Synthesis Aromaticity idk Flashcards
4 rules of aromaticity
- Cyclic. 2. Fully conjugated pi electron system (every carbon is sp2 and p-orbs overlap). 3. Atoms in ring planar otherwise p-orbs don’t overlap. 4. Huckel’s rule: 4n+2 pi electrons in the ring
Why do anilines have a lower basicity than expected and why is it only slighlty lower
Delocalisation of N lone pair into aromatic ring (lone pair doesnt want to react with another H). However! N LP is in sp3 orbital therefore not optimal orbital overlap as it has a different angle so only PARTIAL DELOCALISATION
What is inductive effects
Bond polarisation due to electronegativity differences
What is mesomeric effects
How a functional group extends the resonance/delocalisation of e- in a molecule
What does a lower pKaH mean
It means a stronger conjugate acid therefore a weaker base
In the para position, does EWG or EDG give a stronger aniline base?
Donating group gives a stronger base
Benzoic acid can’t be stabilised by ring conjugation, but despite this what can increase the acidity of benzoic acid?
The substituents. An electron withdrawing group stabilises it more aka more acidic
Will a phenol be more acidic with an ewg or edg as a substituent
EWG otherwise both the OH and egd will donate e- into the ring giving 2 negative charges = unfavourable!
What is a heteroaromatic compound
Benzene ring where a C is replaced with any other atom but mostly O, N, S (+ all the rules for aromaticity)
What is pyridine
Isoelectronic w benzene but i C is an N
What is pyrrole, furan, thiophene
Isoelectric w cyclopentadiene anion but 1 C swapped with NH, O, S respectively
Why does pyridine (with an N) have a fully conjugated system
N is sp2, so p-orbital parallel to the rest. Extra LP is orthogonal therefore is not involved in delocalisation
Is sp3 or p orbital higher in energy
P because no s character. S closer to +bve charge in nucleus which stabilises e-
Explain change in reactivity (eg resonance stabilisation) of pyridine vs benzene
Electronegative N causes dipole. It has lower HOMO/LUMO energies than benzene -> worse orbital overlap -> less efficient delocalisation -> less resonane stabilisation. Lower HOMO causes less reactivity with nucleophile
Why is pyridine a weaker base than piperidine (pyridine without double bonds basically)
LP is sp2 hybridised vs sp3 so has more s-character. Held closer to nucleus -> more stabilised -> LP less available for reaction with protons
Do EWG or EDG substituents on pyridine make it more basic
EDG becasue it causes higher e- density on nitrogen -> more nucleophilic
What happens to basicity of pyridine if more nitrogen atoms are added
e- density pulled away from nitrogen -> less nucelophilic -> less likely to react -> less basic!
How is hydroxypyridine more acidic than phenol
N is slightly electronwithdrawing so stabilises negative charge formed when H is taken off
Is 2 and 4 hydroxypyridine more or less acidic than 3/5?
Less acidic. Tautomerism reaction happens where H goes from O to N forming =O and NH. Less likely to get H taken off by base
Is pyridone (=O and NH) still aromatic
Yes becasue LP on N can still be delocalised into ring
Name of molecule that 2 or 4 hydroxypyridine goes into during tautomerism
Pyridone
What can pyridine be used for
Nucleophilic catalyst in ester production
Structure of pyrrole
Like cyclopentadiene anion. LP on nitrogen is in p-orbital, part of conjugated system - delocalised - not available to do reactions.
Is HOMO/LUMO higher or lower in pyrrole than benzene
Higher because very e- dense due to delocalised LP
Why does furan (O) have a low stabilisation energy
O is very electronegative meaning not efficient p-orbs -> not efficient delocalisation -> not as stabilised aka more reactive
What is imidazole
Has one pyridine-like N and one pyrrole-like N
How to make Br2 react with benzene
Add lewis acid FeBr3. Br makes dative bond to empty p-orbital of Fe making Br+ and Fe-. Makes Br even more electrophilic
What is Wheland intermediate
When a benzene has added one atom on to a carbon which made a positive charge on the carbon next to it and “only 2 double bonds”
What can go wrong during friedel crafts alkylation of benzene
Over-alkylation. If straight chain alkyl halide then it can become branched in benzene because unstable primary carbocation rearranges to a more stable secondary carbocation
How to add a primary carbocation onto benzene
Friedel-Crafts ACYLATION (not alkylation) and reduce ketone to alkane
Why does only one ketone group add on during friedel crafts acylation
Ketone is electron withdrawing making product less reactive
What type of substituents increase the rate of aromatic nucleophilic substitution
Electron donatic making benzene more e- rich -> more nucleophilic
Why is ortho and para more likely than meta with EDG. And why is para most likely
Ortho and para have more resonance structures because they can be stabilised by EDG bc form a double bond to it. Intermediate is more stable. Ortho less likely bc of steric hinderance
How does EDG substituent effect selectivity on benzene
EDG makes aromatic ring more nucleophilic. It stabilises positively charged intermediate. Stabilisation most effective when e-phile adds ortho or para to EDG.
How does EWG substituent effect selectivity on benzene
EWG makes ring less nucleophilic. It destabilises positively charged intermediate. Least effective destabilisation (giving most stable) when electrophile adds meta to the EWG
Mesomeric and inductive effect of halogens on benzene
Inductively e- withdrawing bc electronegative = deactivating - reacts slower. Mesomerically e- donating: o/p-directing but it is weak bc bad overlap betw halogen and C p-orbs. No effect on rate. In total deactovating BUT ortho/para directing
Why does electrophilic aromatic substitution of pyridines not happen
Thermodynamics: N in ring lowers HOMO compared to benzene - makes ring e- deficient + less nucleophilic. Kinetics: LP on N will attack instead and cationic intermediate is inert to further elecphilic attack
If electrophilic aromatic substitution of pyridine is forced, what position will electrophile add on to
3 bc doesn’t become δ+ - resonance structures
How can you activate pyridines so they react
Add electron donating group or make an N-oxide
How is an N-oxide made + useful on pyridine
Oxidise pyridine - forms N(+)-O(-) = N-oxide = dipolar but is stable. Eletro arom susbtitution as N-oxide becomes EDG. Lone pair is in bond so no side reactions. Deprotection by reduction with PPh3, PCl3 or P(OMe)3 - all form strong O=P bond. Faster + para selectivity
What does it mean for HOMO etc if there is a build up of negative charge
High HOMO so very nucleophilic
Difference in conditions between nitration of 6 membered and pyrrole
Milder conditions bc pyrrole more reactive (e- rich). Acetic acid instead of conc sulphuric + only 5 degrees temp
5-membered heteroaromatics reactivity betw O, N and S
N>O>S because higher electronegativity means more localised on atom - less delocalised in ring - less nucleophilic. Also, S has high resonance stabilisation energy! Much less likley to react
What happens with pyrrole and a very strong electrophile
It adds on to every position so fully bromonated if Br2
Reaction conditions to mono-formylate (H-C=O) pyrrole (electronrich)
Pyrrole + DMF (HC(=O)NMe2) —-(1. POCl3)—(2. Na2CO3, H2O)–> pyrrole + formylate
How to made furan (O) do mono-formylation
Normal Friedel-Craft conditions because less reactive than pyrrole
Where is electrophilic substitution preferred on indole (benzene+pyrrole(5-N))
On 3-position bc it doesnt break aromaticity of benzene
Why is SN2 impossible for aromatics
Negative nucelophile has electrostatic repulstion with e- in p orbitals
Why is SN1 very unfavourable for aromatics
Leaving group leaves positive charge/empty sp2 orbital. Orthogonal to pi-system so is not stabilised by it. Also more s-character so closer to nucleus = repulsion
What is a Meisenheimer complex
A negatively charged intermediate formed by the attack of a nucleophile upon one of the aromatic-ring carbons during the course of a nucleophilic aromatic substitution reaction
What is needed for a 2-step addition-elimination reaction for aromatics
EWG on benzene. Good leaving group BUT this means F: something small to Nu can sterically get past and electronegative to pull e- away from carbon that Nu- adds on to
What is the RDS for 2-step addition-elimination reaction for aromatics
The addition of the nucleophile (not leaving of leaving group so it doesnt need to be mega good at leaving)
What is a diazonium compound
R-N≡N+
What is an aniline
Benzene-NH2
How to make diazonium salt from anilines (make aniline first from benzene-R)
Benzene-R + HNO3 and H2SO4 -> R-Ph-NO2. Then (Sn, HCl) or (H2, Pd/C) -> R-Ph-NH2. Then (NaNO2 + HCl, < 5C) -> R-Ph-N≡N+
What can diazonium salts be converted into (4 things)
1) + PO2H3 (weak acid) -> benzene (protonated). 2) +H2O + heat -> phenol. 3) + CuX -> Benzene w halogen ligand. 4) CuCN -> benzene with CN ligand
First step in diazotisation
Forming nitrosonium ion from NaNO2
What is a nitrosonium ion
N≡O+
What is benzyne/aryne
Benzene with one triple bond
What is needed for benzyne formation then addition of nucleophile
Very strong base + benzene good leaving group + Nu
What happens during Diels-Alder reaction
3 pi bonds broken, 2 C-C single bond formed and 1 C=C pi bond formed
3 ways of adding nucleophile on to aromatics
- Addition-elimination mechanism. (Nu adds by LG). 2. Via SN1 mechanism (N2+ is the LG). 3. Benzyne intermediate
3 modes of reactivity of imines
- Susceptible to nucleophilic attack (-ve charge on N + loses double bond). 2. Halogen derivative readily displaced w Nu. 3. α-protons are acidic (similar to ketoenol)
What is an imine
carbonyl but N instead of O and it has one more bond to something else
Increasing N-atoms in pyridine + reactivity (nucleophilic attack)
Ring becomes more e- deficient -> more susceptible to nucleophilic attack
Is H- the leaving group when going from pyridine -> pyridine - NH2
No, forms NaH not just H-
How to make pyridines more reactive towards ucelophilic attack
2-chloropyridine where Nu just swaps out the Cl in addit elim reaction
What to do if we don’t have a good leaving group on pyridine
React pyridine N-oxide with POCl3 to form pyridine-Cl. No acts as nucleophile in beginning, then becomes good LG
Is pyrrole or pyridine better at nucleophilic attack
Pyridine because pyrrole is electron rich
Where does heteroatom direct electrophile during lithiation of 5 membered
Ortho
What is needed to make lithiation work
Strong base eg Li-nBu
What type of directing group is needed for benzene to do lithiation + reaction
Some electronegative atom to coordinatie with base to pull it close -> deprotonation on C-H next to directing group
Last step in all lithiation reactions
Work up with water, - protonate negative charge
Which position is preferred for electrophilic arom susbtit on 5-memebered heteroaromatics
2-position as it has more resonance forms!
What is the Vilsmeier-Haak reaction for
If you want monosubstitution on pyrrole
What is a acid-free alternative to friedel-crafts reaction
Vilsmeier-Haak reaction
Why is Paal Knorr formation of furan easier than formation of pyrrole
Don’t need an external nucleophile - just acid which does tautomerism straight on the carbonyl
Reactants for Paal-Knorr mechanism to make thiophenes (from 1-4 dicarbonyls)
P4S10 or Lawesson’s reagent
Why is hydroxylamine (NH2OH) used instead of NH3 in synthesis of pyredines by 1,5-dicarbonyl by conjugate addition
Hydroxylamine used as nucleophile to allow for the elimination of three water molecules and the installation of 3 double bonds. Not needed for 5 membered ring
What happens when pyridine is made with NH3 instead (Hantzsch synthesis)
First 1,4-dihydropyridine is made and then it oxidises in air to give pyridine
2 main ways of making heteroaromatics
1 Synthesis of heteroaromatics exploiting carbonyl chemistry:
(imine, enamine and oxime formation, Aldol, tautomerism…)
2. Synthesis of fused heteroaromatics using electrophilic aromatic substitution
approach
