Heteroaromatic molecules Flashcards
What are heteroaromatic molecules?
Aromatic molecules in which one or more carbon atom are replaced by a hertoatom
O, N, S
Draw:
pyridine, pyrrole, furan, thiophene,
imidazole, oxazole, thiazole,
quinoline, isoquiniline and indole
What is the structure of pyridine?
Obeys Hückel’s rule [4n+2] π electrons when n = 1
N is sp2 hybridised so contribues 1 electron to the π system
6 π electrons over 6 orbitals.
N is electronegative so the ring is π deficient compared to benzene
Describe the proton environments of pyridine
In the ortho position to the N: δH = 8.5 - string withdrawing effect from the nitrogen so very deshielded
In the meta position to the N: δH = 7.1 - alost the same as benzene environments - no mesomeric effect from the N
In the para position to the N = δH = 7.5 - less deshielded as further from N but still feels mesomeric effect due to resonance forms
In pyridine is the N lone pair involved in the ring structure
NO
N donates 1 electron t the ring
The lone pair is in an orbital in the planne of the ring and orthogonal to the pi system so cannot interact with the other pi orbitals above and below the ring
Draw the resonance forms of pyridine and use it to eplain the proton environements
There are 4 resonance forms
At no point s the +ve charge on the meta position so the H environment is similar to benzene
+ve charge can be placed on the oprtho p;ara position so the protons are more deshielded
What is the reactivity of pyridine?
The lone pair allowes pyridine to act as a weak bae (pKa = 5.5). The pyridinium ion is acidic
The lone pair also makes pyridine nucleophilic at the N
Draw N-alkylation of pyridine
Use a haloalkane
Draw N-acylation of pyridine and show the further reaction that can occur
Use acyl halide
The N-C-O bond is not an amide because the lone pair is involved in bonding to the carbon rather than delocalised into the C=O bond
The further reaction can produce an ester and the pyridinium ion using an alcohol
Adding pyridine to the reaction between an acyl chloride and an alcohol speeds up ester formation
Explain why electrophilic substitution does not often occur on pyridine
Electrophiles tend to attack at the nitrogen rather than the carbon forming pyridinium ions or complexes which are inert to other electrophiles
The elecron deficient ring is not very nucleophilic
Pyridines nitrogen atom destabalises the cationic intermediate
How does N destabalise the cationic intermediate involved in electrophilic substitution of pyridine
Substituion at the C4 position (para) places a +ve charge on the C3 position. In resonance forms this moves to the N which is very unstable
Substitution of the C2 position place a +ve charge directly on the N which is very unfavourable
Substitution of the C3 position would be the most favourable as it has 3 resonance forms that do not place the +ve charge on the N - substitution only works in this position under very forcing conditions and produces ~5% yield
How can make a pyridine undergo electrophilic aromatic substitution?
Activate the ring - one method is to convert to a pyridine N-oxide
How can we convert a pyridine N-oxide back to pyridine?
Use PCl3
Forms substituted pyridine and POCl3
Reaction is driven by the strength if the P=O bond - similar to Wittig reaction
Can pyridines undergo nucleophilic substitution and why?
The N atom makes pyridine more reactive to nucleophilic substitution particularly at the C2 and C4 positions as the -ve charge can be delocalised onto the N.
What is the reactivity of enones?
substitution occurs at the C4 and C2 prosition but not at C3 similar to pyridines
What is the mechanism of the Chichibabin reaction?
Nucleophilic substitution of pyridine with the unusual example of hydride (H-) as a leaving group.
Requires high temperatures
What is the mechanism of reaction of pyridines with grignards and organolithiums
There is the fomal loss of hydride but the mechanism is actually more complex.
What is the mechanism of substitution of 2- and 4-Halopyridines
What is the mechanism of substitution of Pyridine N-Oxides
How do we know which reaction to use for nucleophilic substitution?
Striong nucleophiles can be substitued directly with the Chichibabin reaction
Medium nucleophiles can be substituted if a suitable leaving group is present on pyridine (halogen)
If a weak nucleophile must be substituted pyridine N-Oxide can be substitued with a halogen and then further substituted
Describe the reactivity of 2- and 4- methyl puridines
2- and 4-Methyl pyridines can be deprotonated with a base as the resulting anion is resonance stabalised (-ve charge can be delocalised on N and aromatic ring)
Protons alpha to the ring are basic
Addition can then occur
What is the RSA of pyridine?
Pyridines have enamine like and an imine like features
This allows disconnection back to a 1,5-dicarbonyl compound and an amine equivalent
What is the mechanism of the synthesis of pyridines?
Uses an enone, ketone and an amine
Ketone tautomerises to enol, addition to enone, tautomerisation to ketone, addition of amine, enamine formation, imine formation, loss of water (in situ when NH2OH is used)
What is the mechanism of the Hantzch synthesis for pyridines?
Uses 3 carbonyls (2 ketones, 1 aldehyde) and ammonia
Enone is made in situ
Addition of ammonia to one ketone to form enamine, tautomerisation of other ketone, aldol reaction between enol and aldehyde, dehydration to form enone, addition of enamine, tautomerisation to ketone, imine formation, dehydration, tautomerisation to enamine, oxidation
Usually a drying agent used to push the reaction in forward direction, Imine, enamine formation is reversible
What is the structure of pyrrole?
Pyrroles obey the Huckel’s rule where n=1
There are 4 sp2 hybridised carbons contributing 1 electrons each and 1 sp2 hybridised nitrogen which contributes 2 electrons to the pi ring.
The pi ring is pi excessive as the nitrogen lone pair is delocalised into the ring. The N-H bond is orthogonal to the ring.
The proton environments reflect the pi excessive
What are the resonance forms of pyrrole
What is the reactivity of pyrrole?
A consenquence of nitrgens lone pair being delocalised into the ring is that pyrrole is not basic at nitrogen. If when prrole does act as a base it protonates on C2 carbon and has a pKa of -4
The N-H is acidic with the pKa of 16.5
Does pyrrole undergo electrophilic substitution?
Pyrrole readily undergoes electrophilic substitution at the C2 position
Sunstitution occurs at C2 as there are 3 canonical forms compared with 2 canonical structures associated with C3
Examples of electrophilic aromatic subsitution
What is the Vilsmeier Formylation?
Electrophilic aromatic substituion of pyrole using DMF and POCl3
What is the Mannich reaction?
2 step reaction
Step 1: use methanal and Me2NH to form an iminium and then add this to the pyrrole with a loss of H+
Step 2: Use MeI and NaOH to subsitute the NMe with an OH group
How can susbstitution on the N take place in pyrrole?
Deprotonation with a strong base and then trapping eith an electrophile
Explain lithiation of N-Methylated Pyrrole
N-Methylated pyrroles can be deprotonated at the C2 position by a strong base
Deprotonation occurs at C2 because of the electron withdsrawing nature of the heteroatom
The 2-lithopyrroles are mucleophilic and can react with a variety of electrophiles to get substitution in the 2 position
What is the RSA of a pyrrole?
Pyrroles have enamine like features which allows a disconnection to a 1,4-dicarbonyl and an amine equivalent
What is the Hantzch sythesis for pyrroles?
Use of a bromoketone, ketone and ammonia
enamine formation, alkylation, tautomerisation, imine formation, loss of water, tautomerisation
What is the Paal-Knorr synthesis
Use of diketone and BnNH2
enamine formation, imine formation, loss of water, tautomerisation
What is the Knorr synthesis of pyrroles?
3 step process
Step 1: form oxime from ketoester and HNO3
Step 2: Zn reduction of NOH on oxime to NH2
Step 3: USe ketone with AcOH to make pyrrole
What are furans and thiophenes?
Oxygen and sulfur analogues of pyrrole
THey obey Huckel’s rule when n=1
They have 4 sp2 hybridised carbons whch contributre 1 electron each and 1 sp2 hybridised heteroatom which contributes 2 electrons
Has 6 electrons over 5 atoms and is therefore electron rich
What is the reactivity of furans and thiophenes?
Both have aromatic character
Undergo very similar reactions to pyrrole
Furan and thiophene are less nucleophilic than pyrrole (thiophene is the least reactive to electrophiles)
This is due to the 3p orbital conjugating with the ring rather than the 2p used by N and O
pyrrole > furan > thiophene > benzene
Do furans and thiophenes undergo electrophilic subsitution?
Bith can undergo electrophilic subsitution at C2 same as pyrrole
Slightly more forcing conditions must be used as furan and thiophene are less reactive than pyrrole
e.g use of lewis acid activator (ZnCl2/Ac2O)
What are ghe differences in electrophilic substitution of furan and pyrrole
Furan can undergo either electrohphilic aromatic substitution or addition depending on conditions
Furan is boarder line aromatic - low stabalisation energy, can act like a diene
How can furans act like dienes?
Furan can undergo Diels-Alder reactions due to its low stabalisation energy
How can furan or thiophenes act as organometallics?
The protons at the c2 position are acidic due to the electron withdrawing effect of the heteroatom
It can therefore be removed by a strong base (BuLi)
The resulting lithiated form can act as an organolithium
What are the RSAs for furan and thiophene?
Furans and thiophenes have enol like features that allow their disconnection to 1,4-dicarbonyls
What is the mechanism to form a furan using a 1,4-diketone and acid?
Addition of proton, tautomerisation, attack on carbonyl, H+ transfer, loss of water, tautomerisation
How can you convert a 1,4-dicarbonyl to a 1,4-diC=S?
Use P2S5
Mechanism to form thiophene then the same as furan
What are imidazoles, thiazoles and oxazoles?
Structures with the replacement of the C3 carbon in a pyrrole, thiophene or furan with a nitrogen atom
Aromaticity is retained
General term is 1,3-azoles
Aromaticity comes from delocalisation of lone pair of the second heteroatom
What is the reactivity of imidazoles, thiazoles and oxazoles?
All can be deprotonated at the 3-N
Imidazole (pKa = 7), Thiazole (pKa = 2.5), Oxazole (pKa = 0.8)
Imidazole is a stronger base than pyridine
Oxazole is such a weak base that when protonated it acts as strong acid
Can 1,3-azoles undergo electrophilic aromatic substitution?
The presence of the pyridine like 3N deactiviates the ring to electrophilic attack
However if the ring has an electron donating group on it electrophilic aromatic substitution can take place.
Can 1,3-azoles act as organolithiums?
The protons at the 2 position are acidic due to the withdrawing nature of both heteroatoms
It can be removed by a strong base (BuLi)
What is the reactivity of C2 alkyl groups?
Alkyl groups at the C2 position of a 1,3-azole can be deprotonated by a strong base and quenched by a range f eletrophiles.
This leads to functionalisation
What is the RSA of an 1,3-azoles?
Disconnection at the heteroatoms reveals an a-substituted ketone and a carboxylic acid derivative
What is the mechanism for synthesis of an imidazole?
Use α-bromoketone and an amidine
Attack of =NH onto α-carbon, attack of =NH2 onto carbonyl, tautomerisation, loss of water
What is the mechanism of a synthesis of a thiazole?
Use α-bromoketone and a thioamide
Attack of =S onto α-carbon, attack of =NH2 onto carbonyl, tautomerisation, loss of water
What is the mechanism of synthesis of an oxazole?
Do not use a bromoketone and an amide - amides are not nucleophilic enough to react so the nucleophilic and electrophilic partners are swapped
Use α-aminoketone and acyl chloride and SOCL2
Attack of amine onto carbonyl, electrons from N-H bond form N=C and the carbonyl attacks SOCl2, chloride attacks carbon of N=C-O and SO2Cl is lost, carbonyl attacks carbon of N=C-Cl
What are quinolines and isoquinolines?
Contain a pyridine ringfused to a benzene ring
Two possible isomers: N fused in 1 position (quinoline) or in 2 position (isoquinoline)
Both are aromatic: obey huckels rule when n=2
N is sp2 hybridised so contributes 1 electron
What is the recativity of quinoline and isoquiniline?
The N containing ring has reactivity similar to pyridine
The carbocyclic ring has reactivity similar to benzene
Can quinolines/isoquinilines undergo electrophilic aromatic substitution?
N deactivates the rig making it less reactive to lectrophilic aromatic subsitution
Electrophilic substituion takes place on the benzene ring at positions 5 and 8 (2 canonical forms without distrupting the aromaticity ofthe heteroaromatic ring)
Position 6 and 7 only has 1
Can quinolines/isoquinolines undergo nuceophilic substitution?
Nucleophilic substitution does not occur take place on the carbocyclic ring.
Nucleophilic substitution can occur on the pyridine ring
In quinoline substitution happens on the 2 and 4 position
On isoquinoline it happens on the 1 position
What is the reactivity of methyl quinolines/isoquinolines
2- and 4- methyl quinolines and 1-methyl isoquinolines can be deprotonated by a base - the resulting the anion is resonance stabalised and the negative charge can be delocalised onto the N
What is the RSA of a quinoline?
Disconnection at the imine like functional group reveals an aromatic amine and a 1,3-bis-electrophile either 1,3-ketone or enone
What is the mechanism of a quinoline synthesis?
Use aromatic amine and1,3- diketone
enamine formation, Friedel Crafts, tautomerisation, loss of water
What is the Skraup synthesis of quinolines?
Uses aromatic amine and unsaturated ketone
Michael addition of amine, tautomerisation, benzene ring attacks carbonyl, tautomerisation, lossof water, air oxidation
What si the RSA of an isoquinioine?
Disconnection a imine like functional group reveals an aromatic aldehyde or ketone and an aminoketone
To stop the aminoketone reacting with itself the ketone needs to be protected as a ketal
What is the mechanism to synthesise an isoquinoline?
Use an aromtic aldehydeand an aminoketal
Amine attacks carbonyl (imine formation), deprotection, Friedel Crafts, tautomerisation, loss of methanol
What is the alternative RSA for isoquinolines?
Disconnect between N and C3 and between C1 and bridge to form an amine and an acyl chloride
What is the Bischler-Napieralski synthesis of isoquinolines?
Uses amine, acyl chloride and POCl3
Amide formation, carbonyl attacks POCl3, Vilsmeier, tautomerisation, oxidation
What are indoles?
Pyrrole ring fused to a benzene
Obeys Huckels rule when n=2
The indole N is sp2 hybridised and contributes 2 electrons so indole is not basic
What is the reactivity of indole?
The indole ring is electron rich and can therefore undergo electrophilic aromatic substitution
Electrophilic aromatic substitution occurs at C3 position as substitution at C2 distrupts the aromaticity of the benzene ring
What effect does a strong base have on indoles?
The N-H can be deprotonated with a string base. The resukting anion can react with electrophiles at the N or the C3
With lithium, sodium and potassium counter ions reaction tends to occur and the N whereas with Mg (due to more covalent nature) reaction tends to occur and C3
When the nitrogen is blocked deprotonation can occur at C3
What is the RSA of an indole?
Disconnection at the enamine like function reveals an aminal
Further disconnection at the aminal reveals an amide which can be formed from a substituted analine and an acyl chloride
What is the Madelung synthesis of indoles?
Uses substitutes aniline, acyl chloride and tBuOK
Amide formation, deprotonation of α carbon, -ve charge attacks carbonyl, loss of water
Alternative RSA of indoles?
Disconnection at the enamine like feature reveals a ketone
Further disconnection betweent the aromatic ring and a position of the ketone reveals an amine precursor and a ketone
The precursor can be a hydrazine
What is the Fischer indole synthesis?
Uses hydrazine, and ketone and acid
Enamine formation, sigmatropic rearrangement, addition of NH2 to C=N, loss of ammonia, tautomerisation
Loss of ammonia is the driving force
