Heterocycles (McM chapt 28) Monocyclic or fused rings Cont. one ore more ring atom ≠ C (normally O; N; S) Aromatic, partly saturated or saturated ring(s)

Heterocycles (McM chapt 28)•Monocyclic or fused rings•Cont. one ore more ring atom ≠ C (normally O; N; S)•Aromatic, partly saturated or saturated ring(s)

5-Membered rings (Heteroatom N, O, S)

S

Thiophene

NH

Pyrrole

O

Thiophene

Other examples

N

NH

Imidazole

N

S

Thiazole

NH

Indole

NH

R'' NHR

R'

R=HR'=CO2HR'''=H

Tryptophane

R=HR'=HR'''=OH

SerotoninR=AcR'=HR'''=OCH3

Melatonin

N

NH

N

N

NH2

Adenine(purine der.)

N

NH

H2N

R

R=CO2H: HistidineR=H: Histamine

N

S

N

NH3C

HO

H2N

CH3

Thiamin(Vit B1)

X X X X X XX: S, Se

e- in d-orb.

Cyclopentadienyl anion

Thiophene

S

Criteria for Aromaticity (Hückel)(Monocyclic) ringPlanarNo of -electrons in conjugation 4n+2 (n: 0, 1, 2,....)

S

5-membered rings - electron rich - reactive i E-fil. Ar subst.

X+ E

XE

H XE

H XE

H X E

X+ E

X

EH

X

EH

X E

React. in -position generally preferredSelectivity not always goodReact.: Pyrrole > thiophene > furan

6-Membered rings (Heteroatom N)N

Pyridine

Other examples

N

Quinoline

N

N

Pyrimidine

NN

Pyridazine

Rare in nature

N

N

Pyrazine

N

NH

NH2

O

Cytosine

N

Quinine

H3CO

HO

N

N

Ant pheremone

NN

HydralazineAntihypertensive drug

H2NHN

NH

H H

H H

Pyridine as a base

N NH

+ H

NH

H H

H H

NH

H H

H H

H

pKa: 5.2

NH

pKa 0.4

NH

pKa 11.3

N

NH

pKa 7.1(≈amidine)

N

S

pKa 2.5

sp2 N less basic than sp3

Electrophilic Reaction on Carbon: E-phil. Ar. Subs.

6-membered rings - electron deficient - reactivity

N

NE

N

H

EN

E

+ E

+ res. forms

•Both C and N may react

•3/5 pos. most reactive C

•Diazines less reactive

•Sulfonation, Nitration, halogenatil

•Not FC react.

N NH

NH

H NO2

N

NO2H / NO2 H / NO2

+ res. formsBenzo ring most reactiveMuch slower react. than naphthalene

N N N N N

6-membered rings - electron deficient - reactive in Nu-fil. Ar subst.

N Cl

OMe

NOMe

Cl

+ res. form

N OMe

2 / 4 Pos. reactive; electron def. C, neg. charge partly on N in intermed3 / 5-Pos. much less reactive (benzenoid pos.)

Nucleophilic Aromatic Substitution

•SNAr

•SN1: Via arylic cation

•Benzyne

•SRN1: Involves radicals

•VNS: Vicarious nucl. Subst.

X Nu X

Nu

X

Nu

X

NuNu

Nucleosides, Nucleotides, Nucleic acids (DNA; RNA)

DNA bases

DNA Nucleosides

2-Deoxyribosides

RNA bases

HN

N

O

O

Thymidine

N

N

NH2

O

Deoxycytosine Deoxyadenosine

N

N N

N

NH2

HN

N N

N

O

H2N

O O O O

OH OH OH OH

HO HO HO HO

Deoxyguanoosine

HN

NH

O

O

Thymin

N

NH

NH2

O

Cytosin Adenine

N

N NH

N

NH2

Guanine

HN

N NH

N

O

H2N

HN

NH

O

O

Uracil

Cytosin Adenine Guanine

RNA Nucleosides

Ribosides

HN

N

O

O

Urinine

Cytosine

Adenosine

O

OH

HO GuanoosineOH

Nucleotides

OO

XHO

B

P

OO

XO

B

P

O

O

OHO

XO

B

O

O

5'

3'

Double -helix (DNA)

A-T and G-C Base pairs

NN

O

O CH3

HNN

N HH

N

N

NN

O

N

NN

ON

N

H

NH

H

H

H

DNA

Procaryotes and eucaryotes

5'

5'3'

3'

Leading strand

Lagging strand

3' 5'

5' 3'

3' 5'

3'5'

Replication

Transcription

DNA polymerase

DNA

5'

5'3'

RNA polymeraseDNA

5'

5'3'

3'5'

(+) stranded RNA

Translation

mRNA(+) stranded RNA

3'5'

Protein

3'5'

3'5'

Nucleotide sequence in DNA - genetic information

DNA helicases: UnwindingDNA binding proteins: Prevents winding backDNA primase: formation of DNA/RNA primer (from free nucleosides in cell)DNA polymerase: Catalyse elongation of new strand (5’ - 3’)

Lagging strand:DNA ligase: Connects Okasaki fragments

OO

O

T

P

OO

O

C

P

O

O

O

O

5'

3'

Template strand

OO

OH

G

P

OO

O

A

P

O

O

O

O

5'

3'

New strand

OO

O

T

P

OO

O

C

P

O

O

O

O

5'

3'

Template strand

OO

OH

G

P

OO

OH

A

P

O

O

O

O

5'

3'

New strand

Next nucleotideGuanosine triphosphate

O

P

O

O

O

O

O

O

3'

DNA

5'

5'3' RNA polymeraseDNA

5'

5'3'

(+) stranded RNA3'5'

Uracil instead of thymine

Transcription: DNA - RNA

Translation: RNA - Protein

3 RNA bases coding for one AA (see Table 28.1)

Protein synthesis occurs at ribosomes

mRNA(+) stranded RNA 5' 3'

50S

30S

Ribosom

Protein

NH3+

NH3+

CO2-

70S

initiator tRNA

OH 3'

tRNA-Met

OS

O

NH2

tRNA-fMet

OS

O

HN

O

mRNA30S ribosoe

OS

O

HN

O

3'mRNA

5'

30S initiator complex

AUG

50S ribosome

3'5'AUG

U A C U A C AU C

U A C

OS

O

HN

O

U A C

Anticodon

Codon

3'

5'

fMet

U A C

A U G C G A G C U

3'

5'

fMet

U A C

A U G C G A G C U

Arg

G C U

3'

5' A U G C G A G C U

A-site

Arg

G C U

fMetRibosomewithP-site and A-site

3'

5'

U A C

A U G C G A G C U

Arg

G C U

fMet

3'

5'

fMet

U A C

A U G C G A G C U

Arg

G C U

3'

5'

U A C

A U G C G A G C U

Arg

G C U

fMet

OS

O

HN

OfMet

OHN

O

NH2

Arg

NH

NH2OH O

O

NH

HN O

O

S

NH

NH2HN

Formyl groupProtection of N-terminal

DNA / RNA Synthesis: Protecting groups and activating groups (cf. peptide synth)

OO

O

B

P

OO

O

B

O

O

O

OO

HO

B

P

OHO

O

B

O

ON

NH3 / H2O[ox]

OO

O

B

P

OO

O

B

O

O

N

Phosphite Phosphate

acidcatalyst

OHO

O

BP

OO

O

B

O

O

NN

P

O

O N

Phosphoramidite

The Polymerase Chain Reaction (PCR, 1986)

technique for quickly "cloning”(make many copies of) a particular piece of DNA in the test tube (rather than in living cells like E. coli).

primers: short oligonucleotides (ca 20 nucleotides) precisely complementary to the sequence at the 3' end of each strand of the DNA

DNA

5'

5'3'

3'

95 oC(denaturation)

5'

5'3'

3'

Addition of primers

5'

5'3'

3'

Taq polymeraseMg2+

Nucleoside-triphosphates

5'

5'3'

3'

Repeat cycle

4 copies

Repeat cycle

16 copies

ca 1011 copies in a few hours

Tac DNA polymerase: Heat stable enzymefrom Thermus aquaticus (bacteria)in hot springs Yellowstone Nat. Park