1. General Information Two Hetero-atoms: 1.1. Recommended textbooks N N N 1. 'Heterocyclic Chemistry', T.L. Gilchrist, 2nd Edition, Longman, 1992. N O S H 2. 'Heterocyclic Chemistry', J.A. Joule , K. Mills and G.F. Smith, Third Edition, Chapman imidazole oxazole thiazole and Hall, 1995. (1,3-diazole) (1,3-oxazole) (1,3-thiazole) 3. 'Aromatic Heterocyclic Chemistry', D. T. Davies, Oxford Chemistry Primers, 1992. 1.2. Nomenclature N N N N O S The heteroaromatics are typically described by trivial names and for the purposes of this H lecture course these will suffice. For those interested in the authoritative method of naming pyrazole isoxazole isothiazole such compounds they are referred to the recommendations published by the International (1,2-diazole) (1,2-oxazole) (1,2-thiazole) Union of Pure and Applied Chemistry which have been summarised in a review article [McNaught, A.D. Adv. Heterocycl. Chem. 1976, 20, 175]. A method which is in more common use and which comprises a hybrid of trivial and systematic names made up of 6-Membered Rings standard prefixes and suffixes has been described (the Hantzsch-Widman system). A good One Hetero-atom: introduction to this system can be found in Gilchrist, Chapter 11, pp 369. Except for the isoquinolines, numbering always starts from the heteroatom (as shown below for pyrrole). The most frequently encountered heteroaromatic systems are: NOS ++X- X- 5-Membered Rings One Hetero-atom: pyridine pyrilium thiapyrilium (azine) (oxinium) (thiinium) 4 3 5 1 2 N OS H N pyrrole furan thiophene N (azole) (oxole) (thiole) quinoline isoquinoline (benzo[b]azine) (benzo[c]azine) N OS H indole benzofuran benzothiophene (benzo[b]azole) (benzo[b]oxole) (benzo[b]thiole) 5 6 2. Introduction 2.2. Background and context 2.1. A few examples of important heteroaromatics About one-half of all known compounds contain a heterocyclic ring, and many of these, an aromatic heterocyclic ring. Heteroaromatics are found in very many of the products of both O NH2 NH2 primary and secondary metabolism as well as in many synthetic compounds of commercial H N N N N NN interest such as drugs, pest control agents, colouring agents, flavourings. They comprise the N basic building blocks for many new materials such as porphyrazines and semi-conducting N N O N N N S OH polymers, and as ligands for homogeneous asymmetric catalysis. Thus they are of vital N H Cl- adenine importance and (still) represent a very active area of current research. nicotine caffeine thiamin - vitamin B (RNA/DNA) 1 R O OMe 2.3. Ring Synthesis S Cl OH 2.3.1. General Comments N O N There are a (seemingly overwhelming) number of methods (each of which generally has it H N OOHO own name) for the construction of heteroaromatic ring systems, but the heteroaromatics are R = H; epothilone A Roseophilin: exhibits submicromolar typically synthesised by the pertinent use of a small family of well known reaction types: R = Me; epothilone B cytotoxicity against several human more active than taxol cancer cell lines and much easier to make! 1. Aldol Reactions 2. Michael Additions N O NHNH2 3. Enamine Reactions NO2 2Br- 4. Condensation Reactions Me NS 2 NNHMe N O H Isoniazid: Ranitidine: extremely successful drug used N 2.3.2. Type I and Type II used for treatment for treatment of stomach ulcers of tuberculosis paraquat: As far as disconnection strategies go almost every angle has been explored, but the majority used as a herbicide of the most efficient syntheses can be classified as either "Type I" or Type "II": H Pr Pr H Type I C4 fragment + X (for a five membered ring) N N O N N N Pr C5 fragment + X (for a six membered ring) O O N NMe2 NN N Zn N PPh2 NMe Type II C2 fragment + C2X (five) Pr 2 MeO OMe N N N O C3 fragment + C2X (six) N N atropisomeric P-N In these cases, X is a heteroatom and usually a nucleophile, hence the C-fragments must be chelating ligand for Pr Pr electrophilic. Ligand for the osmium catalysed asymmetric catalysis Sharpless Asymmetric dihydroxylation seco-Porphyrazine: Efficient 1 2.4. General properties of 5-membered rings O2 Photosensitizer Furan, thiophene and pyrrole are aromatic by virtue of their planarity and the uninterrupted Bu Bu Bu Bu cycle of p-orbitals containing six electrons: four from the two double bonds and two from a SiMe3 lone pair of the heteroatom (i.e. obeys Hückel's 4n + 2 rule). However, the extent of Me3Si SSS S S S B aromaticity (as determined by resonance energies, see below) for these compounds is SSS S S S SiMe Me3Si 3 different from that of benzene (which undergoes electrophilic substitution reactions) and this Cr(CO)3 Bu Bu Bu Bu "borabenzene" is the determining factor in their chemistry (vide infra). An example of an orthogonally fused conjugated oligomer comprised of thiophene units as a potential molecular scale electronic device 7 8 Resonance Energies (experimental and theoretical values): 3. Furan (read this before lecture 2) Furan 88 KJmol-1 3.1. General Pyrrole 100 KJmol-1 The aromatic furan system is a familiar motif in many natural products, occurring widely in Thiophene 130 KJmol-1 secondary plant metabolites. The extremely important Vitamin C (ascorbic acid) is formally Benzene 151 KJmol-1 a 1,2,3-trihydroxyfuran, but assumes a tautomeric lactone form. [This is a first clue towards the somewhat "lacklustre" aromaticity displayed by furans]. Furan is derived commercially from the decarbonylation of furfuraldehyde which in turn is readily available from the action Electron Distribution / Polarisation of mineral acids on vegetable matter (e.g., oats, maize etc) and hence the name furan (furfur is Latin for bran). σ-framework: π-framework: inductive effects mesomeric effects HO OH (weak) (strong) X HO CHO O O O Overall C-framework is electron rich, the heteroatom (X) is electron deficient HO H Furfuraldehyde Vitamin C Reactivity Consideration of the electron distribution within the π-framework shows that the 5-membered heteroaromatics should be susceptible to electrophilic substitution processes. Indeed, they undergo electrophilic substiution much more readily than benzene and attack is predominately in the 2-position (due to relative stabilities of Wheland 3.2. Physical and spectroscopic properties intermediates). Low boiling (b.p. 31˚C), toxic liquid. Planar with 6π-electrons and hence aromatic. Bond Other facets of their reactivity, including metallation, which are generally not lengths show intermediacy between single and double bonds characteristic of aromatics (cf available to benzene derivatives will be examined later in the course. typical bond lengths: C-C single bond, 1.53Å, isolated C=C bond, 1.34Å; aliphatic C-O bond, 1.43Å; benzene C-C bond 1.39Å). J = 3.3 Hz 1.44Å δ = 6.19 ppm H H H dipole moment: 1.35Å J = 1.8 Hz 0.72 D (due to lone pair on oxygen) H = 7.26 ppm O δH 1.37Å Chemical shifts consistent with aromatic compound but resonances at somewhat higher field as expected from increased electron density on carbon atoms. 9 10 3.3. Syntheses and Reactivity 3.3.1. Paal-Knorr (Type I) Syntheses: Two classical methods: 1. Paal-Knorr Synthesis (Type I). Very general "H+" OH Involves the dehydration of 1,4-dicarbonyl compounds (γ-hydoxy-α,β-unsaturated R R R O enones can also be employed) under non-aqueous acidic conditions. R O R O O OH R + H 2. Feist-Benary Synthesis (Type II). Very general Involves an aldol addition of a (deprotonated) 1,3-dicarbonyl compound to an α- -H2O halocarbonyl moiety followed by subsequent ring closure. Commercial process: R R O + H+ Xylose H Oat Husks fufuraldehyde Many products (pentoses) steam distill 3.3.2. Feist-Benary (Type II) Miscellaneous methods: There are many, many, other elegant and efficient routes to access furans (browse through any recent copy of the journal Heterocycles) and these cannot be discussed at length H EtO C OH here. Some representative examples will be given. EtO2C EtO2C OH 2 O "OH-" H Reactivity of furans: O O Cl O Due to the relatively small aromatic stabilisation in furan [resonance energy 88 Cl -1 KJmol ] the chemistry of furan is not only that of electrophilic substitution but also that of -H2O the other functionalities: enol ether and diene chemistry. EtO2C "normal" electrophilic substitution 2-substituted furans O O but enol ether chemistry ring opened adducts/polymeric material EtO CR EtO2C 2 O RCl - EtO C R EtO2C R "OH " 2 -H2O O O O OH diene chemistry O O O bicyclic adducts e.g., Diels-Alder O 11 12 3.3.3. Representative example of a curious furan synthesis: 3.4.2. Nitration + PPh AcONO2 O 3 NO2 NO2 EtOHC CHPPh3Br O O AcO O O - H H OH NaH OEt AcO O py - Ph3PO - EtOH NO O 2 O 3.4.3. Sulphonation 3.3.4. Miscellaneous N O BF 3 SO Et Et 3 O Et O OH O HO S SO H O 3 O 3 3.4. Reactivity 3.4.4. Halogenation 3.4.1. SEAr Recap Reactions with Cl2 or Br2 result in polyhalogenation. Mild reaction In the absence of a nucleophile Wheland intermediates loose a proton conditions required to give the re-aromatised products. -HBr Electrophilic aromatic substitution on furan requires very mild non- Br2/dioxane Br acidic reagents. 0 + - O C Br H Br 1. Nitration using NO2BF4 or AcONO2 O O O 2. Sulphonation with py/SO3 complex 3. Halogenation 4. Alkylation not generally practicable 5. Acylation (Vilsmeier-Haack formylation) or using RCOCl in the presence of mild Lewis acids such as BF3, SnCl4 6.