Aromaticity and Conditions. Neutral and charged homo- and hetero aromatic systems. Electrophilic aromatic substitution reaction its mechanism and basic cases. Substituent effects in electrophilic substitution reactions to the rate (reactivity), directing rules (regioselectivity). Electrophilic substitution reactions of five- and six-membered heteoaromatic compounds. Addition reactions. Reaction of aromatic hydrocarbons containing alkyl side chain, the benzyl type reactive intermediates. Some polycyclic aromatic hydrocarbons. Aromatic compounds and their classification Formally, cyclic compounds containing conjugated double bonds (and non-bonding electron pairs) - BUT itself is not a sufficient condition for aromaticity Aromatic compounds - characteristic chemical properties (in spite of unsaturation no addition reaction, BUT substitution reactions) + Anomalous NMR spectroscopy behaviour Classification 1. Homo aromatic compounds - carbocyclic (carbon atoms only!) 1.1. Monocyclic homo aromatic compounds - substituted benzene derivatives Mostly trivial or semi-trivial names (BUT the suffix is often misleading)
benzene toluene xylene styrene phenol anisole aniline xylidine (o-, m-, p-) (o-, m-, p-)
Some important groups 1.2. Polycyclic homo aromatic compounds 1 1.2.1. Isolated polycycles Ar-(C)n-Ar
n = 0 Biphenyl and its derivatives
E conjugation interaction between electron system of the two rings: coplanar nature? No! In gas and liquid phases decreasing overlap due to the van der Waals repulsion 90o 180o 270o o 360 between o, o'-hydrogens n ≥ 1 Aryl-substituted alkanes Consequence: Atrop isomerism
Trityl cation (radical, anion) very stable. Reason: electron delocalization on 19 C Resonance structures of trityl cation 1.2.1. PAH: Polycyclic aromatic hydrocarbons: Condensed polycyclic - rings connected through two points (anellation points) Linearly condensed Angularly condensed
naphthalene anthracene phenanthrene coronene
Trivial names: special numbering: reason: highlighted position with different reactivity
2. Heteroaromatic compounds ≥ 1 hetero atom (mostly O,S,N) in the ring – BUT! not all heterocyclic or unsaturated heterocyclic compound is heteroaromatic! Classification according to : • ring size (most important: 5 and 6-membered) • type and numbers of heteroatoms (most important: systems with 1 and 2 heteroatoms) Nevezéktan – itt is sok triviális név
furan thiophene pyrrole pyrasole imidazole isoxazole oxazole pyridine pyrimidine Systematic nomenclature of heterocyclic compounds Hantzsch-Widman (it can be used for each heterocycle )
Element oxygen sulfur nitrogen priority order increasing from right to left Prefix Oxa Thia Aza Ring Size 3 4 5 6 7 8 9 10
Suffix: Unsaturated irene ete ole ine epine ocine onine ecine Saturated irane etane olane inane epane ocane onane ecane • The terminal "e" in the suffix is optional though recommended. • Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine", "etidine" & "olidine" suffix. • Unsaturated nitrogen 3-membered heterocycles may use the traditional "irine" suffix. • Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered unsaturated heterocycles is prevented by their former use for similar sized nitrogen heterocycles. • Established use of oxine, azine and silane for other compounds or functions prohibits their use for pyran, pyridine and silacyclohexane respectively. Aromaticity and its requirements - starting point: benzene Discovery: Faraday (1825) - whale oil pyrolysis, naming: Liebig, molecular formula (C6H6): Mitscherlich Special Features: • There is no detectable unsaturation • Mono-substituted single all hydrogen equivalent • one 1,2 - (or 1,3 - or 1,4 -) disubstituted product all carbon equivalent (There are only three di-substituted products); ideas for structure:
Exists! Spectroscopic studies: plane six-membered ring, Exists! prismane symmetrical structure with equivalent C-C and C-H Benzene: dC-C = 0.140 nm, dC-H = 0.108 nm bonds, C-C bond order between 1 and 2! dC-C = 0.154 nm, dC=C = 0.134 nm Requirements for aromaticity: E The simplest model: 6 + bonds, ‚continuous ’ e-flow in the, 6 system, 6-centered MO Not a simple conjugation, totally symmetric electron distribution! 2 (i vagy i )
„ Benzene is not cyclohexa-1,3,5-triene …” Extra stabilization energy (empirical resonance energy)
= Ecyclohexa-1,3,5-triene - Ebenzol = 147 kJ/mol (but this value depending on model!!)
Robinson-ring (1925) - only good for benzene, for polycyclic aromatic compounds it is misleading
Evidence - hydrogenation
Heat of hydrogenation: difference is 149 kJ / mol
far exceeding a simple conjugation stabilization energy gain! Something more… Representation of extra stability associated with aromaticity with resonance structures
Note: resonance forms very often are fictitious / not representing the current structure forms Requirements for aromaticity 1. The molecule is cyclic 2. The molecule is planar (all atoms in the ring lie in the same plane, sp2 hybridised C)
3. The molecule is fully conjugated (pz orbitals at every atom in the ring) 4. The molecule has 4n+2 π electrons (n=0 or any positive integer, Hückel’s rule) Other versions for formation of aromatic systems 1.1. Charged homoaromatic systems (Hückel’s rule, n = 1) sp3 → sp2 rehybridisation: aromatic system Cyclopentadienyl anion Resonance structures – show a completely symmetrical, smooth charge distribution
Evidence: unusually strong CH acidity of cyclopentadiene Realization in case of a cation - cycloheptatrienylium (tropylium) ion
Note: the number of atoms in the ring has no significance in terms of the aromaticity! The electron distribution is completely Empty p z smooth on carbon atoms of the ring orbital Resonance structures:
1.2. Polycyclic homoaromatic hydrocarbons (Hückel’s rule, n > 1) PAH („polycyclic aromatic hydrocarbons”)
naphthalene phenanthrene anthracene chrysene tripnenylene n = 2 n = 3 n = 3 n = 4 n = 4 But! -electron cloud is not symmetric, different bond lengths, different electron density decreasing resonance energy (stabilization energy) Resonance E: 152 255 385 351 (kJ/mol) Per ring 152 127.5 128.3 117 2. Aromaticity of heteroaromatic compounds 2.1. Five-membered heteroaromatic compounds Source: March, Advanced Organic Chemistry The simplest case: ✓One heteroatom (O, N, S):a Formal e- densities common characteristic: non bonding e-pairs ✓sp2 hetero atoms which participates in 6 system with one nonbonding e-pair by resonance structures: ✓Non-symmetric charge distribution, reduced aromatic character - the electron density is decreased on the heteroatom, while on the C-s it is increased „electron rich” heteroaromatic system Resonance E: 149 68 122 90 (kJ/mol) The less aromatic five-membered system! Insertion of further heteroatoms into the ring: the preservation of aromaticity is possible only with the insertion of "pyridine-like" nitrogen!
Nitrogen: two types sp2 hybrid state 1 1 1 2 1 1 2 1 „pyrrol-like”: h1 h2 h3 pz „pyridine-like”: h1 h2 h3 pz
2.2. Six-membered heteroaromatic compounds
Pyridine: analogous structure to benzene, the nitrogen heteroatom gives only one pz electron into 6 system nonbonding e-pair on hybrid orbital Bond length Due to differences in EN the electron distribution is distorted, (nm) but in this case the electron density is increased on the heteroatom and the electron density is decreased on C-s "Electron-poor" heteroaromatic system Benzene Pyridine
Energies: MO's are similar to one of benzene, but! the equivalence of doubly degenerated orbitals disappears. Highly aromatic system, resonance energy: 117 kJ / mol
Resonance structures of pyridine:
Further "pyridine-like" nitrogen can be inserted into the six-membered heteroaromatic ring. Oxygen and sulphur heteroatoms can exists only as positively charged in the six-membered heteroaromatic ring! 1. Acid-base properties
2 Acidity: weak CH acidity (pKa 36), reason: sp carbon has higher EN order of acidity: R-H < Ar-H < RC≡C-H after deprotonation nonbonding e-pair (negative charge) remains on sp2 hybrid orbital no interaction with the -electrons, there is no stabilization effect so less favoured Basicity: due to the presence of -electron cloud weak -donor bases so Lewis acids can attack it
2. Electrophilic aromatic substitution (SE) Starting point: Due to its -donor base character (similar to alkenes) it attacks electron-deficient particles, primarily electrophiles. First step: formation of -complex, E is not yet linked to any carbon atom only interaction with the -cloud (some debates this idea…) Step Two: disorganisation of 6 system, formation of -complex (Whelan complex); the electrophile is linked to a carbon atom But! By the formation of complex the -sextet is disrupted, the stabilization energy arising from aromaticity is lost large G‡ necessary to apply strong electrophiles and / or the catalyst Alternatives for the second step: addition or substitution Re-aromatisation is favoured: substitution occurs
Summarizing…
Usually the formation of complex is the rate-determining step The most important electrophilic aromatic substitution reactions 2.1. Halogenation The formal electrophile: Hlg Function of catalyst: generation of Hlg
Hlg: usually Cl, Br Lewis acid: AlHlg , FeHlg , BF , etc. 3 3 3 „push-pull” mechanism
2.2. Friedel-Crafts alkylation – formal electrophile: alkyl cation (carbenium ion, R)
„push-pull” mechanism Function of catalyst: generation of R
Lewis acid: AlHlg3, BF3, SnCl4, SbF5, etc.
Note: alkyl cation (carbenium ion) can be generated in some other way - industrial significance
Proton source: HF, H2SO4 2.3. Friedel-Crafts acylation – formal electrophile: acylium ion (RCO)
Function of catalyst: generation of RCO
Acylating agents: acid chloride or acid anhydride Easy synthesis of aryl ketones: di-acylation has low risk, high selectivity 2.4. Nitration – formal electrophile: nitronium cation (NO2 ) Essential difference: electrophilic generation with Bronsted acid
Fuming nitric acid di-and poly nitro compounds. (Note: the nature of nitration reagent depends on the group G) 2.5. Sulphonation – electrophile: sulfur trioxide (reagent: fuming sulfuric acid, oleum) Difference: sulfonation is a reversible reaction
Synthetic applications: aromatic sulfonic acid cooked with dilute acid can be desulfonated
The 2.1-2.5. reactions the most important types of SE, a lot of other SE process are known! Substitution of a polycyclic aromatic compound Starting point: non symmetric charge distribution, decreasing stabilization energy (lower aromaticity) greater reactivity, substitutions without catalyst! Regioselectivity Bromonation without catalyst, its reactivity is 105 times faster compare to benzene
Preferred reaction pathway Similarly: easy chlorination, nitration, Friedel-Crafts acylation Anthracene, phenanthrene - even easier reactions In case of more rings: Ad + E mechanism appears SE reactions of substituted benzene derivatives - reactivity and regioselectivity
3 competitive reactions ortho meta para Nitration isomers Rates activating
o,p Rate
deactivating m effect Directing
Substituents (G) can be classified 1. According to reactivity (rate)
•activating (kPh-G / kPh-H > 1) – but! Activates each position (o-, m-, p-) •deactivating (kPh-G / kPh-H < 1) – but! Deactivates each position (o-, m-, p-)
2. According to directing effect (regioselectivity) •I. order (o-, p-product dominates) •II. order (m-product dominates)
Two independent but mutually complementary phenomenon (controlled by different factors) I. order
II. order
Classification of substituents Competitive reactions - according to TS energy level, based on the Hammond principle an approximation of stabilities of -complex
Possible -complexes and their resonance structures:
If G has non-bonding e-pair (+ M effect!!!)
If G has non-bonding e-pair (+ M effect!!!) Overall, electron-donating substituent more stable -complex (higher reactivity) Overall, the electron-withdrawing substituents less stable -complex (lower reactivity) For a given substituent due to the more stable structure -complex increased interest among products! Effect Reactivity (rate) Regioselectivity (position) +I +M activation I. order (o/p) -I +M -I < + M activation I. order (o/p) -I +M -I > + M deactivation I. order (o/p) -I -M deactivation II. order (m) For the electron density of aromatic ring (for the stability / reactivity of -complex) the inductive and mesomeric effects are collectively responsible. For the stability of a given - complex (dicerting, regioselectivity) solely the mesomeric effect is responsible: - o,p-dicerting + M effect (reason: one more resonance structure) See next page!!! 3. Other reactions 3.1. Oxidation Starting point: reactivity is increased by decreasing aromatization Benzene: very low reactivity
– KMnO4, CrO3, H2O2, OsO4: no reaction Important chemical starting material: polyester copolymer resins, plastics, varnishes, pesticides + ideal dienophile Diels-Alder reactions
Oxidation of polycyclic aromatic compounds - due to reduced aromaticity increased reactivity
Important chemical starting material: polyester copolymer resins, plastics, varnishes, pesticides
highlighted 9,10-positions reactivity 3.2. Reduction
Only forceful conditions, intermediates can not be isolated The decreasing stabilization energy reduction becomes easier and the maximum number of intact six 6 system be retained. 3.3. Diels-Alder reaction Formal diene structure. Benzene does not react, naphthalene can react but with low yield. but! highlighted reactivity of 9,10 carbon atoms (the maximum degree of stabilization energy will be retained!)
Reaction of alkyl-benzenes – highlighted reactivity of benzyl position
benzyl C
benzyl
Reason: high stability of benzyl radical – delocalised system, resonance stabilisation
7 centered MO, 7 electrons 1. Acid-base reactions Reactions of Heteroaromatic Compounds 1.1. Basicity Azoles and azines: protonation through the non-bonding e-pair of N. Determining point: the non bonding e-pair is part of the six aromatic 6 system? „Pyrrole-like” N weak base „Pyridine-like” N stronger base
Terminating aromatic feature!
Furane – protonation on C-2 Diene and enol-ether property
Acid sensitivity, polymerisation
1.2. Acidity „Pyrrole-like” N weak Brönsted-acidity 2. Electrophile substitution (SE) 2.1. Five membered (-electron rich) heteroaromatic compounds
-electron-rich atoms, less aromatization energy than Formal e- density benzene increasing reactivity Reactivity order: pyrrole> furan> thiophene> benzene
Because of the high reactivity, different reagents can be used. 2-, or 5-substitution
Nitration: acetyl nitrate instead of HNO3 / H2SO4
Furan reacts as an enol ether
+ Sulfonation: py.SO3 complex (soft E ) instead of cc. H2SO4 2.1.3. Friedel-Crafts acylation Furan and pyrrole are instable in the presence of strong
Lewis acids (at the most BF3• Et2O, TiCl4, SnCl4)
More resonance structure, more stable -complex
2.2. Six membered (-electron deficient) heteroaromatic compounds – pyridine
-electron deficient C atoms, aromatic E is similar to benzene weak reactivity Further problems: because of he non-bonding e-pair of N it is Lewis base a -e-cloud and the non-bonding e-pair compete for E+, reagent and non-bonding e-pair compete for the catalyst weak reactivity Example for competition
Brönsted- basicity N-alkylation
Feature: For pyridine only a limited number of SE reaction, "brutal" conditions, poor yields
No reaction
Substitution in position 3 Explanation of regioselectivity (directing) in case of pyridine
Preparation of homoaromatic compounds
Basic compound (benzene, toluene, xylene, naphthalene…): from natural source • formerly coal - distillation, chemical treatment, fractionation
• Now: base crude oil - gasoline cracking, catalytic reforming of C6-C8 fraction (dehydrocyclisation) Substitute derivatives • Electrophilic substitution reaction of benzene, toluene, xylene then the subsequent modifications of the functional group
Example: aniline, phenol
Synthesis of alkylbenzenes Wurtz-Fittig-reaction
Friedel-Crafts alkylation – note: higher than C ≥ 3 it is unfavourable, mixture of products, and polyalkylation is also could occur Friedel-Crafts acylation then reduction