Gábor Krajsovszky
Heterocyclic compounds
ISBN: 978-615-5722-01-1
© Gábor Krajsovszky
Responsible editor: Gábor Krajsovszky Publisher’s reader: István Mándity Translated by Péter Tétényi
Department of Organic Chemistry Pharmaceutical Faculty Semmelweis University Budapest, 2018 Acknowledgements
The editor wants to express many thanks to Dr. István Mándity, who is Associate Professor and Director of Department of Organic Chemistry, for the careful proofreading service of the current manuscript, as well as to Dr. Péter Tétényi, who is Assistant Professor, for the translation to English language.
Moreover, the editor renders many thanks to Mrs. Ferenc Juhász and Ms. Nikoletta Zlatzky laboratory assistants for drawing material of the figures.
Dr. Gábor Krajsovszky Associate Professor Department of Organic Chemistry Literature used
Alan R. Katritzky, Charles W. Rees: Comprehensive Heterocyclic Chemistry Parts 2-3, 4-6, 7 Pergamon Press 1984 Oxford • New York • Toronto • Sydney • Paris • Frankfurt
T. Eicher, S. Hauptmann, A. Speicher: The Chemistry of Heterocycles Structure, Reactions, Syntheses, and Applications Wiley-VCH GmbH 2003 Weinheim
E. Breitmaier, G. Jung: Organische Chemie Grundlagen, Stoffklassen, Reaktionen, Konzepte, Molekülstruktur Georg Thieme Verlag 1978, 2005 Stuttgart • New York Clauder Ottó: Szerves kémia II/2. Egyetemi jegyzet Semmelweis OTE Budapest, 1980
Bruckner Győző: Szerves kémia III−1. Tankönyvkiadó, Budapest, 1964
Természettudományi Lexikon − Harmadik kötet Clauder Ottó: 'Heterociklusos vegyületek' címszó, 155-161. Főszerkesztő: Erdey-Grúz Tibor Akadémiai Kiadó, Budapest, 1966
Szabó László: Szerves kémia előadások - heterociklusos vegyületek Semmelweis OTE Budapest, 1978-1996
Three-, four- and five-membered heterocycles with one heteroatom and their derivatives Three-membered heterocycles with one heteroatom and their derivatives Nomenclature
1 1 H O S N 1
3 2 3 2 3 2 Hantzsch-Widman name oxirane thiirane aziridine
Radicofunctional name ethylene oxide ethylene sulfide ethylene imine
Replacement name oxacyclopropane thiacyclopropane azacyclopropane
1 1 H O O N 1 diazomethane 2 2 2 3 O 3 NH 3 NH H2C N N dioxirane oxaziridine diaziridine structural isomers
H 1 1 1 N O S N N 3 2 2 3 2 3 N H H oxirene thiirene 1H-azirine 2H-azirine 3H-diazirine 2-azirine 1-azirine Preparation [2+1] intermolecular ring closure With contribution of atoms from olefin [2] and peracid [1] O R CO3H R CH CH2
R Br2 / CCl4 R: oxirane derivatives
Cl Cl2 / H2O perbenzoic acid m-chloroperbenzoic acid KOH HCl
Br OH
R CH CH2 R CH CH2 Br Cl +HCl halohydrin Ethylene oxide is used for gas sterilisation. It must be diluted with carbon dioxide, otherwise explosive mixture would be formed with air. Peracids are explosive, toxic compounds! Br OH
R CH CH2 R CH CH2 Br Cl halohydrin OH Cl H2S NH3 SOCl2 R CH CH2 R CH CH2
aminoalcohol NH2 haloamine NH2 SH KOH S R CH CH2 HBr KOH +HCl HCl Br +HBr R halothiol H thiirane derivative N
2 R
CH2 3 1 aziridine derivative N C N carbene Aziridines are carcinogen compounds. benzonitrile 2H-azirine derivative Only singlet carbene (not triplet) e.g., CH2N2 is suitable for the reaction. Epoxidation with peracid without catalyst
O C C O H H CH (CH ) 3 2 7 (CH2)7COOH H H CH3COOH C C enantiomers ° H H CH3(CH2)7 (CH2)7COOH 20 C, 3 h 1:1 one-step C C CH (CH ) (CH ) COOH oleic acid syn-addition 3 2 7 O 2 7
O C C O CH3(CH2)7 H H (CH2)7COOH CH3(CH2)7 H CH3COOH C C enantiomers H (CH ) COOH 20 °C, 3 h 2 7 CH3(CH2)7 H 1:1 one-step C C elaidinic acid syn-addition H (CH ) COOH O 2 7 Asymmetric oxidation of alkenes Sharpless epoxidation
Knowles, Noyori, Sharpless 2001 Nobel-prize, Chemistry, chiral catalysis
A) diastereo(enantio-)selective
EtOOC OH Ti[OCH(CH ) ] O H 3 2 4 O H + O HO (CH3)3C O OH H COOEt CH OH O H CH Cl 2 2 2 H O
CH2OH diethyl tartrate enantiomers H EtOOC H Ti[OCH(CH ) ] O OH 3 2 4 H allyl alcohol + O derivative H (CH3)3C O OH HO COOEt CH OH CH Cl 2 2 2 H O
B) O
HO H OEt OEt H HO S O OH (2S,3S)-(-)-Diethyltartrate 2 R R R O 1 R2 R i R (CH3)3C-O-O-H / Ti(O Pr)4 molecular sieve R Z 1 R OH R2 HO O S
O R R1 H HO OEt OEt 1 2 HO R < R < R H O (2R,3R)-(+)-Diethyltartrate O
HO H OEt OEt H HO S O OH (2S,3S)-(-)-Diethyltartrate 2 R R1 S O R2 R i R1 (CH3)3C-O-O-H / Ti(O Pr)4 molecular sieve R E R 2 OH R HO O R 1 O R R H HO OEt OEt 1 2 HO R < R < R H O (2R,3R)-(+)-Diethyltartrate Chemical properties 2,2'-iminodiethanol 2,2'-[(hydroxymethyl)imino]diethanol 2-[(2-hydroxyethyl)amino]ethan-1-ol 2-[bis(2-hydroxyethyl)amino]ethan-1-ol O O CH2CH2OH CH2CH2OH
HN N CH2CH2OH CH CH OH CH CH OH O δ 2 2 2 2 NH3 OH NH2 diethanolamine triethanolamine CH2 CH2 δ In ointment, lacquer KOH H N SOCl2 Cl NH2 KOH
CH2 CH2 aziridine Baeyer strain is greater for 3-membered rings than for 4-membered ones. As a consequence of this ring opening, reactions are easier for the former ones. Ring opening – it may occur with acid or with base Different regiochemistry:
with acid: SN1-like mechanism (alkyl cation of higher order is more stable) with base: SN2 mechanism (for sterical reasons, the nucleophile attacks the carbon of lower order)
H H H
O O O O H Y Y OH
R CH CH2 R R R R
Nu O Nu OH Nu H R CH CH2 R CH CH2 OH
CH2 CH3 LiAlH4 OH OR RO CH2 CH2
O OH HO CH2 CH2 OH RMgBr
MgBr
O R NH4Cl OH R
CH2 CH2 CH2 CH2 O 1 2 HO / H2O H2S HO CH2CH2 SH 2-sulfanylethanol RO / ROH 2 1 O S RO CH2CH2 SH SCN 2-alkoxyethanethiol HCl Cl CH CH SH thiirane R1 2 2 2-chloroethanethiol NH R1 R2 N CH2CH2 SH R2 2-dialkylaminoethanethiol Some important derivatives
O CH3 O (CH3CO)2O + N CH3 HOCH2CH2N(CH3)3 H3C COCH2CH2N(CH3)3
CH3 Cl Cl HCl choline chloride acetylcholine chloride
Acetylcholine: neurotransmitter of parasympathic nervous system (it can be found in the parasympathic part of the vegetative nervous system and in the central nervous system) b) pathway
Ar OH competing reaction O O OH Cl b) pathway HO Ar OH + Ar O CH2 CH CH2 a) pathway HCl CH2 Cl Ar O CH2 a) pathway (main pathway) epichlorohydrin RNH2 steric reason
OH NHR prototypes: RNH2 Ar O CH2 CH CH2 Ar R name β-adrenoceptor blocker
CH3 CH propranolol
CH3
CH3 CH pindolol N H CH3 Four-membered heterocycles with one heteroatom and their derivatives Nomenclature 1 2 O S HN
4 3 Hantzsch-Widman name oxetane thietane azetidine Radicofunctional name trimethylene oxide trimethylene sulfide trimethylene imine Replacement name oxacyclobutane thiacyclobutane azacyclobutane
1 2 1 2 1 2 1 2 O S N HN N
4 3 4 3 4 3 4 3 oxet(ene) thiet(ene) 1-azetine 2-azetine azet
1 2 1 2 S S HN NH
4 3 4 3 1,2-dithiet 1,2-dihydro-1,2-diazet Preparation
By intramolecular ring closure
O
OCCH3 Cl HS Cl O Cl H2S Cl KOH S HO AlCl3 HCl
H3C SO2NH2 Br Ts Br Ts NH2 N LiAlH4 HN ether Chemical properties
RMgX R CH2CH2CH2OH
LiAlH4 CH3CH2CH2OH
O HBr Br CH2CH2CH2 Br
RNH2 RNHCH2CH2CH2OH HO O O propano-3-lactone OH O 1 β-propiolactone H O 2 β α cyclic ester β α 3 2
EtO O O propano-3-lactam NH2 NH ether β-propiolactam EtOH cyclic amide β α β α (antibiotics)
O O S propano-3-thiolactone [2+2] S C β-propiothiolactone cycloaddition cyclic thioester C C H3C Ph H3C Ph Ph Ph Ph Ph
HY O O Nu O Nu Y YH Nu H Nu H Some important derivatives β-Lactam antibiotics • Penicillins • Cephalosporins Antibiotics: natural compounds produced either by microorganisms (e.g., fungi), or by a higher organism against other microorganisms (e.g., bacteria) to block the life and reproduction of the bacteria. Antibiotics are efficient in low concentration. β-lactame ring of penicillins is sensitive to acids, bases, or penicillinase enzyme. Nowadays penicillins with broad therapeutic range also exist (see microbiology). Cephalosporins (1948) makes the other main group of the β-lactame antibiotics. These are resistent to penicillinase enzyme. The bacterium produces penicillinase/cephalosporinase enzyme in order to be resistent against the given penicillin/cephalosporin derivative. Thus, newer and newer penicil- lin/cephalosporin derivatives must be synthesized. Their total synthesis is possible, but it would be too expensive, thus new derivatives are produced by semisynthetic me- thods. The fermentation processes are combined by chemical methods (beginning of biotechnology). Clavulanic acid: inhibitor of the β-lactamase with low antibiotic effect. Clavulanic acid is produced by Streptomyces clavurigeus (the same fungus also produces penicillin as well as cephamycin). Augmentin® contains amoxycillin and potassium clavulanate. β -Lactam antibiotics
Basic skeletons
azetidine + thiazolidine azetidine + [1,3]thiazidine
1 1 6 5 7 6 S 2 S 2
7 8 N 3 N 3 4 5 O O 4
penam cepham lactam lactam Penicillium notatum Cefalosporium acremonium
6-aminopenicillinic acid 7-aminocephalosporinic acid H H 1 H H 1 H2N 2 H2N 5 S CH3 6-APS 7-ACS 6 S 2 6 6-APA 7-ACA 7 CH3 7 penicillinase enzyme cephalosporinase enzyme 8 N OH N O CH3 4 3 5 3 O cleaves cleaves O 4 O O penicillins "-cillin" cephalosporins "ceph(a)-" O OH
O NH2 O H H H H CH2 C N CH C N 3 6 7 CH3
benzylpenicillin cephalexin G-penicillin
O O H H H H S N N O CH3 3 7 N 6 O CH O oxacillin 3 cephalotin O
N OH H O RNH COOH RNHX S Y CH3 Clavulanic acid
N CH3 N Z O COOH O Penicillins COOH Cephalosporins (X=H, Y=S)
NH Cephamycins (X=OCH3, Y=S) OH O β -Lactam skeleton H3C Y Z RNH N OH O O COOH N P O K H C Y O Penems (Y=S) 3 OCH NHR 3 Carbapenems (Y=CH2) N S 2-Azetidinon-1-phosphonate O COOH
Thienamycin (R=H) RNHX
N SO2O K O Monobactams Five-membered heterocycles with one heteroatom and their derivatives with condensed ring systems I/ Furan and its derivatives Nomenclature
CH O O O O O C furan α-furyl- β-furyl- α-furfurylidene- α-furoyl-
Preparation
1/ By Paal-Knorr synthesis from dioxo compounds
NH3 P2S5 R R R R R N ((NH4)2CO3) R OO S H
R NH2 P2O5 160 oC
R N R R O R R Its mechanism: E P2O5, H
H +E R R R R R R OO O O O O E E E
H
H H2O
E R R R O R O O H E 2/ From polyhydroxy oxocompound
HO OH 4 3 H H O O 5 Found in wheat germ, HO C 3H O 2 C H OH H 2 O corn germ 1 H
pentosane furfural (furfurol) furan-2-carboxaldehyde
3/ From mucoic acid
HO OH H H HCl HO OH HO OH OHHO O O O O O
4/ By decarboxylation from dehydromucoic acid
OH O - CO2 O O 5/ By ring synthesis from β-oxoester and from α-chloroketone
Cl ROOC H NaOEt - EtOH - NaCl O O
ROOC ROOC
O O O Feist-Benary
aldol
1 EtOOC H R EtOOC R1 + O
2 2 R O SNi Cl R O
O-alkylation This can be the side reaction of Hantzsch reaction
EtOOC H Cl EtOOC + 2 1 R2 O R1 R O O R C-alkylation EtOOC H EtOOC EtOOC 3 R -NH2
2 2 R2 O R N R NH 3 R R3 Hantzsch
EtOOC Cl EtOOC + 2 1 R2 N R1 R NH O R C-alkylation 3 R3 R
1 EtOOC R EtOOC R1 O + 2 R2 NH Cl R N R3 N-alkylation R3 Physical properties
The parent compounds (furan, pyrrole, thiophene) are poorly soluble in water, but imidazole and pyrazole are water-soluble due to hydrogene bridges
Their UV spectra are rather different from benzene IR spectra: there are group vibrations pyrrole has ν NH band at 3400-3300 cm-1 (sharp and strong band)
1H NMR spectra: the signal of α H appears at lower δ value (more shielded), compared to the signal of β H (each within the usual aromatic range) There are usual couplings typical for aromatic compounds. Chemical properties
O O O O O O
1/ SEAr reactions E attacks the α position ground state
E H H H α O O E O E O E E β E E H H
O O
α > β σ−complex is more stable, since more mesomeric structures can be written for it. Friedel-Crafts alkylation
R Cl previous explanation: furan is a superaromatic AlCl or ZnCl 3 2 R compound, since the aromatic reactions take O O place much easier, than of benzene
current explanation: furan is much less aromatic, than benzene, since its reaction is energetically much easier, than of benzene R Cl AlCl3 O R O Nitration
cc. HNO3 is destroying the ring
O O acetic anhydride CH C O NO anhydride HNO anhydrous 3 2 3 acetyl nitrate
O NO2 O2N O NO2 2/ Addition reactions
1,4-addition
Br Br 2 CH3OH CH3O OCH3 Br2 CH3OH O H O H H O H
CH3O > Br 1,4-addition -HBr C atoms with acetal characters
1. H2 Ni 2. H O H 3 O Br
O O Diels-Alder reaction
O H H O
O O O O maleic anhydride H O O H 3/ Other reactions
Cannizzaro reaction
1. cc. KOH + 2 H OH 2. H3O O O CH2OH O O O furfural furfurylalcohol furan-2-carboxylic acid (furfurol)
Acyloin condensation
KCN H KOH CH C O O O O OH O furoin (similar to benzoin)
C C O O O O furyl (similar to benzyl) Polymerisation
n H
O O O O n
1,4-addition addition polymerisation O O
Reduction
H Ni 2 butan-1,4-diol 150 oC 100 atm O (for preparation of diolefins by Reppe synthesis) O THF tetrahydrofuran More important derivatives H H O, 400 oC H /Ni 2 2 cat. 80 atm H - H2, - CO2 O CH2OH O O O o Al2O3 350 C furfurol, the cheapest - H O aromatic aldehyde H2 /cat. 2
4 3 5 ROH/H 6 2 H O O O 3 O OR 1 - ROH butadiene polymer, BUNA or copolymer
O OH OH OH O O O OR H H
- H2O
cc. HCl
O Cl Cl O OR cc. HCl 2 KCN HCN Cl Cl N C C N O O O N 1,4-dichlorobutane red. NaCN 1 H3O . c H2/cat. c. 2. H . N C a l O CN O C N N C HO NH2 pimelic acid dinitrile OH HN H H2/cat O H3O adipic acid butan-1,6-diamine 6 C 6 C HO OH hexamethylene diamine C C O O NH2 NH2 O
HO NH2 pimelic acid butan-1,7-diamine N 7C 7C H 6C 6C O polymerisation
HO OH Nylon 66 HN NH2
O O H - H2O
H HO N NH2 polimerisation O O 7C 7C Nylon77 ε-caprolactam + ε-aminocaproic acid 2 2CO 2NaCN Na 2 2 O H2 O O O O -H2O O N γ ε-amino- H2O ε α NH 2 OH caproic acid H2N OH O H2N δ β N 6C 6C H O O Nylon 6 ε-caprolactam Nylon 6
OH
H +CH2O CH2 N(CH3)3 CH3 H OH O polymer plastics O H H O
OH OH HO OH OH (+)-2S,3R,5S H2 HO (H H C CH CH2OH Muscarin ) alkaloid of O -H2O O Amanita muscaria C H H
−δO OH polymerisation chances H R C H OH +δ R CH OH II/ Furan derivatives with condensed rings
Nomenclature
4 4 3 5 3 5 6 2 O 6 2 O 7 O 1 1 benzo[b]furan benzo[c]furan dibenzofuran coumarone isocoumarone diphenylene oxide (derivatives of it are known only) Preparations
H H OH C O Perkin O H C C CH Br 2 synthesis CH H 2 + O H C C NaOAc C O O OH 3 OH OH O O O O HO coumarin C O H3C Br
Br +KOH Br H -KBr OH O O O O -H2O OO O HH O 3,4-dibromocoumarin coumarilic acid coumarone
HO ZnCl2 Cl - HCl -H2O OH O OO O HH coumarone dibenzofuran R CH R' CH2 R 2 C + O C N O NH2 R' O
O-phenylhydroxylamine O-phenyloxime
R R CH R' C R' C C NH O OH NH2
R according to Fischer’s indol synthesis O R'
CH2 R R + O C NH2 ' N R N R' H H III/ Thiophene and its derivatives
Nomenclature
β' β O α' α S S S S CH2 S CH S C
thiophene α−thienyl- β−thienyl- thenyl- 2-thenal 2-thenoil-
2 - t h i e n y l 3 - t h i e n y l α-thenal α-thenoil-
Preparations 1/ By Paal-Knorr synthesis from dioxo compounds
NH3 P2S5 R R R R R N ((NH4)2CO3) R OO S H
R NH2 P2O5 160 °C
R N R R O R R 2/ From acetylene
CH CH
HC CH S S
3/ By dehydrogenation, then by ring closure
4S + 3 H2S 650 oC S
-2 H2S 2S 2S -H2S
4/ According to Hinsberg
R R R R CH ONa C C 3 20 oC O O ROOC S COOR
CH2 CH2 ROOC S COOR 5/ From dialkyl acetylenedicarboxylate
COOR COOR ROOC COOR C C S o C C 150 C ROOC S COOR ROOC COOR
Chemical properties
1/ By halogenation
SO2Cl2 SO2Cl2 sulfuryl chloride Cl Cl Cl S S S
2/ By chloromethylation
CH2OH, HCl
CH2Cl S S ClCH2 S CH2Cl 3/ By Mannich reaction
CH2O CH2O NH Cl 4 CH NH HCl CH S S 2 2 S 2 HN Cl CH2 4/ By Vilsmeier formylation
N CH3 C H O H POCl3 S S O 5/ By Friedel-Crafts acylation O Wolff-Kishner CH3C Cl red.
AlCl3 CH3 S S C S CH2CH3 O 6/ Transformation to mercury derivatives
HgCl2 ClHg S HgCl HgCl2 CO2 S S HgCl NaSCN O OH R C S Cl O NaI Br2
S SCN R S O Mg S I S Br S MgBr 7/ By Diels-Alder (addition) reaction
F F S F F
F S F F F
8/ By polymerisation
S S S n
9/ By hydrogenation
Raney Ni H2 CH C OH R CH2 S C OH EtOH R CH2 S C OH 2 O O R O + H2S 10/ By indophenin reaction
O O
S S N O O N H H
isatin HCl
S S compound with blue colour N O O N H H indophenin IV/ Thiophene derivatives with condensed ring system
Nomenclature
4 4 5 3 5 3
6 2 6 S 2 S S 7 1 7 1 thionaphthene iso-benzothiophene dibenzothiophene benzo[b]thiophene benzo[c]thiophene isonaphthene Preparations
O O III K3 Fe (CN)6 OH H2O / OH OH O H - H C - H - CO2 SH S S O S oxid. mercaptocinnamic acid
white-hot iron S S O O S III S K3 Fe (CN)6
S oxidation S O thioindoxil O trans thioindigo
red precipitation
O O
S S
cis thioindigo Chemical properties
NO2 NO2 NO2 NO2
HNO3 KNO3 / H2SO4 + o 25 C S S S S O2N main product side product
the aromatic system H H is saved Y Y preferred C 3 S S
Y S C 2 H H
S Y S Y the aromatic system is decomposed disadvantageous
H H H
S Y S Y S Y V/ Pyrrole and its derivatives
Nomenclature
N N N N H H H H O pyrrole α-pyrryl- β-pyrryl- α-pyrroyl-
Preparations
1/ By Paal-Knorr synthesis from dioxo compounds
NH3 P2S5 R R R R R N ((NH4)2CO3) R OO S H
R NH2 P2O5 160°C
R N R R O R R 2/ By Hantzsch synthesis
CH2 Cl ROOC ROOC ROOC C O R CH2 R NH2 CH2 CH2 C R = alkyl, C C H3C O aralkyl H3C N H3C NH R R
ROOC ROOC CH CH2 C C R H3C R Cl H3C NH O N R R 3/ By Knorr synthesis
H3C C5H11ONO H3C C O (isopentyl nitrite) C O Zn / CH3COOH or CH2 C ROOC NaNO2 CH3COOH ROOC N OH R = Et
- H2O H3C COOR H3C COOR H3C COOR C O H2C CH C ROOC CH3 ROOC CH3 ROOC NH O CH N N 2 3 H
- H2O EtOOC H EtOOC EtOOC 3 R -NH2
2 2 R2 O R N R NH 3 R R3 Hantzsch
EtOOC Cl EtOOC + 2 1 R2 N R1 R NH O R C-alkylation 3 R3 R
1 EtOOC R EtOOC R1 O + 2 R2 NH Cl R N R3 N-alkylation R3 4/ By pyrolysis of ammonium mucoate
HO OH
NH3 HO OH HO OH O O N - 2 CO2 N O H H O O H O H main product
NH2 N H O side product
5/ From dehydromucoic acid through furan
NH3 450 °C OH O - CO2 O Al2O3 N O H 6/ According to Reppe, from butyn-1,4-diol
NH3, HO CH2 C C CH2 OH Al2O3 - ThO N H H2CO CH2O
H C C H
according to Reppe NH3 O Al2O3 N H THF Chemical properties
1/ Acid-base properties
a/ pyrrole, as base Absorption of a proton is an addition process (not SEAr) Protonation takes place at the C-2, not at the N Protonation ceases the aromatic system, resulting in H a conjugated diene with much higher reactivity. For this reason, pyrrole is sensitive to acids H N N H H pKa = - 0.3
b/ pyrrole, as acid Pyrrole is a weak acid – and an amphotheric compound Furan, pyrrole, thiophene are stable against bases
H N N H
pKa ~ 15 (pKa water = 15.6) 2/ Tautomerism
Tautomerism of hydroxy- and amino-derivatives
The hydroxy compounds exist mostly in oxo forms, the amino compounds in amino forms (→ can be diazotised)
tautomers tautomers
α α OH N OH N NH2 N NH N N O H H H H H lactam amino form imino form cyclic amide (stable) mesomers NH NH2 β
N O N N H H H
OH tautomers O tautomers OH β
N N N H H vinylogous lactam mesomers O
N H 3/ SEAr reactions Take place in two steps, with much greater reaction rate, compared to of benzene
E H H H α E N N E N E N H H H H E β E E H H
N N H H
α > β σ−complex is more stable, since more mesomeric structures can be written for it.
If attack happen to β position E = H protonation reaction takes place. Otherwise the electrophilic reagent attacks the β po sition, if the α position is occupied.
Protonation
H protomers H addition N N N H H H H By bromination
Br - Br H H - HBr 1,4-addition elimination N Br N Br Br N H H
By chlorination
Cl Cl
Cl2 SO2Cl2 sulfonyl Cl N Cl N chloride N Cl H H H
By nitration, sulfonation
O equimolar HNO O 3 N S O (CH CO) O N S N 3 2 N NO2 H OH O H explosive mixture H O the reaction runs at low (20 oC) temperature O
O N SO3 HO N O CH3 C O N HO C CH3 O O O acetyl nitrate By Friedel-Crafts acylation
pyrrole > benzene (SnCl4 < AlCl3 both are (CH3CO)2O electrophilic catalyst, but the latter is much CH SnCl4 3 more powerful, therefore the latter is not N N H H used for the acylation of pyrrole, since the O reaction would be too vigorous
By Reimer-Thiemann reaction
CHCl hydrolysis 3 Cl O(H cc. base N N CH N CH H H Cl H (OH Cl Cl CH δ δCl
H pyrrole > benzene (reacts more easily) -H2O N H O
KOH At first, N-potassium salt is formed due to cc. KOH N N H K Formation of dipyrrylmethane
H C O H N H H N N CH2 OH -H O H H 2
analogous process to the formation of phenol resins
O' from the air ' -H N CH N N CH N H H H H H dipyrrylmethane mesomers
conjugate acid (many mesomeric N C N of dipyrrylmethene structures can be written) H H
there are 4 pyrrole rings in the synthetic intermediates -H N C N of compounds with porphin H H ring system dipyrrylmethene By Fischer-Orth reaction
O CH3 C N CH3 HCI N H CH3 N CH N H H CH Ehrlich reagent 3 (dimethylaminobenzaldehyde) mesomers
CH3 N CH N CH3 red colour
By Fischer-Bartholomäus reaction
N N Cl N N Cl
N N N N H H
4 3 5 N N 2 N N N1 H 2,5-bis(phenylazo)pyrrole 4/ Transformation to heteroalkene-, or heteroalkane derivatives
By reduction reactions
4 3 Zn / H Pt / H2 5 2 N 1 HCl N N H H H 3 - pyrroline tetrahydropyrrole 3 - pyrroline Ph-Al2O3 (pyrrolidine) H2 Zn: electrondonor water: protondonor 4 3 4 3 5 2 5 2 N 1 N 1 H H 2 - pyrroline 1 - pyrroline 2 - pyrroline 1 - pyrroline
LiAlH4 or O O N Na metallic / pentan-1-ol N H H By oxidation reaction
CrO3
N glacial O N O H acetic acid H maleic acid imide
By Diels-Alder reaction
F F F F F F + NH N H F F F F F F
there is no reaction with pyrrole, but there is formation of adduct with hexafluoro-Dewar-benzene
By polymerisation
H N N N N H H H H 5/ Amphotheric properties of pyrrole
Metal derivatives and their transformations thermodynamic kinetic control KOH control RI R N N N rearrangement N H H K R CO2 Kolbe synthesis O HCl R C Cl OH OK R N N N rearrangement N H H H O O O C O R
CH3MgI R I R N - CH4 N - MgI2 N N H H O MgI R
H5C2O C Cl ethyl chloroformate
O O R C Cl R N C OC2H5 N N H H C O O R Pyrrole does not react by nucleophilic substitution reactions H The H at α-metil group is not active (the C-H bond is stable due to π electron excess) N C H H H
electron rich C-atom CH CH N 2 N 2 H H H More important derivatives
a/ monocyclic pyrrole derivatives
X O X = H proline C = OH hydroxyproline OH N N O N CH3 H H H pyrrolidine pyrrolidone
HO OH 200 °C
OH cc. NH HC CH HO 3 O O N O O H butyric acid butyrolactone
N O N O
HC CH2 CH CH2 N H + H C C H N CH CH2 n vinylpyrrolidone polyvinyl-pyrrolidone MW 5 - 10 thousand X-H addition to acetylene b/ compounds with porphin skeletone Porphin
N N N N H tautomers H H
H 4 tautomers N N are possible N N
- bonds in aromatic system 4 n + 2 n = 4 - alkene bonds (double bonds) 18 π electrons The Fe, Mg, Co salts of porphin can be found in nature. Very stable, what is necessary for it purposes. Mp: 300 °C, red crystals
N N N N H mesomers H H there are 12 H N N mesomers N N totally
The tautomer forms can be also described by mesomers. Each tautomer may have many mesomers. Vitamin B12 (cyanocobalamin) Preparation of it was carried out from liver, from mud of canals, or by fermentation (Streptomyces griseus) Structure determination was executed by X-ray analysis (Dorothy-Crowfort Hodgkin) Synthesis of it was carried out by Robert Burns Woodward (Harvard University) and Albert Eschenmoser (ETH Zürich)
Vitamin B12 has been isolated from mud of canals by Richter Pharmaceutical Works (Budapest, Hungary) since Years 1950s. Woodward synthesized chlorophyll by total synthesis in 1965, while Woodward and Eschenmoser in cooperation prepared Vitamin B12 in 1972-73. Vitamin B12 has important role in biological methylation. It is the antidote of Anemia perniciosa (pernicious anemia). Its appearence is in deep red needles. Liver extracts were useful in this disease. It was the first macromolecule, which structure was elucidated by X-ray analysis. There is delocalisation in Vitamin B12, but it is neither a cyclic delocalised system, nor aromatic system. The current Vitamin B12 extract is of not synthetic origin. The question is the following: how did these compounds appear in nature and why not other compounds were prepared by biosynthesis. There are building blocks for living organisms – hem, or chlorophyll were prepared at rather low stage of evolution. Usually the most symmetric structure is set – the rest is prepared, but disorderness has always greater probability → enthropy is increasing by having the least symmetry elements. It is selected by molecular evolution and does the job perfectly. The role of cobalt in
Vitamin B12: it depends on ring size. Woodward’s report on it is a complete chemical thriller. VI/ Pyrrole derivatives with condensed ring systems
Nomenclature H
N N N CH3 H 1H-indole 3H-indole N-methylisoindole benzo[b]pyrrole benzo[b]pyrrole (isoindole does not exist) (indolenine) benzo[c]pyrrole
O O
N N O N N O H H H H indoline oxindole indoxil isatin
HO OH
NH2 NH2 O N N N H H H tryptamine serotonine 3-indolylacetic acid heteroauxin takes place in the 5-hydroxytryptamine plant growing biosynthesis of indolealkaloids important for brain work hormone Preparations
1/ Preparation of indole
H3C COOH H3C COOH COOH ZnCl 250oC + O 2 N -CO NH NH2 N N 2 H N H H
CH3 KOC(CH3)3 O -H2O NH CH N H
2/ Preparation of indole derivatives a/ Fischer’s indole synthesis
2 2 R2 R R CH2 ZnCl2 or + CH2 C polyphosphoric acid NH2 C 1 1 N 1 N N R N R O R -H2O, -NH3 H H H
CH CH CH3 3 3 ZnCl2 + o - H2O 180 C NH NH2 O NH N NH - NH3 3-methylindole Mechanism of the Fischer’s indole synthesis O HC CH N OH CH N OH CCl3 C Cl C OH NH2 H2N OH N N H Cl H OH
N O N OH cc. H SO 2 4 C H2O O -NH3 N O N O N H H isatin H Zn/HCl
OH red. oxidation Na/Hg O O O H red. N N N H H oxindole N H O indigo b/ Heumann’s indigo synthesis H HO O HO C NaNH2 + Cl CH2 COOH -HCl CH2 -H2O NH2 N H
O H ONa N O2 Fe3+ N N cis H H O Na2S2O4/NaOH O deep blue, insoluble in water reduction 2 trans indigo oxidation it is reduced at first, Na then is oxidised O H Indigofera tinctoria N colourless, water soluble N leucoindigo it is adsorbed and H O keeps its colour Na O O O NaOBr NaOH ONa OH NH HCl CO2 NH2 NH2 O O anthranilic acid
O O O OH ClCH2COOH OH KOH CH2 melting NH2 NH COOH N COOH H
-CO2 O H N O oxidation N H O N H indigo O O
OH HO OH O + Cl CH2 COOH -HCl CH2 C OH NH2 N H
O O KOH O2 melting OH -CO Fe3+ N 2 N H H O indoxil indoxil-2-carboxylic acid
O H O N oxidation
N N O H H O isatin indigo Chemical properties
1/ SEAr reactions
E halogenation goes to nitration β position mainly sulfonation N H alkylation acylation
2/ Other reactions
O
CHCl3 H KOH N N H H
N N Cl N N
N H CH3 CH2N(CH3)3 (CH3)2NH CH2N CH3I I CH3 N HCH H N gramine N O H H
COOR KCN
H C NHCOCH3 CH2CH2NH2 CH2CN COOR red. KOH N tryptamine N -NH(CH3)2 H H indole alkaloids COOR CH2 C NHCOCH3 hydrolysis, COOR decarboxylation
N H
H2/cat. H2/CuCrO4
N N N H H H octahydroindole indoline O
OR CH3MgI ClCH2COOR -CH N 4 N N H H Na MgI K 1 N NH2 1 - /2 H2 - /2 H2 H N N CO2 H Na O OH N K R X
N H N R R
R: alkyl, acyl N H Benzocondensed systems with five-membered heterocycle
SEAr
4 X: NH 1H-indole β (α) 5 3 (β) O coumarone α 6 2 (α) X S thiocoumarone β (α) 7 1
β alkylation (β) E E acylation (β) α NH alkylation N rearrangement NH sulfonation (α) acylation E sulfonation
E : R O R C
SO2OH H
O E coumarone advantageous
E E H H
E O O disadvantageous
E N N N H H H aromatic 1H-indole and nonaromatic advantageous thiocoumarone disadvantageous E
E S S S Five-membered heterocycles with two or more heteroatoms and their deri- vatives with condensed ring systems Compounds with two heteroatoms Nomenclature
4 3 4 N 3 4 3 4 N 3 4 3 4 N 3 5 N 2 5 2 5 N 2 5 2 5 N 2 5 2 O O S S N N 1 1 1 1 H 1 H 1 isoxazole oxazole isothiazole thiazole pyrazole imidazole 1,2-oxazole 1,3-oxazole 1,2-thiazole 1,3-thiazole 1,2-diazole 1,3-diazole
Introduction of another nitrogen → the pyrrole-like properties are shifted to the pyridine-like properties, e.g., at basicity, water solubility. I/ Isoxazole and its derivatives
Preparations
1/ By 1,3-dipolar cycloaddition (Huisgen)
H5C6 C H H C C H 6 5 5 6 6 5 It takes place by 4n+2 electrons, n=1 C C suprafacial reaction, 1,3-dipolar C N N cycloaddition, in one step through a H5C6 O H5C6 O cyclic transition state nitrile oxide
1,3 - dipolar one of the components (nitrile oxide) is dipolar
C6H5 C6H5 C mesomers C 1 the charged atoms (C, O) N N O O are in 1,3 positions 3 By 1,3-dipolar cycloaddition
1 1 R 1 R a R a a a b b 2 b + + + + 2 b R c 2 c R c - R - c E-olefin dipól dipól (dipolarofíl)
1 1 R 1 R a R a a a b b 2 b + + + + 2 b R c 2 c R c - R - c dipól Z-olefin dipól (dipolarofíl)
1 1 1 R R R a a a a b 2 b + + + b+ 2 R R b c c c - 2 - c R
+ a a+ a b c a b c a a C N N N N C b b b b + C N N N N N + c c C N O N N O c c - - - - R. Huisgen, Angew. Chem. 75 (1963) 604-637. 742-754. A. Padwa, 1,3-Dipolar Cycloaddition Chemistry. Vol. 1-2. John Wiley and Sons 1984. 2/ By other ring syntheses
H CH3 R R R
H2N OH H3C N N N O O - H2O O Cl - H2O Cl OH HO R = H
CH3 H2C C C N R = CH H3C 3 O HO Chemical properties
1/ It is sensitive to bases, resulting in ring opening It is relatively stable against acids H R = CH3 H2N NH2 OH N N N R R R N base O base OH OH H R = H E - H2O
E
2/ SEAr reactions N N R R O O R = H
+ + + E: Br , NO2 , HSO3 3/ Basic strength in aqueous solution
pKa values for the conjugated acids of the bases
N N N NH N S N O H H
pKa values 7.0 2.5 2.5 1.3
basicity Imidazole >> Thiazole > Pyrazole > Isoxazole More important derivatives
H2N O H Oxamycin antibiotic N O NH Oxacillin semisynthetic O O N penicillin O
benzisoxazole anthranil H5C6 C NH benzo[d]isoxazole benzo[c]isoxazole 6-amino- O CH3 penicillanic - H2O - H2O acid fragment
N O OH OH OH NH
Sn / glacial acetic H2N OH acid, red. Penicillin: was prepared from Penicillium notatum fungus (Fleming, 1929) at first by O O fermentation method. It was the first antibiotic compound: 6-amino-penicillanic acid. Some OH NO2 microorganisms are preparing it by cleavage of the acyl group. This is useful for preparation of salicylaldehyde other semisynthetic derivatives II/ Oxazole and its derivatives Preparations 1/ From 1,2-bifunctional compounds
H5C6 H5C6 2. 2.C O H2N C N 3. H2C 1. C 3. H CH C O CH - H2O 1. Br 3 Br O CH3
C atoms with 1., 2., 3. oxidation levels H5C6 3. N 3. O CH3
H3C H3C 1. 1. HC NH Cl HC NH 2 1. PCl5 2.C C 3. 2.C C 3. O - HCl H C R 2. NaOH H5C6 O R 5 6 O O
H3C H3C N N 3. 3. H5C6 R - H2O H C R O O 5 6 O H H 1. 1. H2C NH2 Cl HC NH 4 3 1. N HC C 3. CH C - HCl 1. 3. H3C OH O R H3C OH O R H3C 5 2 R O1
H 2-oxazoline derivative . C 2 O R 1. CH NH 1. NH 1. 2 HC 1. 2. CH H3C OH O R HO R H3C oxazolidine derivative
More generally:
1 H 1 R 1 R R = CH NH2 Cl N 3 C6H5 C 3 2 3 2 O O R O R R R
2 R = -H,-CH3,-C6H5 3 R = -CH3,-C6H5 a. a. Cl H N it is difficult to alkylate the amide nitrogen N 2 b. Cl HN C O a. O O OH HO
reactions run similarly at both pairs b. b. NH2 Cl NH2 Cl C O O OH O
it is easy to acylate the primary amine nitrogen
Differences in saturation of the products can be reached by selection of the proper oxidation level of NH2 Cl N the starting materials. R OH O R O
N 6 π-electrons NH2 O NH the nonbonding electron pair of O takes part in the formation of an aromatic sextet R O OH H R O
1 due to C-N bond 1,5 due to the 1/2 alkene N N 3. N 1/2 C=N O C-O O O 1,5 3. 3. 1 due to C-O bond R R
NH2 Cl N -HCl Ph R' Ph R' O S -H2O S
R': Alkyl, NH2
R R R
NH2 Cl N NH3 N
-HCl Ph Ph O O Ph -H O Ph O Ph N Ph 2 H
NH4OCOCH3
CH3COOH
Ph Ph O H2N N -HCl Ph Cl X Ph Ph X Ph -H2O X: O, S, NH Chemical properties
1/ SEAr reactions
4 N E
5 One of the most stable derivatives of 2-oxazoline is 2-methyloxazoline. This O 2 compound has an interesting feature, since mechanism of acyl migration (Bruckner, at ephedrine or alkaloids with tropane skeletone), as well as the ring opening due to bases or acids can be easily demonstrated.
2/ Sensitivity against bases and acids
N N NH CH NH HO CH3 HOH CH3 2 HO CH2 C CH3 O CH3 O OH O OH OH O
NH H NH HOH 2 CH2 NH3 N CH3 CH H 2 COCH CH O OH 3 O CH3 O 3 O More important derivatives
O O OR H2N EtONa NH C + NH3 + ROH H2N O OH O O
2,4-oxazolidindione
NH2 Cl EtONa NH C + HCl + H2O O O OH Cl O O O
2,5-oxazolidindione
O C H C C N H3C ROH/H H3C HCN 3 H3O C OH C C H C OH H3C OH H3C O 3 aceton-cyanhidrine
O CH O O 3 H2N N C OR NH ( CH3O )2SO2 H3C H3C H3C C ) H2N O O H3C O O H3C OH H3C O Ptimal
Drug of the ‚petit mal’ form of epilepsy NH2 NH H N formylation C hv O OH OH O
NH CH3 N C (CH3CO)2O CH3 O OH O
blocks maturation of rye mould III/ Isothiazole and its derivatives
O O O2N H H cc. H2SO4 Na2S2 2 o 2 cc. HNO3 160 C EtOH Cl Cl
O O O
O2N O2N HH Br2/CCl4 H 100 oC S S S Br
O2N H2N cc. NH4OH N FeSO4 N ox. benzene S alcohol S red.
O O
1. CH3N2 H2N HO HO N N 2. H2NNH2 N HO -CO2 3. Curtius S S degrad. S O
1. NaNO2 /HCl N 2. H3PO2 S 3. base isothiazole SH SnCl2 S cc. HCl NO2 N thioanthranil
O rotation NH CONH2 C NH3 C CO NH O = NH3 NH2 S SH SH
CONH2 COOH
H O o 2 2 N 1. OH N 175 C N ox. 2. H O -CO2 S 3 S S benzisothiazole IV/ Thiazole and its derivatives
1/ Hantzsch synthesis N 6 π electrons (similar to oxazole) 1 S R 1 HN R OH 3. N 2 HS R 2 Br S 3. R 2/ Gabriel’s preparation
R1 2. H2N 3. O NH 3. N 2 P S . 1. S R 2 5 3 2 2 Br R1 OO R R1 S R
( oxazole is formed without P2S5) R R 2. . N O H2N . 3 4. 4 . 1. 1 S NH2 NH2 (Preparation of partially or fully S NH2 saturated compounds: see at the Br 2. Cl . 3 more important derivatives) R1 O 2 1 O R 1 R 2. R O NH2 P2S5 N 3. 3. 1. 3. O R2 2 Cl S R
( oxazole is formed without P2S5) R R
NH2 Cl N -HCl Ph R' Ph R' O S -H2O S
R': Alkyl, NH2
R R R
NH2 Cl N NH3 N
-HCl Ph Ph O O Ph -H O Ph O Ph N Ph 2 H
NH4OCOCH3
CH3COOH
Ph Ph O H2N N -HCl Ph Cl X Ph Ph X Ph -H2O X: O, S, NH Chemical properties N N E
S E S 1/ SEAr reactions
N N E E S XH S XH
X=O, NH 2/ SNAr reactions
H3C H3C N N NaNH2 pyridine-like property
S S NH2
N N N N melting NH NH S S H2N S S NH2
N N NaNO2/HCl 0-5 oC S S N N Cl reduction Y = halogene, hydroxy, etc. (see reactions of (aromatic) diazonium compounds) N
S Y 3/ By oxidation
N N ox. HO H3C S S O thiazole ring is resistant to oxidation
More important derivatives
1 1 R 1. R 1. 3 NH2 4 N 3. -NH3 1. HN C 5 3. 3 -ROH 2 R 2 1. 2 3 R SH RO R S R 1 2-thiazoline derivative
4 . 3 1 1. NH2 NH 2. 2. 1. O 5 2 C 1. SH H S H 1 thiazolidine NH2 N O 3. . C 3 HO H S Cl benzo[d]thiazole benzo[d][1,3]thiazole
CH3 O C NH CH3 NH C CH2 N SH Cl O S O S SO2 NH
1. Ultraseptyl 2. NaOH NH C CH3 chemotherapeutic agent O NH2 with antibacterial effect H O R = H 6-aminopenicillanic acid (6-APA) HOOC N O H3C α β H3C S NH R R = C6H5 CH2 C H H benzylpenicillin penam skeletone Penicillin G
(condensed ring system of thiazolidine and R = azetidine monocycles) O C C6H5
N H3C O Oxacillin (see at isothiazoles) Β lactam ring is unstable group, sensitive to acids, to bases, as well as to penicillinase enzyme. They are inhibitors of synthesis of cell walls. If a microorganism produces penicillinase, then it will be resistant to the given penicillin derivative other derivative must be prepared. Previously, penicillin derivatives were prepared from ferment solution, adding phenylacetic acid to it, generating benzylpenicillin. Benzylpenicillin + enzyme 6-APA +R-COCl many thousands penicillin derivatives. Source: Penicillium notatum, P. crysogenum bacteria. Antibiotics are more uniform compounds, than vitamins. Antibiotics are natural compounds, produced by some microorganisms against other microorganisms, blocking the latter. Fleming observed extinction spots, thus he had hard earned the Nobel Prize. Currently penicillin derivatives are prepared by semisynthesis methods: 6-APA is made to be produced by bacteria. This was one of the first trials of biotechnology. V/ Pyrazole and its derivatives
Preparations
1/ By 1,3-dipolar cycloaddition (Huisgen)
R R 2. 2. 2. R O N 2. O R NH2 N H R = H, alkyl H2N R H 2. R R C C 2. CH 2. C 2 C 2. N N N R R C N N N H R
2/ By isosteric replacement from isoxazole
NH3 N N O pressure N H Chemical properties
1/ Acid-base properties
Introduction of a nitrogene shifts the pyrrole-like properties to the N HO R N pyridine-like properties. H
makes a H-bridge weak base pKa = 2.5 (pyrrole< pyrazole< imidazole< pyridine)
very weak acid pKa = 14 (it is amphotheric compound)
2/ Tautomerism virtual tautomerism N NH (equivalent tautomerism) N N the two tautomers can not be distinguished from each other H H real tautomerism - if a R group (alkyl group) is attached N N to the ring, the tautomer is fixed. The indicated H is migrating R N R N - it can be marked by isotope or substituent H E 3/ SEAr reactions E
N N N N N E N E N N H H H H E advantageous not advantageous not advantageous
4 3 substitution on the C-4: 5 2 N bromination, nitration, sulfonation N 1 H
O2N H2N
HO-NO2 H2 OH N N N N N N H H H OH
NaNO2 / HCl 0-5 oC Cl N N N N coupling N N reaction H
N N H More important derivatives
O NH N acrolein 2 N H2N H 2-pyrazoline
Br NH NH Br 2 N H2N H pyrazolidine
CH3 benzene O o N N 20 C -benzoic acid N N N - H2O H C C O C H indazole 6 5 O C6H5
N-benzoyl-N-nitrozotoluidine CH3 CH3 NH O N N H HO N N O N CH3 pyrazol-3-one
(CH3O)2SO2 tautomerism antipyrin CH3 CH3 H CH3 fever- and pain-killer compound NaOEt - H O CH C O 2 NH O OEt C N tautomerism O O N N NH2 - EtOH NH
norantipyrin O O OH tautomerism NaOEt OEt NH N O O HO OEt NH2 N N H H H2N
O O O tautomerism NaOEt OEt N N O HO O OEt N N
NH NH H9C4 O H9C4 O NaOEt NH OEt N NH O N O OEt
Phenylbutazone inflammatory drug
E (NO, Br )
O N CH3 CH3 H2N CH3 HO-N=O H2 N N N O O O N CH3 N CH3 N CH3
H C O H O H C Br 2 OH H3C N CH3 (CH3)2NH H3C Leukart-Wallach's reductive methylation N O N CH3
Amidazophene CH3
H2N CH3 CH N CH3 CH N CH3 CHO N N CH X N O N CH3 O N CH3 3 O N CH3
CH3 CH3
HN CH3 N CH3 O3S CH2 HCHO N HSO3 N O N CH3 O N CH3 SO OH H3O 2 CH2OH
Methamisole VI/ Imidazole and its derivatives Preparations
1/ From 1,2-bifunctional compounds
C6H5 H5C6 - H2O N C6H5 2. C N 3. 3. C O H2N H CH C 1.CH2 3. C N C6H5 N C6H5 Br HN C6H5 - HBr
C6H5 1. C6H5 CH NH2 Cl CH NH 2. 3. C C C C C6H5 O O R C6H5 O O R
O C6H5 CH3C O NH N 4 3. 3. C6H5 N R H R R
NH2 Cl N -HCl Ph R' Ph R' O S -H2O S
R': Alkyl, NH2
R R R
NH2 Cl N NH3 N
-HCl Ph Ph O O Ph -H O Ph O Ph N Ph 2 H
NH4OCOCH3
CH3COOH
Ph Ph O H2N N -HCl Ph Cl X Ph Ph X Ph -H2O X: O, S, NH R1 O R2 pyridine, water, NaOH HOOC CH NH C CH NH2 + N C S pH=9, 40 oC
R1, R2: alkyl groups
2 R1 O R2 R1 R CH3NO2 NH HOOC CH NH C CH NH HOOC CH NH3 Cl + HCl C O N S HN S
thiohydantoin
Edman sequencing of peptides Chemical properties
1/ Acid-base properties 2/ Tautomerism H N N virtual N pKa 7.2 tautomerism amphotheric compound N N N H N NH H pKa 14.5 real tautomerism R N R N H
as base as acid H N tautomers N N N
N N N N H H
-H +H -H +H mesomers
NH NH N mesomers N N H H N 3/ By SEAr reactions
E (sulfonation, nitration, coupling with diazonium salt)
N
N (methylation, formylation by N-methyl E formamide derivative) H
4/ By SNAr reactions More important derivatives
N N 1. 1. Y NH2 O 3. N - X C 3. N X N Y 1. 1. H HO R R H NH2 N H X =Cl, Br R = H, alkyl 2 - i m i d a zoline derivative
Ar Ar 1. N 1. N H O 1. CH 1. 2. NH 2 N 2. Ar Ar imidazolidine derivative H5C6 H5C6 1. 1. H2N H5C6 H5C6 C OH NH diphenylhydantoin 4. 4. 3. 3. phenytoin C N O N O O OH O Diphedan H2 H diphenylglycolic acid
O O H C NH 4. 1. 3. 4. N . C OH H2N 3. red. 4 C O O 3. C O C OH 3. 3. H2N C O NH N hydantoin O O H parabanic acid
H 1. H 1. NH Cl N N N . 3 . HgO 4 4 S S O C 3. 3. S K N N N H N O OR O O 2 O H O H R
O CH2 COOH O CH C C CH2 CH COOH N H HN N H2 N NH C O N O hydrolysis 2 C N N N H H H histidine azlactone essential amino acid
CH2 CH2 N histamine NH2 biogenic amine -CO2 generated in allergic reactions N H 2 2 2 NH 2 NH COOH R R R 2 R 3 KCN, (NH4)2CO3 NH C O C C R 3 CO , pressure 3 3 2 C C O R R R HN O N N
2 2 R R 3 1 3 H2O R NH R X R NH O OH O O N O N H 1 R
R1 R2 R3
Phenytoin H
Diphedan antiepilepticum
Mephenytoin CH3 C2H5
Sacerno antiepilepticum H2N NH X NH2 X NH2 R NH C + R NH C R NH C S CH3 S CH3 H2N S CH3
- CH3SH R - CH3SH 1 - NH3 NH - HX R2 N R NH C NH N R NH C H N R1
R2
C2H5OH NH CH2 CN CH2 C HCl OC2H5
CH2 CH2 o 200 C H N NH2 NH2.HCl 2
N H2N CH2 N H tolazoline sympatholytic CH3 CH2 Br CH2CN
CH3Cl Br2 KCN
AlCl3 hν DMF
N
CH2CN CH2 N H2N CH2 CH2 NH2 / HCl H melting
Naphazoline X' H H O N Cl / H O, H SO N R: S 2 2 2 4 Cl N N N X" H Ph
N N R NH2 + R NH Cl N N H X H
NH2 POCl3 X 1) PhSCN R N X 2) CH SO Cl NH 3 2 NH2 C Cl NH X 2 R' NH POCl3 R' NH2 R N C N Ph R NH C N Ph
H2N CH2CH2 NH2 - PhNH2 R NH C N Ph NH HN 2 CH2 CH2 NH 2 N O 3. H3C N C H 3. HO N NH2 H H3C N o-phenylene diamine benzimidazole ribose (structural element of B12 vitamine)
1 NH2 OH NH + 2 NH2 O H N 3
Br C N benzimidazole - HBr
NH C N NH NH
NH NH NH N NH2 H benzimidazol-2-amine Monocyclic compounds with more than two heteroatoms I/ Triazoles and its derivatives
4 3 4 3 4 3 N N NH2 5 N 2 2 HO 2 5 5 N N N N 6 N 1 N 1 N 1 H H NH2 O H 1,2,3-triazole 1,2,4-triazole 1,2,3-benzotriazole
R R NH R NH N N N N N R R N R N H H acetylene azoimide derivative H ROOC stereospecific reaction ROOC H N N H geometry of the starting material and of the final product are identical N ROOC N N Huisgen ROOC H N for 1,2,3-triazoles R alkylazide R dialkyl maleate
R H N R 3 O N O NH N R N R N H H 1,2,4-triazoles II/ Tetrazole and its derivatives
4 3 4 3 N N N N N N N N 5 N 2 NH C N N 2 N 1 N H N N H 1 H H 1H-tetrazole 2H-tetrazole
H N N N O hydrogen azide O (azoimide) - N2 NH H N N N mesomers
N Pentetrazol N analeptic agent N N
1,5-pentamethylenetetrazole III/ Thiadiazole and its derivatives
4 3 4 3 N 4 N 3 4 3 N N
5 N 5 N 5 N N 5 2 S 2 S 2 S 2 S 1 1 1 1 1,2,3-thiadiazole 1,2,4-thiadiazole 1,2,5-thiadiazole 1,3,4-thiadiazole
NH NH2 N N (CH3CO)2O N N C C S S H2N S SH HN S SH H2N S C thiosemicarbazide O CH3
N N N N O NH3 O
HN S S Cl HN S S NH2 C O C O O CH O 3 CH3 Fonurit Diamox
diuretic compound with carboanhydrase blocking effect
IV/ Oxadiazole and its derivatives
3 4 3 4 3 4 3 4 N N N N 5 N 5 N 5 N N 5 2 2 2 2 O O O O 1 1 1 1 1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole (azoxime) (furazane)
H3C CH3 H3C CH3 H3C CH3 C C C C - H O N N O O N N 2 O OH HO + 2 H2N OH dimethyl glyoxime
N N HN NH
CH H3C O CH H3C O O 3 3
symmetric diacyl hydrazine Prenoxdiazine
H2NOH.HCl H2N N C Na2CO3 HO N
N Cl
N N O
O N
Libexin O H2N N O N Less frequent heterocyclic rings and ring systems I/ Dioxolanes and dithiolanes
4 3 4 3 4 3 4 3 O S
5 O 2 5 2 5 S 2 5 2 O O S S 1 1 1 1 1,2-dioxolane 1,3-dioxolane 1,2-dithiolane 1,3-dithiolane
OH O tosylic acid O CaCl CH 2 OH 2 O
Br Na2S S Br S II/ Crown ethers and cryptands
O O O O O O O Na Li O O K O O O O O O
4 crown 12 5 crown 15 6 crown 18 number of Crown ether with O atoms: cyclic polyether heteroatoms number of elements of Crown ether with S, P, N atoms: cryptands the skeletone
C.J. Pedersen, J.M. Lehn and D.J. Cram 1987 Chemical Nobel Prize Crown ethers C. J. Pedersen discovered these cyclic polyethers with many oxygen atoms in 1967. Their curiosity is that they are able to form insoluble complex with various metal cations, e.g., Li, Na, K, depending on the inner diameter of the ring, resulting in removal of these cations by filtration. This discovery had great importance from organic chemical point of views. Large-scale pre- paration of crown ethers was carried out by industry. There are crown ethers with 4, 5 and 6 oxygen atoms. Application of crown ethers may take place in organic chemistry by dissolu- tion of a crown ether in aprotic solvent, then adding potassium, or sodium salts to it, the crown ether makes complex with the cation, and precipitated. There is a highly reactive anion in the solution after filtration. E.g., potas- sium permanganate becomes soluble in benzene after treating it with crown ether, then this apolar solution of permanganate anion is used as strong oxi- dating agent. Similarly potassium cyanide, potassium fluoride, potassium nitrite, potassium iodide can be dissolved apolar solvents. Reduction by so- dium borohydride can be carried out in aromatic solvents, if crown ether was added. E.g., dehydration of an O-tosylate runs for 42 hours at usual condi- tions, while the yield is only 9 %. The same compound has dehydration in the presence of crown ether within 1 hour with yield of 70 %. Many such kind of applications can be found in the literature. Pedersen, then Jean Mary Lehn were working with such crown ethers in 1965. They prepared ethers with greater ring size → crown ethers. The oxy- gen atoms are arranged in the structure in order to make noble gas confi- guration with the proper cations. The counter anion is attached from outside.
KMnO4 is insoluble in benzene. However, adding some crown ether to the suspension, − e.g., [18] crown [6] − colour of benzene turns to be of violet, ⊕ showing dissolution of KMnO4. The crown ether can solvate K , while per- manganate ion is attached to this complex in form of ion pair, from in front of the ring or from behind the ring. Permanganate ion is naked, there is only electrostatic attachment of ions. Therefore, the oxidating behaviour of per- manganate ion is remained. KOH can be dissolved in apolar solvents by a crown ether. Hydroxide anion is naked, its nucleophilic power is remained in
SN reactions. The only condition of dissolution of the reagent is that the ca- tion must make stable complex, while the anion is naked. The similar disso- lution happens in dipolar aprotic solvents. The naked anions are of much more nucleophilic, than any solvated anions. Such kind of dissolutions are called as solid-liquid transfer. Liquid-liquid transfer: see PTC reactions (phase transfer catalysis). III/ Pyrrolizidine
H2C C CH2 NH3/ H2 O CH2 O CH2 70 atm,70 oC C HO NH2 -2 H2O N C OH HO OH O O O O O
8 7 1 LiAlH4 6 N 2 4 5 3
pyrrolizidine (in alkaloids) Six-membered heterocyclic compounds with one heteroatom and their derivatives with condensed ring system I/ Pyrane and its derivatives
Nomenclature H 4 4 4
5 3 5 3 5 3
6 6 6 O 2 H O 2 O 2 X 1 1 1 2H-pyrane 4H-pyrane pyrilium salt α-pyrane γ-pyrane the benzopyrilium salts these are not stable compounds are stable compounds
Preparations
C6H5 C6H5
C6H5 C O H H5C6 OHO C6H5 H5C6 OO C6H5 H H3C H3C
H5C6 O O C6H5
C6H5 C6H5
H3O oxidation
H5C6 O C6H5 H5C6 O C6H5
pyrilium salt O acetone O O H O C 3 CH2 CH2 R-ONa H aqueous acid H H - 2ROH anhydrous ROOC OO COOR acid ROOC O COOR OR OR
ROOC O O COOR
dialkyl oxalate
O O O OH tautom. NH3
-2CO2 HOOC O COOH HOOC N COOH N N H H Cu γ-pyrone derivative γ-pyridone derivative γ-pyridone 4-hydroxypyridine ( chelidonic acid)
O O O -2CO2 O O NH
O N O H ester acid amide vinylogous ester O acid amide γ-pyrone O C H2C CH2 NaOEt/EtOH O H H anhydrous anhydrous hydrochloric acid OEt OEt heating EtOOC COOEt EtOOC O O COOEt O O
O O aqueous hydrochloric acid NH3
pressure EtOOC O COOEt HOOC O COOH
O O OH
heating
HOOC N COOH N N H H OH HOOC H O H NaOH HOOC H C H aqueous medium H O heating H O HO O OHO
OH H HOOC HOOC H heating heating
-2H O -CO H O 2 O O 2 OH OH
CH3NH2 / H2O
pressure, boiling O O N O
CH3 More important derivatives O 4 5 3
6 2 O O O O O 1 3,4-dihydro- tetrahydro 2H-pyran--2-one 4H-pyran--4-one -2H-pyran -pyran α-pyrone γ-pyrone
O O O α-chromen chroman γ-chromen 2H-chromen (stable) 4H-chromen (unstable)
O O
O O O O O O 2H-chromen-2-one α-chromanone γ-chromanone 4H-chromen-4-one α-chromone γ-chromone coumarin O O chroman isochroman 5 4 5 4 5 4
6 3 6 3 6 3
7 2 7 2 7 O 2 O O 8 1 8 1 8 1 2H-chromen 4H-chromen isochromen O
O
O O O O coumarin chromone isocoumarin
O
O
O O O O 2-chromanone 4-chromanone isochromanone (dihydrocoumarin) (dihydrochromone) (dihydroisocoumarin)
+ - + O X O chromilium salt isobenzopyrilium salt (benzopyrilium salt) H
Al2O3 H3O o O CH2 OH 350 C O - H O O HO 2 Raney Ni/H2 H3O ROH protection of alcoholic O OH RO O Br
KOH 1,7-heptandiamine
O O Nylon 77 (see at tetrahydrofuran) OH H HOOC H HOOC
-2 H2O - CO H O O O O 2 O O aldol dimeri- α-pyrone sation HOOC
H OH enol R = H α-pyridone O H R = CH3 N-methyl- HOOC H α-pyridone N O R C H O HO O formylacetic acid
O O It is a double vinylogous lactone Both mesomers contribute to the real structure mesomers
O O 4.08 D measured 22 D 1.75 D calculated oxo reagents
H2N NH2 O or H3C O H there is no reaction HO NH2 1. CH3MgI 2. H2O H O O stable it is an ester, O +HCl it can be Br2 hydrolysed base Br Br -H2O by base substitution (vinylogous (it is not addition) ester) O O CH3
O HO OH O Cl shifted to the oxo form pyrilium salt O O aromatic it can be isolated from wheat germ oil Vitamin E it participates in α-Tocopherol keeping pregnancy CH 3 (tokos: birth, ferein: carry) HO CH * * * 3 H3C O CH3 CH3 CH3 CH3 CH3
Coumarin - its hydroxy derivatives occur in glycoside form in nature
OH OH
dicoumarol an anticoagulant these differ from each other in the position of a (its antidote is Vitamin K) O OO O tautomers H (H anion) and of a double bond H
H (difference lays at oxo-enol taumerism in differences in mobile H as well as O O H position of a double bond) 4H-pyran 2H-pyran - H oxidation
C6H5 stable aromatic not existing compound
O H5C6 O C6H5
ClO4 Anthocyanines
These derivatives are compounds with conjugated double bonds (conjugated: 2H-pyran, or isolated: 4H-pyran) (heterocyclic alkenes). The compounds are reactive ones with high energy content. hydrolysis Anthocyanines are glycosides anthocyanidine (aglycon) + sugar component Flavinium salts: coloured materials of plants with glycoside type (flower petals, fruits, strawberry, pelargonium, red poppy, black grape, bluebonnet, chrysanthemum): these might be red, purple, violet, blue α-Chromene derivatives are polyhydroxy compounds with 5 hydroxy groups. Its derivatives occur in the nature only, e.g., methyl ether, acetyl derivative, or with free hydroxy groups. The glycoside structure is the remnant of molecular phylogenesis, representing its carbohydrate origine. Cyanin (greek) – blue The actual colour depends on pH of cells as well as on depth of layers, since coloured components do not move freely within the cells, these form layers. Blue colour of bluebonnet and red colour of red poppy comes from the same molecule.
Colour depends on: 1. pH value 2. number of hydroxy groups 3. the actual form of hydroxy group (free, methyl ether, glycoside) 4. position of glycoside group OH OH OH OH -H
+H HO O HO O
2 sp OH O
OH O H cyanidine chloride salt anhydro base pH = 3 red (red poppy) pH = 8 violet (bluebonnet)
+H O +H 2 - H2O +H -H
OH OH OH OH sp3
HO O HO O HO OH O OH O
pseudobase pH = 11 colourless blue (flower petals) These differ in the number and positions of hydroxy groups, in quality and position of the sugar components. Source of red colour can be carotenoids (red pepper), while other carotenoids are yellow. White colour of flower petals come from the colourless air, but from not a coloured material. There is sp2 conjugated system in cyanidine chloride, where the pyrilium salt is the auxochrome component. Appearence of a sp3 carbon separates the two chromophores, resulting in no absorbance in the coloured range. Flavonoids Colour of tulips and other plants by springtime. There can be 4 types of hydroxy derivatives (free, Yellow colour of yellow plants (flavus – yellow) methyl ether, acetoxy derivative or glycoside), γ-chromene derivatives similarly to the anthocyanines.
Ο Ο 5 4 ΟΗ 6 3
7 ∗ Ο 2 Ο Ο 8 1
2−phenylchromane flavanone flavanonol flavane Ο Ο ΟΗ
Ο Ο Ο
2- phenyl-4H-chromene flavone flavonol flavene
Ο
Ο Ο x Ο 2-phenyl-2H-chromene flavinium salt isoflavone O O O
CH3 Cl CH3 pyridine O OH O C O O KOH glacial acetic acid pyridine H2SO4 , o OH O 50 C -H O 2 O
OH OH OH H HO O O HO O O O OH Prof. Géza Zemplén O Technical University at Budapest : he was a flavonoid HO O researcher
rutin OH D - glucose L- ramnose flavanol type coloured dye of OH Ruta graveolens rutinose Vitamine P: discovered by Szent-Györgyi, Rusznyák, Bruchner It decreases permeability of capillaries, increasing their resistance.
OH O erythrodicthiol + hesperidin R = H R = CH3
sugar O O
OR OH
O O O
Na Et O OH O O O OH C H H O
- H2O
O
isoflavone O O O CH3 C + O / NaOAc - H O - CH COOH OH CH3 C 2 O O 3 O O H salicylic aldehyde O CH3
Perkin-synthesis
O O coumarin O O H O 1) KOH /EtOH CH3 H / MeOH + or 2) H OH O H NaOAc/MeOH
hydroxychalcone
OH O
O O H flavanone Anthocyanines: α-chromene derivatives Flavonoids: γ-chromene derivatives Anhydrobases: compounds forming salts with acids without generating water (see the examples on the previous slides) Pseudobases: some secondary carbons with OH can dissociate to hydroxy, similarly to the effect of bases pseudobases
- OH
H OH
+ OH O OH O N OH R OH OH
OH N + + OH O O N R R anhydrobase H H H H O O OH O H + H2O OH H O I II OH compound II is an anhydrobase, since it contains one water molecule less, than compound I
OH OH O
+ OH X OH II - H2O O does not run O H O I anhydrobase
Dibenzopyrans and their derivatives HO H xanthydrol red. O O O 8 1 Cl 7 2
6 3 O O O 5 4 xanthene xanthone
CH3
OH COONa
CH3 O CH3 HO O O tetrahydrocannabinol fluorescein indicator psychotomimetic agent Cannabis indica II/ Thiapyran and its derivatives
O Structure
S S S α-thiapyran γ-thiapyran tetrahydrothiapyrone
Preparation Na2S EtOH Br Br S tetrahydrothiapyran
O
S S O S α-thiachromene thiacoumarin thiaxanthone
O
S S S thiachroman γ-thiachromone thiaxanthene III/ Pyridine and its derivatives
Structure
X X N O N H
aromatic compounds with π - electron deficiency Preparations Homologues of pyridine are isolated from coal tar Homologues of pyridine with 1 methyl groups are called as picolines 1/ Isolation from coal tar Homologues of pyridine with 2 methyl groups are called as lutidines Homologues of pyridine with 3 methyl groups are called as collidines Homologues of pyridine with 4 methyl groups are called as parvolines
picolines: CH3
CH3
N CH3 N N α β γ
lutidines: CH3 CH3 CH3 H3C CH3 H3C CH3
N CH3 N CH3 N CH3 H3C N CH3 N N
collidines: CH3 CH3 CH3
CH3 H3C CH3 CH3 H3C
N CH3 N CH3 H3C N CH3 N CH3 H3C N CH3
parvolines: CH3 CH3
H3C CH3 H3C CH3 CH3
N CH3 H3C N CH3 H3C N CH3 2/ Hantzsch synthesis O O O R O H H H R H EtO OEt EtO OEt CH - H2O O O O OO aldehyde
ethyl acetoacetate
O R O O R O
EtO OEt - 2 H2O EtO OEt O
H H atmospheric OO N N HH H H enol form 1,4-dihydropyridine derivative O R O pyridine derivative stabilised, therefore its dihydro EtO OEt derivative is easily oxidised to aromatic compound
N 3/ From 1,5-dioxo compounds
H3O
R OO R R OO R R O R HH
NH3 ox.
R N R R N R 4/ By isosteric exchange
see at pyran and its derivatives
5/ By Chichibabin synthesis CH3 CH3 C - 3H2O O H - 2 H H C CH H3C N CH3 3 3 (oxidation) C C collidine H3C O O CH3
NH3 Physical properties
The parent compounds have high solubility in water Their UV spectra are similar to of benzene. There are group vibrations in their IR spectra: pyridine counts to monosubstituted benzene, in respect to the fingerprint region of 700-900 cm-1 Their NMR spectra: 7.50 6.20 7.12 compare to: 6.68 6.61 N N H 8.00
Chemical properties
1/ Acid-base properties The compounds are stable against acids (salt formation), while are somewhat labile to bases (hydrolysis), except for pyridine. Base sensitivity increases by the number of heteroatoms. Pyridine is of basic property – introduction a second N decreases basicity.
+Η
Ν pKa = 5.2 Ν Η 2/ Tautomerism This is function of solvent, of pH, of structure, and of functional group(s) NH2 NH tautomerism tautomerism
N NH2 N NH N N H H amino amidine amino vinylogous amidine
tautomerism mesomerism
N OH N O N O H H lactim lactam
OH O O
tautomerism mesomerism
N N N H H vinylogous lactim vinylogous lactam
OH O protomerism there is no tauto- merism N N H N α XH N X N X H H
XH X X
N N N H gas phase H in polar solvents
XH X
N N H
X = O, S, NH in water only; 50% ratio of it
Diazotization if the amino group is possible, NH2 N N proving that the equilibrium is shifted to the NaNO2/ HCl amino form in highly acidic conditions. 0 - 5 oC Cl The 2- or 4-diazonium derivatives can be N N decomposed easily, while the 3-diazonium derivative is stable. β 3/ SEAr reactions It takes place with difficulties, and into position only Ο O Br Br ΗgO C CH3 Br2 Hg(O-C-CH3)2 o 300 oC 150 C N Ν N KNO 3 * + H2SO4/SO3 o 300 C Hg Friedel-Crafts reaction SO3/ cc.H2SO4 300 oC does not run oleum Ο NO2 S O Ν with low yield Ο twin ionic structure N H
* Sulfur trioxide absorbs the water generated in the reaction. KNO3 is less volatile, than HNO3. HNO3 is generated in the reaction mixture. Pyridinium ion withdraw electrons from ring carbons even more. Pyridine reacts in SEAr reactions with difficulties due to two reasons: a) electron density is decreased in α- or in γ-positions especially, the least in β-position b) Protonation of the N atom (NH+) increases electronegativity of N, thus withdrawing electrons from the ring carbons even more. It takes place in α- and γ-positions mainly due to the lower electron density in these 4/ SNAr reactions positions
NaH is deprotonating the amidine NH2, resulting in H2. The reaction becomes irreversible, since H− is the leaving group, and it reacts with α-substitution: the proton source NaH.
acid amidine system Na-NH2, liq. NH3 H
o N -33 C N NH2 N NH2 Na +NaH
H2O
N NH2 N NH α-pyridinamine Na +H2
RMgX RMgX 150 oC N N R R N R Regioselective α- and γ-substitution
N X
CH3 alkyl pyridinium salt HO M KCN C N N C H III K3 Fe (CN)6 H I2 N O N OH N oxidation N CH3 CH3 MX CH3 CH3 +KX
NH2
Cl NH2 γ KNH2/NH3 liq. + NH3 -substitution - 33 °C + N - HCl N N N
3,4-dehydropyridine 25% 45% ("hetaryne")
KCN H α-substitution - KI - CH OH N N 3 N CN I CN OCH3 OCH3 Pyridine in nucleophilic reactions
H H H
N NH2 N NH2 N NH2
NH2 NH2 NH2 Z H H H
N Z =NH2 N N N
H2N H H2N H H2N H
N N N
Pyridine in electrophilic reactions
H H H N Br N Br N Br
Br Br Br Y H H H N N N Y = Br N
Br H Br H Br H
N N N In ground state There are lower electron densities in α- and γ-positions
In nucleophilic reactions The ring N causes –Iα>-Iγ, the β carbon does not react. The negative charge in the intermediate can appear on the N, as well.
In electrophilic reactions The relatively highest electron density is found on the β ring carbon, since there is no positive charge on the N, and moreover, there is no positive charge in any mesomers if β-substitution takes place.
Pyridine in ground state
N N N N N 5/ Reactions at a lone pair of electrons oxidation H2O2 HX CH3COOH pyridin-N-oxide PCl3 N N N H X X = Cl O O O R-I I-I O C SO3 R C X R
Thus pyridine X is catalysing acylation N N N N I C R I O S O I R O O R' OH
Fixing the salt structure results O in difficult cleavage of the R group R' O C R acyl pyridínium salt acyl cleavage + it is less stable, than the alkyl pyridínium salt
+HX N
Reactions of pyridin-N-oxide One of the nonbonding orbitals of oxygen can be coplanar (in the same plane) to the combining p AO-s of the ring atom. Thus, the +M effect of the oxygen is overcompensating the -I effect of the nitrogen, resulting in O N electron richness in α- és γ- positions of the ring. One electron is excited to the LUMO orbital. Size of delocalisation is increased. NO2 NO2 NH2
HNO3/H2SO4 PCl3 red. o 100 C -POCl N N 3 N N O electrophilic reaction O in γ-position
Not at 300 oC-on, like for pyridine t = 200 oC the difference in reactivities is 108 times
NO2 H NO2 O
Hg(OCCH3)2 -H the electrophile N N N goes into N Hg O O O α-position O O σ-complex C O CH control of orbitals are the reasons of α-, or γ-selectivity 3 control of charges X NO2
H2SO4
N N N N O O O OH
X = NH2, Br, Cl, CN
SO2OH SO2OH MgBr H2SO4
N N N nucleophilic reaction OH SO3
SO2O
N N N H O S O O 6/ Addition reactions
The Diels-Alder reaction has a very complex mechanism with pyridine, the reaction is not concerted (asynchronous) and the final product is formed by aromatic stabilization of the previous, coloured intermediate.
CH3 CH3 O CH3 O O O CH3 O O + O O CH3 O N 2 O O O O CH N 3 O O O CH3 O O CH3 dimethyl acetylene- O O dicarboxylate CH3 CH3 oxidation by red intermediate Hg(OCOCH3)2 ring closure O O CH3 O O O CH3 CH3 H O CH O 3 N O O N O O CH3 O CH3 O O CH3 O CH3 colourless product O yellow product 7/ Reduction Ni or Pd piperidine H N 2 N H Reduction is the easiest, if the compound has strong electron absence.
NaBH4 +NaCl III N K3 Fe (CN)6 N Cl CH3 CH3
O O reduction H H NH2 +H NH2
N -H N R oxidation R R = H nicotinic acid amide
This system can be reduced even It is a biochemical H-transfer agent, more easily, since it has stronger electron main ingredient of coenzymes absence reduction takes place NAD, NADH in α- or in γ-positions 8/ Oxidation 9/ Polymerisation The stronger the electron absence, the more difficult is the It does not run, in the contrary of five-membered oxidation. heterocycles. There is no ring opening for pyridine by oxidation. Formation of N-oxide is possible from pyridine. There is active H at α- and γ-methyl groups for heterocycles with π-electron deficiency
- H
N CH2 H N CH2 N CH2 H N CH2 H
R R N CH2 N CH C C 2 CH O CH2 H HO 2
CH2 H CH2
- H CH2 H CH2 N N
N N CH2 CH2 H
N N N N N
N CH2 N CH2 N CH2
CH CH N 2 N 2 N CH2 N CH2 H H H X=CH3, O X X 10/ Reactions of the active C-H group O CH3 C H O HO N CH2 H N CH2 CH CH3 H
HO H D (deuterium) -H2O exchange is possible OH
N CH CH CH3 H
mesomers -H2O
N CH2 N CH2 N CH CH CH3
Na/EtOH N CH2 CH2 CH3 H racemic coniin More important derivatives nicotine: the very poisonous alkaloid of tobacco (Nicotiana tabacum) O O H OH ) N cc. HNO3 OH OH N CH N N 3 N coenzyme complex belonging O O to the vitamin B group 2-picolinic acid nicotinic acid it is oxidised at this carbon NH2 O OH N
N
isonicotinic acid
O OH O OCH2CH3 O NH NH2 CH3
oxidation CH3CH2OH H2N-NH2
cc. H2SO4 N N N N
isonicotinic acid hydrazide, INH Cl first drug of tuberculosis, 1952
CH3 N N CH2 CH2 N R CH3 HOCH2 CH2OH
N CH3 chloropyramine (Synopen) R an antihistaminic drug pyridoxine -CH2OH
(pyridoxol vitamin B6 ) their phosphate ester is used in coenzymes of transaminating O pyridoxal C and of redoxy reactions H
pyridoxamine CH2 NH2 H2 /cat.
- NH4Cl Cl N N H NH2 NH3 piperidine
coal tar CH3I, then AgOH
NaNH2 CN C CN C O H H Na Na CN CH CH OH OCH CH compound with -2NaCl 3 2 2 3 actíve methylene group H2SO4 HH Cl Cl Dolargan, meperidine OH OO N N (pethidine) 2 SOCl CH2 CH2 CH NH 2 CH CH morphine substitute 3 2 CH CH 3 3 H 2 2 N O N O N CH3 CH3 CH3 nitrogen mustard O MgBr C O H H then H2O OH CH2 -H2O C + C CH2 CH2 N C H CH2 CH2 N O N HCl H Parkan Mannich reaction an antiparkinson drug Indolizine, indolizidine
8 7 1
6 N 2 N 4 5 3 indolizine indolizidine (in alkaloids)
Quinolizine, quinolizidine
COOR 9a Diels- COOR COOR Alder 9 H 1 COOR reaction 8 2 + 4 CO2 N N 7 N 3 5 COOR COOR 6 4 COOR COOR 9aH-quinolizine
dialkyl acetylenedicarboxylate H2
N N
quinolizinium salt quinolizidine (in alkaloids) The benzocondensed derivatives of pyridine
2 1 3 5 5 4 4 8 9 1 10 4 6 3 6 3 7 2 9 c 7 b c b 2 7 N 2 6 3 8 N 5 N N 8 8 1 5 4 7 6 1 10 quinoline isoquinoline acridine phenanthridine benzo[b]pyridine benzo[c]pyridine benzo[b]quinoline benzo[c]quinoline
9a 9 1 9 1 9 H 1 8 H 2 2 2 8 8 7 N 3 7 N 3 7 N 3 N 5 5 4 5 X 6 4 6 6 4 H 2H-quinolizine 4H-quinolizine 9aH-quinolizine dehydroquinolizinium salt Quinoline
Preparations
1/ By Skraup synthesis H CH O H glycerol Michael-type addition HC OH H CH2 OH
NH2 cc.H2SO4 O O - 2H O aniline 2 CH CH H CH2 CH CH2 cc.H2SO4 (it is not formation CH2 N of Schiff-base) H acrolein
OH
H NO2
- H2O nitrobenzene isolation by steam N N N distillation H H oxidating agent -2H quinoline dihydroquinoline
isolation of quinoline may take place from coal tar 2/ By Döbner-Müller process O O CH CH CH cc. HCl 2 oxidation + CH CH - H O NH2 CH N CH3 2 N CH3 H H CH3
N CH3
Chemical properties
S S These are similar to of pyridine: E N 5 4 SE reaction takes place at the carbocycle, in position 5, or 8 bromination nitration SE Ar SN reaction takes place at the heterocycle, in 2 sulfonation position 2, or 4 8 N SN
SE oxidation: the carbocycle is oxidized in basic medium, 1/ Oxidation while the heterocycle is oxidized in acidic medium O O
OH KMnO4 KMnO4 HO OH H HO HO N N O O o 2/ Reduction Ni/130 C Pt/acetic acid the carbons of heterocycle have low electron density, therefore oxidation of H H the carbocycle takes place in neutral/ basic medium. Protonation of the N helps improving acidity of the heterocycle, therefore phthalic acid is prepared in N trans N cis a c i d ic medium. H H H H
reduction: depends on catalyst and solvent 3/ Electrophilic reactions
E 5 6 E + N N N 8 E
E = SO2OH E
N kinetic control H SO OH + 2 H2SO4/H
+ N -H N SO2OH H SO 2 4 kinetic + +H control + -H thermodynamic N control + -H + +H SO2OH SO OH thermodynamic 2 control N N H H (see below) H H
N SO2OH H H X X X X H H H H N N H N N A A N N H H
H H X X X X H H
N N H N N N N A A H H
A: advantageous N: not preferred 4/ Nucleophilic reactions KCN O Cl Cl N N CN C C O C H main product Chichibabin reaction O 6 5
NaNH Li H3O 2 H N N NH2 N + Li N NH2 COOH HO CH3I -LiH oxidation by C nitrobenzene O C6H5
N UV light
N OH N I N PCl5 CH3 + OH N HO OH KCN O CN CN N Cl N I2 Cl PCl5 N oxidation N NH3 HO I CH3 CH3 N NH UV light 3 O OH NH2 CN
HO
N NH2 N N N
More important derivatives
O OH CH3
CrO3 oxidation cinchonine oxidation N CH3 N N quinaldine lepidine
O OH Atophen (aciphenoquinoline) drug against gout and joint diseases
N
SN (NaNH2)
O SE mainly H 9 dehydration 2 (nitration)
N N H 4
SE drugs and dyes with acridine skeletone Plasmochin (Chloroquin): against malaria. There were many patients infected with malaria during the II. World War in Japan, due to the tropical climate. There was international cooperation for drugs against malaria: 100 thousand compounds were tested during 3 years, and 11 compounds became drugs.
CH2CH3 H3C CH CH2 CH2 CH2 N NH CH2CH3
8 1 8 1 N N N 7 2 7 2
Cl N 6 3 6 3 N Plasmochin 5 4 5 4
1,5-naphthiridine 1,8-naphthiridine 8-Hydroxyquinoline (Chinosan) pyrido[3,2-b]pyridine pyrido[2,3-b]pyridine
H Al, Fe makes insoluble complexes with heavy metals (see analytical chemistry) N
O H alkaloids with quinoline skeletone (see alkaloids) OH OH OH
NH2 CH N N 2 Skraup Cl2 I2 /KI O CH synthesis CH SEAr
OH Cl I N
Cl Enteroseptol
CH3O O CH3O CH3O CH redukció NH2 CH N N
NO2 O NO2 NH2
CH3O CH3O
H2N NH2 N N O NH NH
CH3CH(CH2)3 NH2 CH3CH(CH2)3 N Primaquin O O O
CH3CH(CH2)3 Br K N CH3CH(CH2)3 N Br Br O O Phenanthridine
H N N
O NH2 benzalaniline 1. CH3I 2. NaOH
oxidation N N N CH3 CH3 CH3 O OH HO drugs with trypanocidal activity Isoquinoline
Origin of it is from coal tar.
Preparations
1/ Bischler-Napieralski synthesis
(R CO)2O ZnCl2 or or O H polyphosph- NH N 2 R C O H oric acid Cl β-phenylethylamine R may contain also P2O5
Pd / 160 oC
- H2O N dehydrogenation N - PdH2 R (palladium hydride) R 2/ By Pictet-Spengler synthesis
CH3O O CH3O CH3O R C o H Pd /160 C NH2 NH N CH3O H2O, pH=5 CH3O CH3O R R
Position 6 is activated by the methoxy groups, similarly to the biosynthesis.
Chemical properties
SE (main) The chemical properties are similar to of pyridine
5 SE the carbocycle reacts mainly - bromination, nitration, sulfonation SN the heterocycle reacts in position C-1
N (8) 1
SE SN (minor) 1/ By oxidation The carbons of heterocycle have low electron density, therefore oxidation of the carbocycle takes place in neutral / basic medium. Protonation of the N helps improving acidity of the heterocycle, therefore phthalic acid is prepared in acidic medium.
O O
OH KMnO4 KMnO4 HO OH H N HO HO N
O Pt/acetic acid/sulfuric acid O H H 2/ By reduction NH NH H H cis trans 4 : 1 3/ By electrophilic reactions
E 5 E + N N N 8 E E = SO2OH 4/ By nucleophilic reactions
NaNH2 CH3MgI N N N
NH2 CH3 CH3I
I KOH oxidation X N N N CH CH3 CH3 3 OH OH More important derivatives
O O
CH3O CH3O
NH2 NR3 NH reduction CH3O CH3O O O Cl NaBH4 OCH3
OCH3
OCH3
OCH3
By Zoltán Földi CHINOIN industrial synthesis OH
CH3O CH3O P2O5 / toluene NH boiling O N CH3O CH3O - 2H2O OCH3 OCH3
papaverine OCH3 OCH3
muscle relaxant drug Six-membered heterocyclic compounds with two or more heteroatoms and their derivatives with condensed ring system Compounds with two nitrogens I/ Azines and its derivatives
N N N N N N pyridazine pyrimidine pyrazine 1,2-diazine 1,3-diazine 1,4-diazine
Similar heteroaromatic compounds with oxygens or sulfur atoms are not important, their partial or fullly saturated derivatives only. Introduction of the second nitrogen makes the derivative with even more π-electron deficient. Pyridazine and its derivatives
Structure
N N N N N N cinnoline phthalazine benzo[c ]cinnoline Preparations
Schiff's base structural unit Hydrazone structural unit O O Cl Cl HN HN N N Cl Cl
O H OH O -H+/+H+ +H+/-H+ R R C N R' R C N R' R C N R' -H O R' R' H 2 H2N R'' R' H R'
R: alkyl, aryl hemiaminal Schiff's base R': alkyl, aryl, H (N-substituted imine) R'': alkyl, aryl
O R C N NHR' R + H2N NHR' R' R' hydrazone Amide structural unit Hydrazide structural unit O O Cl Cl HN HN N N Cl Cl
O H R + - O O -H /-X R R' N C R X X H NHR'
amide R' NH2
R: alkyl, aryl R': alkyl, aryl, O X: halogen, OC R
O O R R + H2N NHR' X NHNHR'
hydrazide Mechanism
O O O Cl O Cl δ Cl AN E + Cl HO HO HO HO O Cl O -H /-H -H2O H2N N Cl Cl Cl δ+ H HO H H N H H NH2 N S i NH2 N
OH O HO O Cl Cl H N HN Cl H N N N Cl Cl -H N Cl lactim lactam 3 R R3 1 R R1 NH2 O N + NH2 O 2 N R R2 4 R R4
O O 1 R R1 NH2 HO HN + NH2 O 2 N R R2 3 R R3
O O 1 R R1 NH2 HO HN + NH2 HO 2 N R R2 O OH
O O 1 R R1 NH2 HN + O NH 2 2 N R R2 O OH CH3 CH3 CH3 4 CH2 NaNO2 / HCl / H2O CH2 3 0-5oC - HCl NH N 2 2 N N Cl N 1 4-methylcinnoline
Ar N N Ar N N electrophile O O
CH3 CH3 N N N N Cl N N
O N O N
CH3 CH3
pyrimido[5,4-c]cinnoline ring system O O hydrazinolysis NH2 NH O + NH2 NH
O O phthalic anhydride phthalic acid hydrazide
There are many drugs O with phthalazine ring O system: NH NH NH2 NH 2 N R + + R NH2 NH NH 2 N O O N N-alkylphthalimide phthalic acid hydrazide Aprezolin renal dilatator O Cl NH NH2
NH POCl3 N 2 H2N-NH2 N NH 150 oC N N
O Cl NH NH2
Nepresor decreasing blood pressure Basic strength in aqueous solution
pKa values for the conjugated acids of the bases
strong repulsion medium repulsion weak repulsion
N N N N N N
pKa values 2.3 1.3 0.7
basicity pyridazine > pyrimidine > pyrazine N N N N N N
strong repulsion medium repulsion weak repulsion
high medium little energy energy energy released released released
N N N N N N H H H Pyrimidine and its derivatives R R Preparations NH if R = H 1. O N + pyrimidine -2H H N R 2O R O 2 R N R
CH3 CH3 CH3 4 2. O NH 5 NH N 2 -H2O 3 + 6 2 -EtOH O OR H N O O N O HO N OH 2 H 1 O O Cl
NH2 3. OR NaOEt NH POCl3 N + H2N O - ROH O OR O N O Cl N Cl H HI reduction O O 1 NH R 2 R1 2 OR R NaOEt 2 NH N + R H2N O - ROH O OR O N O N H barbituric acid pyrimidine derivative O O NH2 4. OR NaOEt NH + HN O N H HN N O H addition step O O
OR H2N NH 5. + O OR H2N NH O N NH H O O
OR H2N NH 6. + O OR H2N S O N S H R R H N O 2 NH 7. + H N O R O 2 R N O R' R
O H2N N 8. + O OR H2N S HO N SH
R' = CH3 Basethyrin hyperthyreotic compound 1 2 3 O R R R X R1 3 CH3 R Amobarbital C2H5 CH2 CH2 CH H O CH 2 N 3 R Dorlotyn (narcotic, with medium length) O N X Butobarbital C2H5 CH2CH2CH2CH3 H O H Etoval (narcotic, long)
Barbituric acid derivatives Cyclobarbital C2H5 H O
The barbiturate name is improper, can be applied for salts only. Uses Hypnoval (narcotic, medium) are against insomnia (usually not for surgical uses). Barbituric acid itself is without Hexobarbital CH3 CH3 O effects. Novopan (parapulmonar narcotic agent) long The efficient Phenobarbital C2H5 H O medium period depends short on the excretion ultrashort} Sevenal (narcotic, long, antiepileptic agent)
CH2 CH3 Inactin C2H5 CH H S CH3 Venobarbital (parapulmonar narcotic agent) O O O C OEt C OEt 1 C OEt 1. OEt 1. OEt R 1 C CH2 R CH 2 2 2. 1 X 2. R X R C OEt R C OEt C OEt O O O
R O H N 1 1 C H ONa R R R COOEt 2 5 N 2 C + C X 2 R COOEt EtOH R H N -2EtOH O N X H H
R = H, CH3 H3O X = O, S, NH (X = NH)
R NH O 2 2 1 HN R R R R R CN C2H5ONa N H3O N 2 C + C X 1 1 R COOEt R (X = NH) R H N 2 O N X O N O R = H, CH3 H H X = O, S, NH barbituric acid derivative O O
R CH CH (CH2)n CH2 OEt OEt + R CH CH (CH2)n CH2 X O OEt O OEt
O O (CH2)n-1 OEt OEt + X (CH2)n X H2C O OEt O OEt
O O O O EtO OEt EtO OEt
+ X (CH2)n X + (CH2)n EtO OEt EtO OEt O O O O
O O O O EtO OEt EtO OEt
+ O C (CH2)n C O + CH (CH2)n CH EtO H H OEt EtO OEt O O O O NH2 NH2 H2N H2N X
X: O, S, NH
CH3 CH3 CH3 N N O O N O N X O OEt H H
O O O
OEt NH NH
O OEt O N O N X H H
NH C N NH NH C NH
N HN N HN N X H H Chemical properties
O H 4 3 NH 5 N NH H2 6 2 O N O N N H 1 H pyrimidine 1,3-diazacyclohexane active H
1. Pyrimidine is a weak base, pKa =1.3 It is able to participate in nucleophilic reactions: OHCl; Cl H 2. Electrophilic reactions do not run. 3. Centre No 5 is the most reactive, it is an active methylene group in barbituric acid. But it is impossible to run alkylation or arylation in centre No 5 of barbituric acid after ring closure, since the alkyl or aryl group attacks the heteroatoms only.
O R H O O C NH R C NH H O N O O N O H H 4. Resists oxidation: the substituents are oxidised only
O OH CH3
N oxidation N KMnO N 4 N 5. There is tautomerism at hydroxy- and at aminoderivatives, e.g.,
barbituric acid dilactam- mainly this trilactam pKa = 3 -monolactim is present OH OH OH at pH4-6 O The tautomeric equilibrium N N N tautomers NH depends on temperature and solvent strongly. HO N OH HO N O O N O O N O Rate of N-alkylation is H H H H higher, than rate of O- alkylation. trilactim is dilactim- Usually more than one H H H H the main tautomer -monolactam tautomer are present in at highly acidic pH crystalline form, the actual (pH=1 or less) O O main tautomer depends on the isolation conditions. N mesomers N
O N O O N O H H
N N NH X = O, S, NH N X N XH N X H
polar medium gas phase Benzocondensed derivatives of pyrimidine
O H2N O OH Cl + PCl OH HN H NH N 5 N formamidine NH2 N N N
HI red. O OH
HO N N KMnO4, H2O N HO KOH ox. N N N O quinazoline S + C H NH2 N S N SH S
NH2 NH NH 2-aminobenzyl-amine N (CH3)2SO4/NaOH + C dihydro derivatives H N NH } Br 2 N S CH3 NH3 N NH NH NH NH NH NH 2 NaOEt / EtOH 2 + H2N NH2 OH NH N NH O O O
Cl S NH NH2 2 Cl NH S LiAlH4/THF CH3I
NH2 NH2 Et2O NH EtOH (anhydrous) - 2HCl O R1 R1 I HN N N NH S CH3 R2 R2 NH NH - CH3SH - HI More important derivatives
O NH2 O
H3C NH NH NH pyrimidine bases N O N O N O H H H uracil cytosine thymine RNA RNA DNA DNA
7H-purine derivatives
7 1 O R R2 R3 1 R R H H N xanthine H N theophylline CH3 CH3 H in Chinese tea theobromine H CH CH in cocoa beans O N N 3 3 3 R caffeine CH3 CH3 CH3 in coffee beans
Each compound can be found in all of these plants, but the main component is characteristic. They have diuretic effect. Synthesis of uric acid and of purine
These are compounds isolated in the XVIII. Century (Scheele, 1776). The following synthetic method for purine was introduced by E. Fischer (1898):
O O O O C C NH HO-N=O N OH H2N RO CH2 (CH3CO)2O NaOH HN ) HN + C C C N SE NH N O NH O N O O N NH O 2 2 H H nitrosation of actíve methylene group
O Cl O NH2 H N HN H N N POCl3 N Al, HCl 2 NH C O O Cl H2N O N NH2 N Cl N N H O N H H H exists in tautomeric forms uric acid I H HI/PH4I N N N N Zn N N
N N N N N I N H H purine Another synthesis of a purine derivative is Traube’s method (1900):
OH O NH2 N N H HN C O HO H N N NH N 2 2 H2N N H guanine
O OH H N N NH N
O N N HO N N H H xanthine Compounds with purine ring system
Synthesis of theofilline (Traube synthesis)
H3C O O O O NH RO C CH3 H3C H3C N O N C + CH2 NaOEt N CH2 N HO - NO O NH C C N O NH O N NH2 O N NH2 CH3 N CH3 CH3 CH3 O O O H3C NH2 red. N HO H3C H3C + N NH N NH H O N NH O C 2 O N NH2 H O N N O CH3 CH3 CH3 theofilline Synthesis of theobromine (Traube synthesis)
O O H2N O NH2 C POCl3 / pyridine HN 1) NaNO2 / acetic acid HN O NH + HO heating 2) (NH4)2S (reduction) CH3 C O N NH O N NH2
N CH3 CH3
O O CH3 H H2N N N HN (CH3)2SO4 HN C H H O O N N CH3OH / HO O N N o boiling H2O, 60 C CH3 CH3 theobromine 2. Cl N N Cl 3. S reactions N N N H 1. Cl 6 5 H 1 N7 N N More important derivatives: N 8 - guanine 2 9 4 N9 N N - adenine N3 H - xanthine (7H)-9H-imidazo[4,5-d]pirimidin - theofilline (unusual, biogenetic numbering) - theobromine Purine - caffeine 9H-purine derivatives purine bases
NH2 O OH N N N N N N N N N N N H N N H2N H H 2 H H adenine guanine RNS RNS DNS DNS
Vitamin B1 Thiamine, aneurine
Cl CH3 Eykmann (1896); absence of it may CH2 N N cause disease beri-beri. It was isolated at first by Funk from rice S CH2CH2OH bran. Peeled rice may cause beri-beri. H3C N NH2 HCl It gives positive thiochrome reaction Pteridine and its derivatives O folic acid COOH OH C 4 5 NH C H N N CH2 3 6 CH N N N 2 H 2 7 CH2 N N H2N N N 1 8 COOH pteridine pterine part p-aminobenzoic acid L-glutaminic acid
pteroyl group
Folic acid is an important vitamin: its N-formyl derivative builts the C1 unit in biosyntheses O O e c f N d N N N NH NH g b N N a N N O N N O H H benzo[g]pteridine alloxazine isoalloxazine
HO CH CH2 OH 3 CH2OH CH2 HO C H 8 9 1 2 H3C N O HO C H 7 HO C H NH 6 3 H3C N 4 CH2OH 5 10 O
Vitamin B2 ribitol take place by prosthetic groups of enzymes (flavoproteide enzymes, e.g., FAD) Compounds with pyrimido-pyrimidine ring system
COOCH3 H2C HN N anhydrous toluene + pyrimido-pyrimidine skeletone boiling S N CH3 N H CH3
COOCH3 COOCH3 HN N HN N stereoisomers S N N S N N H CH3 H CH3 CH3 CH3
regioisomers regioisomers
CH CH H3COOC 3 H3COOC 3 N N HN HN stereoisomers N N S N S N H CH3 H CH3 Pyrazine and its derivatives
H H H Cl Cl N N N NH3 HCl + EtO OEt EtO OEt EtO OEt HO OH HO O OH O O O O chloroacetaldehyde diethylacetal Et Et H H
H NH2 H3N N heating -2 NH Cl NH H N 4 3 2 N piperazine H
N N SN Y N N Y SE Y R NH O R' R N R' R N R' 2 dehydrogenation
' ' ' R NH2 O R R N R R N R Benzocondensed derivatives of pyrazine
O
NH2 O H N N KMnO4 HO + HO NH2 O H N N o-phenylene diamine glyoxal quinoxaline O
NH2 O CH3 N CH3 +
NH2 O CH3 N CH3 o-phenylene diamine dimethylglyoxal 2,3-dimethylquinoxaline
O
O O N NH N O 2 dyes
N NH2 N o-benzoquinone phenanthrene quinone phenazine
dibenzophenazine Compounds with two different heteroatoms I/ Oxazine and its derivatives
4 4 4 5 3 5 3 5 3
6 NH 6 N 6 N O 2 O 2 O 2 1 1 1 2H-1,2-oxazine 4H-1,2-oxazine 6H-1,2-oxazine
4 4 4 5 N 3 5 N 3 5 N 3 6 2 6 2 6 2 O O O 1 1 1 2H-1,3-oxazine 4H-1,3-oxazine 6H-1,3-oxazine
4 4 N N 5 3 5 3 Further derivatives: benzocondensed 6 2 6 2 derivatives O O partially saturated derivatives 1 1 2H-1,4-oxazine 4H-1,4-oxazine H N NH3Cl H2N + OH HO O dibenzo-1,4-oxazine phenoxazine
CH3O O CH3O C + Cl H CH3O CH3O O N N HCl 3,4,5-trimethoxy- benzoyl chloride CH3O C N O O O O NR CH3O H H morpholine 3 4-(3,4,5-trimethoxy- NH ClCl 3 benzoyl)-morpholine
O
NH N 1 2 1 R R R O R RO OR O
acetals of β-acetyl- aminoketones II/ Thiazine and its derivatives
4 4 4 4 H N N 5 3 5 N 3 5 3 5 3 6 NH 6 2 6 2 6 2 S 2 S S S 1 1 1 1 2H-1,2-thiazine 2H-1,3-thiazine 2H-1,4-thiazine 4H-1,4-thiazine
O OH cepham skeletone -NH2 O C O 7- amino-cephalosporanic acid CH3-C-OCH2 N O O S NH C CH2 CH2 CH2 CH C OH NH2
Cephalosporin C antibiotic drug Cephalosporium fungi species
Antibiotics: microorganisms (fungi) are producing against other microorganisms (bacteria) 10 H 9 H 1 N N o 8 2 many important drugs have 120 C phenothiazine ring system 7 3 + S (neuroleptics, 6 S 5 4 anthelmintic agents) phenothiazine
CH Na 3 H CH2 CH2 CH2 N N Cl N Cl N Cl CH3 NaNH2 Cl (CH2)3N(CH3)2 120oC S S S chloropromazin (Hibernal, Largactil, Plegomazin) neuroleptic drug
OCH3 O O CH3 C CH2 N CH2 CH2 CH2 N N CH2 CH2 O C OCH3 CH3 N N OCH3
S S
Ahistan (antihistaminic Frenolon (original Hungarian drug) agent) neuroleptic drug prepared at first by O. Clauder
There are phenothiazine dyes (methylen blue), and other benzocondensed derivatives. Compounds with three heteroatoms I/ Triazines
4 4 4 N 5 N 3 5 3 5N N 3 6 6 6 2 N 2 N 2 N N N 1 1 1 1,2,3-triazine 1,2,4-triazine 1,3,5-triazine / sym-triazine (vicinal) (asymmetric) (symmetric)
N N NH2 6 R NH2 NH2 3 HN C 3 HN C H H N formamidine 6 NaNH2 OH
NH2 3 Na2N CN + N sec. amines HO N NH2 + 6 RX
N NH
N N purine OH O
N N HN NH 3 HO CN cyanic acid HO N OH O N O H cyanuric acid Cl
N N HO 3 Cl CN cyanogen chloride Cl N Cl NH R 3 RNH2 cyanuric chloride N N
R NH N NH R
NH2 H2N C N addition Ca N C N H2N C N H2N C NH C N H2N-CN N N calcium cyanamide cyanamide NH H N N NH dicyandiamide 2 2 melamine important raw material of plastic industry
HCHO
aminoplast polymers Cl
Cl Cl NH NH O
H2N C NH CN H C OH N N
N
NH2 NH C NH C NH2 Neourofort diuretic agent NH NH prepared by O. Clauder at first
Cl N N N N 3 H N N triethylenemelamine against leukaemia, leucosarcoma Cl N Cl N N N [2,4,6-tris(aziridin-1-yl)]-1,3,5-triazine II/ Thiadiazines
5 4 H N Cl N 6 3 hydrochlorothiazide O diuretic agent 7 NH NH 2 S H2N S S 8 1 O O O 2H-1,2,4-benzo[e]thiadiazine
Cl NH2 Cl NH2 Cl NH2 Cl SO3H NH3
ClO2S SO2Cl H2N O2S SO2 NH2
H O Cl NH2 Cl N O H2N C NH2 CH3I N H2N O2S SO2 NH2 H2N O2S SO2 H
H
Cl N O Cl NH2
N OH H2N O2S SO2 CH3 H2N O2S SO2 NH CH3
R CHO
H Cl N R
N H2N O2S SO2 CH3 Cl NH2 Cl NH CHO Cl N HCOOH N H2N O2S SO2 NH2 H2N O2S SO2 NH2 H2N O2S SO2 H
Cl NH2 HCHO H H2N O2S SO2 NH2 Cl N
N H2N O2S SO2 H Cl N NaBH4
N H2N O2S SO2 H Compounds with four heteroatoms I/ Tetrazines
CH N N H2S red. N NH N H2N N N N NH N H2O2 ox. CH H2N
-2CO2
O O OK O OH EtOC CH N KOH N NH H N N N N N NH ox. N N N CH COEt O OK O OH O
N N N
N sym. tetrazine Heterocyclic compounds with seven- and eight-membered rings and their derivatives Heterocyclic compounds with seven- membered rings Nomenclature, some important derivatives
1 1 H 1 1 1 1 2 2 O 2 S 2 N 2 O S 2 Y O S NH 3 3 3
oxepane thiepane azepane 1,2-dioxepane 1,2-dithiepane Y=O 1,2-oxazepane Y=S 1,2-thiazepane
H 1 1 1 1 1 1 H 2 O 2 S 2 N 2 N N 2 N 2 3 3 3 H 4 4 5 H oxepine thiepine 1H-azepine 2H-azepine 3H-azepine 4H-azepine H H H 1 2 1 2 1 1 2 Y N N 2 N N N 3 3 3 N 3 5 N 4 Y=O 1,2-oxazepine 1H-1,2-diazepine 1H-1,3-diazepine 1H-1,4-diazepine Y=S 1,2-thiazepine
10 11 R Name 9 1
CH3 imipramin 8 2 (CH2)3N antidepressant
7 N 5 3 CH3 6 4 R carbamazepine C dibenzoazepine antiepileptics derivatives O NH2 10,11 Benzodiazepine derivatives Sedatohypnotica
CH2CH3 CH 1 3 O 6 4 CH3 9 NHCH3 1 7 5 CH3O N 2 N 8 3 3 N 7 8 7 CH3O N 2 Cl 5 N Cl N 4 9 1 6 4 O
chlorodiazepoxide diazepam tofisopam Elenium Grandaxin Seduxen OCH3 Librium Valium
OCH3
CH O 3 O 1 H 1 N N
7 7 N NO2 4 Cl 5 N O
nitrazepam clobazam Eunochtin Frisium
Grandaxin: anxiolitics free from sedative side-effects (e.g., it can be administered before driving) (J. Kőrösi at GYKI, EGYT, 1966. Hungarian patent) Preparation
CH3O CH2CH3 CH2CH3
CH3O CH3 CrO3 CH3O CH3 CH3COOH / H2O O CH3O O
OCH3
OCH3 OCH3 diisohomogenol H3CO
1/ H2N NH2 . HX 2/ HO
CH2CH3 CH3 CH3O N
CH3O N
tofisopam Grandaxin
OCH3
H3CO CH3 CH3 O CH3 NH H N N N Cl + Cl H Cl Cl H2N O NH
POCl3 P2O5
CH3 N
Cl N
medazepam Rudotel O EtO O H O NO NO N 2 2 C EtO C PCl5 Zn/HCl + CH2 CH2 HO C Cl NH Cl N C N O O O
O O NaOCH3 CH3Br EtO C PCl5 EtO C CH2 CH2 HO C Cl C CH3 O O O N
N O clobazam Frisium O C Cl H O
NH2 N C ZnCl2 2 + 2 Cl Cl
H C N O Cl
H OH N N
N H3O Cl O H N Cl HO Cl Cl
O NH2
O + OH Cl H2N
Cl Cl O NH NH NH C 2 2 C CH2Cl CH2Cl H2NOH O O NOH NOH Cl - H2O Cl - HCl Cl
- HCl H CH3 NH N Cl N CH2NHCH3 N CH2Cl + CH3NH2 N N Cl Cl N O - HCl Cl O - CH3NH2 O
NHCH3 N C CH2Cl
Cl NOH
CH3 H H NH N N N CH3 Cl
Cl N Cl N O O
Chlordiazepoxide Br O
H O O 4 H Br 4 H O N N 5 NH2 N 5 3 3 6 6 2 2 7 SH 7 OH CH3 O S O 1 CH3 1 1,4-oxazepine derivative 1,4-thiazepine derivative
O R R H NH2 + N O OH H2N O N + O R Br SH + S SH S Br SH SCH2COOH S SOCl2 + ClCH2COOH O NH NH 2 2 NH O O O
S SH SCH2CH2NH2
+ BrCH2CH2NH2 O O N Ph Ph Ph
R R SH O S +
NH2 RO N O H O CH3 N O N O CH3 C C N Cl N NH Cl + S N S H
O POCl3 Cl C Cl CH3 clothiapin NH2 Cl N antipsychoticum
S N N Cl
S H3C CH3 N
O O H O N (CH3)2NCH2CH2Cl N OH (CH3CO)2O OCCH3
S K2CO3 S
OCH3 OCH3 diltiazem antihypertensive agent for treatment of heart disease and antiarrhythmics Heterocyclic compounds with eight- membered rings Azocane / Diazocane derivatives
Thiocane derivatives
CH2 CN CH2 CH2 NH2 NH N N
Cl CH2 CN LiAlH4 - HCl azocane NH2 H3C S C HSO4 NH2 - CH3SH S-methylthiuronium hydrogensulfate
NH
CH2 CH2 NH C N NH2
guanethidin blood pressure reducing (antihypertensive) agent