Beruflich Dokumente
Kultur Dokumente
AROMATICKÉ
HETEROCYKLY
(II.)
1
1,2- & 1,3-Azoles – Nomenclature
1,2-Azoles Monocyclic: 1,3-Azoles
Bicyclic:
2
1,3-Azoles – Bioactive molecules
• Histidine (His) is an essential amino acid in humans and acts as a common coordinating ligand in metalloproteins.
• Histamine is produced by basophils and mast cells, triggers the inflammation and local immune responses.
• Thiamine is a water-soluble B1-vitamin synthesized only in bacteria, fungi, and plants, thus essential for mammals.
NATURAL
PRODUCTS
• Cimetidine (Tagamet®) is a histamine H2-receptor antagonist used for the treatment of heartburn and peptic ulcers.
• Metronidazole (Flagyl®) is an antibiotic, amebicide, and antiprotozoal drug used for anaerobic bacteria and protozoa.
• Rosiglitazone (Avandia®) binds to the PPAR receptor, acts as an insulin sensitizer and is used as an antidiabetic drug.
SYNTHETIC
DRUGS
3
1,3-Azoles – Comparison of aromaticity
• Aromaticity and bonding in oxazole, imidazole, and thiazole were investigated through the behavior
of the isotropic shielding σiso(r) within the regions of space surrounding these molecules.
• Aromaticity decreases in the order thiazole > imidazole > oxazole suggesting the detrimental effect of
second heteroatom with O exerting the strongest effect probably due to its highest electronegativity.
LEAST
AROMATIC
MOST
AROMATIC
K. E. Horner, P. B. Karadakov: Shielding in and around Oxazole, Imidazole, and Thiazole: How Does the Second Heteroatom
Affect Aromaticity and Bonding? (J. Org. Chem. 2015, 80, 7150−7157). 4
1,3-Azoles – Imidazole – Structure and properties
• Imidazole is a planar, 5-membered aromatic heterocycle (6pe) with the sp2-nitrogen lone pair lying in the ring plane.
• Imidazole, like water, is both a good donor and acceptor of H-bonds. The imine nitrogen donates an electron pair
and the N-hydrogen, being appreciably acidic, is an acceptor – this is the mode of action of several human enzymes.
p-electron
densities
• Imidazole (pKHA 7.0) is more basic than pyrrole (pKHA 0.4) and/or pyridine (pKHA 5.2) due to the amidine-like resonance.
• Imidazole is also more acidic (pKA 14.5) than pyrrole (pKA 17.5) as both N-atoms share the charges between each other.
• N-unsubstituted imidazoles are subject to tautomerism, and the rapid equilibrium hampers the isolation of isomers.
• In some pairs, one tautomer predominates, for example 4(5)-nitroimidazole favours the 4-nitro-tautomer by 400:1.
5
1,3-Azoles – Imidazole – Reactivity – SEAr (Nitration)
• C2-substituted imidazoles easily undergo SEAr (e.g. nitration) producing the equilibrating mixture of tautomers.
SE of imidazole: 5 4
1 3 3 1
Mechanism:
Application:
6
Metronidazole
1,3-Azoles – Imidazole – Reactivity –
SEAr (Halogenation, Sulfonation)
• (1-Alkyl-)-Imidazoles are brominated („SE“) with remarkable ease at all free nuclear positions including C-2.
• Substitution generally occurs first at C-2, but SE proceeds further yielding 2,4,5-tribromoimidazole as end-product.
• The first step involves an AdE of Br2 to imine nitrogen, then addition of Br- at C-2, and finally elimination of HBr.
• Imidazole can be sulfonated (SE) with concentrated sulphuric acid at elevated temperature at C-5 position.
• Thiazole is much less reactive, generally requiring higher temperatures and HgSO4 as catalyst for any
reaction to take place. On the other hand, electrophilic oxazole sulfonations are unknown up to date.
7
1,3-Azoles – Imidazole – Reactivity – N-Alkylation/Acylation
• Imidazole is easily quaternised (N-alkylated) at the imine nitrogen with alkyl halides (RX). The intermediate
is a protonated N-alkyl-imidazole, which looses its N-hydrogen to unreacted imidazole (acting as a base).
• The subsequent reaction produces the mixture of imidazolium, 1-alkyl- and 1,3-dialkyl-imidazolium salts.
• Due to interaction between the basic nitrogen and Lewis acid, Friedel-Crafts acylations of azoles are unknown.
• However, the aroylation of imidazole with benzoyl chloride in the presence of base (Et3N, NaOH) is feasible.
• N-acylation of imidazole yields N-acyl-imidazoles via deprotonation of initially formed N-3-acyl-imidazolium salts.
• The N-acyl-imidazoles are hydrolytically unstable and are rapidly deacylated even by standing on moist air.
9
5-Membered azoles with multiple N-atoms –
Triazoles – Structure and Properties
• There are two groups of triazoles – 1,2,3- and 1,2,4- – according to the relative positions of N-atoms within the ring.
• Both 1,2,3- and 1,2,4-triazole contain one „pyrrole-like“ N-atom and two „pyridine-like“ N-atoms in their structure.
• Both tautomerise (with 1,2,3-triazole the tautomers are identical) and both are deprotonated to the delocalised anion.
3
2
1
2 1
• Fluconazole (Diflucan®) is a 1,2,4-triazole antifungal drug used in the treatment and prevention of fungal infections.
10
5-Membered azoles with multiple N-atoms –
Synthesis of 1,2,3-triazoles via cycloaddition
The disconnection of 1,2,3-triazoles via cycloaddition requires an alkyne and an azide which can be combined in 2 ways:
R R
R R
+ vs. +
N N N N
R´ R´
R´ N N N N N R´ N N N
1,4-disubstituted 1,5-disubstituted
1,2,3-triazole 1,2,3-triazole
• The 1,3-dipolar cycloaddition (1,3-DCA) is highly exothermic, but the high activation barrier is responsible for a very low
reaction rate, even at elevated temperature. Another drawback is the formation of two regioisomers, as the two possible
HOMO-LUMO interactions of the substrates are closely related in terms of energy. The thermal reaction therefore often
gives approximately 1:1 mixtures of both the 1,4- and the 1,5-disubstituted regioisomers of desired 1,2,3-triazoles.
Rolf Huisgen
(1920)
Inventor of 1,3-DCA
Münich University
„Click Chemistry“
((
• The copper-catalysed azide-alkyne cycloaddition (Cu-AAC) features an enormous rate acceleration of 107 to 108 compared
to the uncatalysed 1,3-DCA. It succeeds over a broad temperature range, is insensitive to aqueous conditions and a pH
range over 4 to 12, and tolerates a broad range of functional groups. Pure 1,4-disubstituted triazoles can be isolated by 11
simple filtration or extraction without the need for tedious chromatography or time-consuming recrystallisation.
5-Membered azoles with multiple N-atoms –
„Click Chemistry“
The term „Click Chemistry“ was coined by K. Barry Sharpless and describes chemistry tailored to generate molecules
quickly and reliably by joining small units together in a biomimetic manner (Ref.: Angew. Chem. Int. Ed. 2001, 40, 2004).
• The isosteric replacement of -CO2H group for a tetrazole reduced the gastric irritation while retaining the NSAID activity.
13
5-Membered azoles with multiple N-atoms –
Synthesis of tetrazoles via 1,3-dipolar cycloaddition
• The disconnection of tetrazoles with 1,3-DCA requires nitrile (RCN) as a common component. The other one would
be either hydrazoic acid (HN3) for the neutral compound or the azide (N3-), thus leading to an anion of the tetrazole.
• The reaction works well if an ammonium chloride buffered mixture of sodium azide and the nitrile is heated in DMF.
• The reagent is ammonium azide (NH4+N3-) and the reaction occurs faster with electron-withdrawing substituents.
• First, the anion of the tetrazole is formed but subsequent neutralisation with acid finally gives the free tetrazole.
• Mechanism involves the “electrophilic activation” of RCN through H-bond formation between the cuttlebone and nitrile.
• Cuttlebone as a natural low cost heterogeneous catalyst with high porosity, high flexural stiffness, high compressive
strength and high thermal stability affords 5-substituted-1H-tetrazoles rapidly with high efficiency.
(85-98%)
15
5-Membered azoles with multiple N-atoms –
Tetrazole-based explosives
• 5-Aminotetrazole is used as a high-speed inflator in car airbags via a controlled explosive liberation of nitrogen.
16
5-Membered azoles with multiple N-atoms –
Tetrazole-based explosives – 1,1´-Azobis(tetrazole)
18
Zhrnutie: Syntéza aromatických heterocyklov
▪ Cykloadície (tetrazol...)
▪ Fischer (indol...)
19
Zhrnutie: Syntéza aromatických heterocyklov
Vytvorenie heterocyklu iónovými reakciami
20
Zhrnutie: Syntéza aromatických heterocyklov
Vytvorenie heterocyklu pericyklickými reakciami
21
Zhrnutie: Syntéza aromatických heterocyklov
Modifikácia už existujúceho heterocyklu - SE
22
Zhrnutie: Syntéza aromatických heterocyklov
Modifikácia už existujúceho heterocyklu – SN a lítiácia
23
SYNTÉZA HERBICÍDU
PACLOBUTRAZOLU
24
Efektívny a účinný herbicíd
OH
N
N Cl
N
バカナエ (bakanae)
CO2H
HO2C H
H3C OH
HO
H
OH O
O H
N
+ N
N N N
N Cl N X
N N
Br O OH
Cl
NaBH4
N N
N Cl MeOH N Cl
NaH, THF
N N
27
SYNTÉZA VÝBUŠNINY
ANTA
28
Vysokoúčinné explozívum
O2N
N
N
N NH2
H
ANTA (5-amino-3-nitro-1,2,4-triazol)
29
Príprava ANTA – Syntézy
•Starting from commercially available 5-amino-1,2,4-triazole, the originally developed three-step synthesis is the most
direct route to ANTA. However, this sequence suffers from variable and very poor yields (~ 20%) in the nitration step.
O2N O2N
N Ac2O, H+ N HNO3/AcOH N 10% HCl N
N N NHAc N N NH2
N NH2 N 0-25°C N NHAc reflux N
reflux H 5h H
H H 5h
1h
5-amino- (~ 20%) ANTA
1,2,4-triazole
•The alternative two-step synthesis of ANTA, starting from commercially available 3,5-diaminotriazole, employs
the problematic nitration first. However, its scale-up poses a challenge due to the presence of diazonium salts.
30