidicity 27

NMP Amidicity 28

ReactivityAmidicity 29 more reactive less reactive

 Aromaticity = Aromaticity (T) – Aromaticity(R)  Amidicity = Amidicity(T) – Amidicity(R) Transamidiation reaction - Soft acylation - Selectivity Pl.: If  Amidicity is positive, then the reaction is allowed If  Amidicity is negative, then the reaction is forbidden Rule: Amidicity 30

Test reactions 1 Amidicity 31

Amidicity 32

Test reactions 2 Amidicity 33

Test reactions 3 Amidicity 34

Test reactions 4 No reaction !! NMP DMF Amidicity 35

36 Test reactions 5 Amidicity 36

Test reactions % 71.9 % 97.0 % reversible orreversible Amidicity 37

Selectivity 2 Amidicity 38

Biological example Blood clotting SPONTANOUS Amidicity %

QUANTITATIVE MEASUREMENT OF CARBONYLICITY B3LYP/6-31G(d,p) Delocalisation stopped 100 % 0 % MEASURE: SCALE (%): ~full conjugationNo conjugation  H H2 ~stabilization energy [Carbonylicity%] = m  H H2 [A] + [Carbonylicity %] 0 40 CarbonylicityCarbonylicity

41 CarbonylicityCarbonylicity Carbonylicity scale

Peptide coupling (1) Activation +3.9 % % +1.2 % +X % CarbonylicityCarbonylicity 42

Peptide coupling (2) % % DCC Active ester CarbonylicityCarbonylicity 43

Peptide coupling (3) Mixed anhydride % % CarbonylicityCarbonylicity 44

Peptide coupling (4) HBTU BOP % % +8.1 % % CarbonylicityCarbonylicity 45

Penicillin synthesis +1.1 % % CarbonylicityCarbonylicity 46

Lactame, Lactone (Amidicity, Carbonylicity) Ring-opening CarbonylicityCarbonylicity 47

Quantitative measurement of Olefinicity B3LYP/6-31G(d,p) Delocalisation stopped 100 % 0 % MEASURE: SCALE (%): ~full conjugationNo conjugation  H H2 ~stabilization energy [Olefinicity%] = m  H H2 [A] + [Olefinicity%] 0 48 OlefinicityOlefinicity

OlefinicityOlefinicity 49

OlefinicityOlefinicity 50

OlefinicityOlefinicity 51 Olefinicity scale

olefinicity(2)(3)  olefinicity H COOMe NO OMe (1) (2) (3) Heck coupling (Olefinicity) OlefinicityOlefinicity 52

Redox reaction in biochemistry 53 COMPLEXCOMPLEX

54 COMPLEXCOMPLEX

55 COMPLEXCOMPLEX

PENICILLIN 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) COMPLEXCOMPLEX SYSTEMS OF COMPONENTS 56

57 AMIDICITY OF PENICILLIN inactiveactive 3 superactive COMPLEXCOMPLEX MORE ACTIVE 57