Aromatic and Heteroaromatic Chemistry Flashcards
Arenes
aromatic hydrocarbons (C and H atoms only in the ring)
Polyarenes
polycyclic aromatic hydrocarbons
Heteroarenes
aromatic compounds that contain also a heteroatom in the ring (N,O, S…)
regioisomers
constitutional isomers that have the same functional groups attached at different positions of the molecular backbone
Furfural
Furan-2-carbaldehyde is an important renewable non-petroleum based, chemical feedstock which can be converted into solvent, polymers, fuels, etc
Lignin
Class of organic polymers made by cross links among various phenolic precursors.
Has a structural role in plants (cell wall). After cellulose, it’s the most prevalent biopolymer and potentially a biofuel.
Aromatic system defined
cyclic, planar, fully conjugated and contains (4n+2) ⫪ electrons (Hückel’s rule n≥0)
Antiaromatic system defined
cyclic, planar, fully conjugated and contains (4n) ⫪ electrons (n≥1)
What are antiaromatic systems like?
they are destabilised, i.e. they are higher in energy, hence they are very reactive and rather unstable and often require isolation at low temperature
Annulenes
monocyclic hydrocarbon compounds with the maximum possible number of non-cumulated double bonds
Can annulenes be aromatic?
Annulenes can be aromatic, antiaromatic and non-aromatic - it depends on the number of their ⫪ electrons AND whether they are planar or not
Diamagnetic anisotropy
Different magnetic fields are found at different points in space due to fields induced by circulating electrons
What is the cationic intermediate in electrophilic aromatic substitutions called?
- Wheland intermediate
- Arenium ion
- σ complex
Why is the cationic intermediate in electrophilic aromatic substitutions higher in energy?
it is a resonance stabilised cation, but it isn’t aromatic
How does sulfonation vary with temperature?
- At high temp = thermodynamic products (reversible)
- At low temp = irreversible therefore kinetic products
How can sulfonation help a desired substituent be selective in position?
can be used to instal SO 3 H as a blocking group on the ring, then remove it by treatment with acid and heat
Why doesn’t fluorine react with aromatics?
the reaction is EXPLOSIVE therefore F is best to be introduced via thermal rearrangement of aryl diazonium tetrafluoroborate salts
Rate / reactivity: ELECTRON-WITHDRAWING SUBSTITUENTS
deactivating
Rate / reactivity: ELECTRON-DONATING SUBSTITUENTS
activating
Regioselectivity: ELECTRON-WITHDRAWING SUBSTITUENTS
m-directing
Regioselectivity: ELECTRON-DONATING SUBSTITUENTS
o,p- directing
Electronic effects: Properties of the inductive effect
- travel along σ bonds
- range: short distance
- origin: electronegativity
- symbol: I
Electronic effects: Properties of the mesomeric effect
- travel along ⫪ bonds
- range: long distance
- origin: resonance and conjugation
- symbol: M
How does electron-donating substituents affect electron density?
+ : electron-donating substituents increase electron density (+M, +I)
How does electron-withdrawing substituents affect electron density?
- : electron- withdrawing substituents decrease the electron density (-M, -I)
How can the transition state leading to the cationic Wheland intermediate be stabilised?
by electron- donating groups
- they lower the energy barrier for the S E Ar and result in easier electrophilic aromatic substitutions, occurring faster and under less forcing conditions compared to the reaction with benzene
Why are electron-withdrawing substituents (e.g. NO 2 ) meta-directing?
less favourable electrophilic attack leads to the most stable Wheland intermediate via the lowest-energy transition state
Why are alkyl groups o,p- directing?
they can form very stable tertiary carbocations which makes the Wheland intermediate lower in energy and so more accessible
(para is preferred over ortho due to the absence of steric clashes)
Why are alkoxy groups o,p- directing?
the 4th resonance form is possible due to the +M effect of the substituent which lowers the energy of the Wheland intermediate
(meta attack doesn’t have a 4th resonance form so is less stable).
What is more acidic a phenol or alcohol?
a phenol - has lower pKa values
How does the acidity of anilines vary from amines?
Anilines are less basic than amines
(they have a lower pKa)
How can you reduce anilines reactivity in S E Ar?
turn it into an amide
3 possible mechanisms for nucleophilic aromatic substitutions that can occur on specially substituted aromatic rings
- S N Ar (classical nucleophilic aromatic substitution via addition-elimination)
- Diazonium salts: S N 1 (via aryl cation), Sandmeyer reactions and synthesis of azo compounds
- Benzyne and arynes (elimination-addition mechanism)
Requirements for a successful S N Ar reaction
1) Nucleophile: O (hydroxide & alkoxides), N (amines, azide anion), S (thiolates), cyanide
2) Leaving group: a halide - order of reactivity: F»_space; Cl ∽ Br»_space; I
3) On the substrate: a strong –M (NO &2 , SO 2 R, SOR, CN, COR) or –I group (CF 3 ) ortho and/ or para to the leaving group (need a strong EW group)
S N Ar: mechanism
What is the intermediate called?
the anionic intermediate is also called Meisenheimer intermediate
(it’s conjugated but not aromatic)
S N Ar: mechanism
What is the slowest step?
formation of the meisenheimer intermediate
S N Ar: mechanism
Conditions of the leaving group
Since the loss of the leaving group (halide) X is not the rate limiting, the leaving group ability of X does not matter
S N Ar: mechanism
Which groups make the intermediate most stable?
The more electronegative the halide, the more stable the Meisenheimer intermediate, and - according to the Hammond postulate - the lower the energy for the TS leading to it.
→ F is better than all other halides as a leaving group
S N Ar: mechanism
Useful tip to prepare substituted arenes
having a group ortho or para to NO 2
(add HNO 3 and H 2 SO 4 to get the NO 2 group)
How is most of styrene produced?
80% of styrene is produced by dehydrogenation of ethylbenzene
conditions: FeO 3 , 600ºC
What is the most common alternative to making styrene?
the most common alternative is the styrene monomer / propylene oxide process
What is polystyrene?
styrene readily polymerises to polystyrene by a FREE RADICAL CHAIN MECHANISM
What happens in the polymerisation of styrene?
the C-C ⫪ bond of the vinyl group is broken and a new C-C σ bond is formed
What allows for complete oxidation of the benzylic position?
if there is at least 1 benzylic H atom in the starting material
Directed Ortho Metalation: Conditions for deprotonation of arenes ortho to a directing group
- deprotonation performed by a strong lithium base (BuLi, LDA), so that Li replaces H.
- the directing group must possess a lone pair to coordinate the lithium cation
How are reductions of alkenes and alkynes generally performed?
Heterogeneous hydrogenations - reduction performed using H 2 and an insoluble metal catalyst
Typical metal catalysts for heterogeneous hydrogenations
Pd, Rh, Pt, Ru dispersed on the surface of a metal (or carbon based) support
Two hydrogenations that can occur with poisoned catalysts
- Semi-hydrogenation pf alkynes to Z alkenes using Pd Lindlar
- Hydrogenation of acyl chlorides to aldehydes (H 2 , Pd/BaSO 4 )
Hydrogenolysis of benzylic bonds
cleavage of ArCH 2 –O and ArCH 2 –N bonds using H 2 and Pd/C
Reduction of nitroarenes
reduction of nitroarenes to anilines using H 2 and Pd/ C
Importance of the H 2 and Pd/ C as catalysts
- the H 2 will be absorbed on the surface of the Pd catalyst
- the mechanism of catalysis is stepwise, with a series of intermediates that can react with each other, starting materials and/or product
Chemoselective alternatives to doing hydrogenation with Pd/ C (since it can affect other functional groups too)
metals in acidic conditions:
e.g.
- Sn in diluted aq HCl
- Fe in AcOH, aq HCl or aq NH 4 Cl
with metals, the reaction mechanism involves single electron transfers (SET) from the metal, protonation and dehydration steps.
Hydrogenations of arenes
Arenes are harder to hydrogenate than alkenes and alkynes.
However, choosing the correct metal catalyst (Pt, Rh or Ni, NOT Pd) can allow arenes to be reduced to cyclohexanes.
There is chemoselectivity over carboxylic acids and esters.
How to completely reduce arenes?
using heterogeneous hydrogenation (Pt/ Rh/ Ni catalysts, often high H 2 pressure and high T)
How to partially reduce arenes?
using dissolving metals: Birch reduction
Heteroarenes
Aromatic heterocyclic compounds
- must obey Hückel’s rule: planar, contiguous array of p orbitals with 4n+2 ⫪ electrons (n integer)
- show ‘anomalous’ chemical properties
- have unusual NMR chemical shifts
Properties of pyridine
- aromatic imine
- its conjugate acid (pyridinium) is as acidic as a carboxylic acid (∼5.5 pKa)
- weak base
- good nucleophile
Why is pyridine a good nucleophile?
the N lone pair is not delocalised into the ⫪ system (it’s an even better nucleophile if it is made more electron-rich)
What is an example of pyridine being used for its nucleophile abilities?
4- (Dimethylamino)pyridine, DMAP, is used as a nucleophilic acyl transfer catalyst
How does pyridine compare with benzene as a nucleophile in electrophilic aromatic substitutions?
- Pyridine’s ⫪ system is more electron-poor than benzene’s therefore it’s less willing to act as a nucleophile in electrophilic aromatic substitutions
- Due to N’s electronegativity, the HOMO of pyridine is lower in energy than the HOMO of benzene
- All Wheland intermediates arising from attack of an electrophile to pyridines are unstable electron-deficient cations
What type of reaction is pyridine a better nucleophile for than benzene?
Nucleophilic substitutions
- Pyridine’s ⫪ system is more electron-poor than benzene’s thus is activated towards nucleophilic substitutions
- due to N’s electronegativity, the LUMO of pyridine is lower in energy than the LUMO of benzene
How to activate pyridine towards electrophilic aromatic substitution (S E Ar)?
- Use pyridines activated by strong +M groups (OMe, NH 2 )
- Turn the pyridine into the corresponding pyridine N-oxide
Why is pyridine N-oxide better towards (S E Ar) than pyridine?
the neutral, zwitterionic compound is more electron-rich than pyridine thus is more reactive for (S E Ar)
What is sometimes the issue of pyrrole in S E Ar?
it’s so reactive, it can be difficult to control
What happens when pyrrole is treated with strong acids?
Pyrrole reacts with electrophiles at C2, and it does the same with acids (E + = H + ).
This protonation starts polymerisation thus strong acids can cause pyrrole polymerisation.
What happens when pyrrole is treated with bases?
Pyrrole is deprotonated on N (pyrrole pKa = 16.5) and the anion of pyrrole reacts with electrophiles at N
How can pyrroles and furans react given they are electron-rich dienes?
- they are locked in the s-cis conformation
- they can react readily with electron-poor dienophiles in Diels-Alder reactions
What is an important characteristic in imidazoles?
- they are amphoteric (can be and acid or base) but generally they act as a base
- they are good silylation and acylation catalysts
How can you form 1,2,3-triazoles?
via a “click” reaction with azides
Conditions for a click reaction
- Heat or
- Cu(I) catalyst or
- Rh(I) catalyst or
- RT, no catalyst if strained, reactive alkynes are used
Where do S E Ar reactions occur on indoles?
On the electron-rich 5 membered ring.
This is because the wheland intermediate is lower in energy as the aromaticity of the benzene ring isn’t disturbed
Paal-Knorr Synthesis: Reagents and losses to form furans
Reagent: H+
Losses: -H 2 O
Paal-Knorr Synthesis: Reagents and losses to form pyrroles
Reagent: RNH 2
Losses: -2 H 2 O
Paal-Knorr Synthesis: Reagents and losses to form thiophenes
Reagent: P 2 S 5
Losses: -2 H 2 O
Pd catalysed cross coupling reactions: Suzuki
- Transmetallation from boronic acid [B] in the presence of an inorganic base (CsF, Ba(OH) 2 , K 2 CO 3 , K 3 PO 4 , etc)
- Pd(OAc) 2 catalyst
- PPh 3 and DME
Pd catalysed cross coupling reagents: Negishi
- Transmetallation from an organozinc reagent [Zn]
- Pd(PPh 3 ) 4 catalyst
- THF
Pd catalysed cross coupling reagents: Stille
- Transmetallation from trialkyl stannane [Sn]
- Pd(PPh 3 ) 4 catalyst
- LiCl, THF
Pd catalysed cross coupling reagents: Sonogashira
- Transmetallation from a copper(I) acetylide formed in situ using an organic base (e.g. Et 3 N, morpholine, pyridine) and a Cu(I) salt (usually CuI)
- Pd(PPh 3 ) 4
How can terminal aryl alkenes be formed by a Pd catalysed cross coupling?
by a Sonogashira reaction with trimethylsilylacetylene, followed by TMS removal using TBAF
Pd catalysed cross coupling reaction: Heck reaction
- Pd(II) precatalyst phosphine ligand + base
- the nucleophilic cross coupling partner is simply a terminal alkene
- useful to making substituted alkenes (generally E selective)
- Instead of transmetallation step, there are migratory insertion + β-hydride elimination steps
