Ciências Farmacêuticas Bioquímica Química AFB QO II 2007/08 1. Química Orgânica II S1

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1 Química Orgânica II Ciências Farmacêuticas Bioquímica Química AFB QO II 2007/08 1 Química Orgânica II S1 Sistemas conjugados Revisão de conceitos fundamentais Ligação química deslocalizada Síntese Reactividade AFB QO II 2007/08 2

2 Química Orgânica II Conjugated systems AFB QO II 2007/08 3 Polyenes Lycopene β-caroten AFB QO II 2007/08 4

3 enones Extended conjugation in ketones hormones progesterone AFB QO II 2007/08 5 AFB QO II 2007/08 6

4 Levonorgestrel implants AFB QO II 2007/08 7 CYPROTERONE ACETATE CH 3 C O O O C CH 3 H O H H Antiandrogenic properties Cl CYPROTERONE ACETATE (ANDROCUR)

5 Steroid Aromatase O A B HO Estrogens AFB QO II 2007/08 10

6 PROGESTERONE CH 3 C O Natural hormone secreted by the corpus luteum and the placenta ( a C-21 steroid) O H H H PROGESTERONE it is also an important intermediate in steroid biogenesis in all tissues that produce steroids (testes, adrenal cortex) Intestinal absorption is quite erratic; must be micronized for most effective absoption (Prometrium) 19-NOR STEROIDS OH C CH OH C CH H H H H H H O O NORETHINDRONE NORETHINODREL Chemical analogues of testosterone - some retain some androgenic activity such as norethindrone

7 Polyene antibiotics Nystatin amphotericin B Polyene antibiotics bind to sterols within the fungal membrane, disrupting its integrity. This makes the membrane leaky, leading to a loss of small molecules from the fungal cell. Nystatin antifungal antibiotic obtained from Streptomyces noursei AFB QO II 2007/08 13 conducting polymers AFB QO II 2007/08 14

8 Names and definitions IUPAC AFB QO II 2007/08 16

9 IUPAC AFB QO II 2007/08 17 IUPAC AFB QO II 2007/08 18

10 Conjugated and Nonconjugated Dienes If double bonds are separated by only one single bond, they are conjugated and their orbitals interact The conjugated diene 1,3-butadiene has properties that are very different from those of the nonconjugated diene, 1,5-pentadiene AFB QO II 2007/08 19 Diens: Compounds with two double bonds Isolated: (two or more single bonds between them) Conjugated: (one single bond between them) Cumulated: (zero single bonds between them: allenes) C C C Conjugated double bonds are found to be the most stable. AFB QO II 2007/08 20

11 Hexadienes 1,4 2,3 2,4 AFB QO II 2007/08 21 conjugation Isolated double bondes: Conjugated: (one single bond between them and alignment of p orbitals) Aromatic: (extra stability) AFB QO II 2007/08 22

12 Conjugated Dienes Synthesis and Stability AFB QO II 2007/08 23 Synthesis of Conjugated Dienes Typically by elimination in allylic halide Specific industrial processes for large scale production of commodities by catalytic dehydrogenation and dehydration AFB QO II 2007/08 24

13 AFB QO II 2007/08 25 Stability Conjugated dienes are more stable than nonconjugated dienes based on heats of hydrogenation Hydrogenating 1,3-butadiene releases 16 kj/mol less heat than 1,4-pentadiene AFB QO II 2007/08 26

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15 14.2 Molecular Orbital Description of 1,3-Butadiene The single bond between the conjugated double bonds is shorter and stronger than sp 3 AFB QO II 2007/08 29 The bonding π-orbitals are made from 4 p orbitals that provide greater delocalization and lower energy than in isolated C=C The 4 molecular orbitals include fewer total nodes than in the isolated case AFB QO II 2007/08 30

16 Molecular orbitals of etene AFB QO II 2007/08 31 Molecular Orbitals of 1,3-Butadiene AFB QO II 2007/08 32

17 Molecular Orbital Description of 1,3-Butadiene In addition, the single bond between the two double bonds is strengthened by overlap of p orbitals In summary, we say electrons in 1,3-butadiene are delocalized over the π bond system Delocalization leads to stabilization AFB QO II 2007/08 33 Electrophilic Additions to Conjugated Dienes: Allylic Carbocations Review: addition of electrophile to C=C Markovnikov regiochemistry via more stable carbocation AFB QO II 2007/08 34

18 Carbocations from Conjugated Dienes Addition of H + leads to delocalized secondary allylic carbocation AFB QO II 2007/08 35 AFB QO II 2007/08 36

19 Products of Addition to Delocalized Carbocation Nucleophile can add to either cationic site The transition states for the two possible products are not equal in energy AFB QO II 2007/08 37 Practice Problem 14.1: Products? AFB QO II 2007/08 38

20 14.4 Kinetic vs. Thermodynamic Control of Reactions At completion, all reactions are at equilibrium, and the relative concentrations are controlled by the differences in free energies of reactants and products (Thermodynamic Control) If a reaction is irreversible or if a reaction is far from equilibrium, then the relative concentrations of products depends on how fast each forms, which is controlled by the relative free energies of the transition states leading to each (Kinetic Control) AFB QO II 2007/08 39 Kinetic and Thermodynamic Control Example Addition to a conjugated diene at or below room temperature normally leads to a mixture of products in which the 1,2 adduct predominates over the 1,4 adduct At higher temperature, product ratio changes and 1,4 adduct predominates AFB QO II 2007/08 40

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