Aromatics and Carbonyls Flashcards
Huckels’s rule
Pi electrons = 4n + 2 for aromatic compounds
Halogenation of benzene
HX and FeX3 or AlX3
- X2 donates lp to halogen carrier
- Creates complex ion
- Benzene acts as nucleophile (attacks s+ X)
- HX and halogen carrier regenerate
Nitration of benzene
Sulfuric acid (H2SO4) and nitric acid (HNO2) -> nitronium ion
- Benzene reacts with nitronium ion
- Water picks up excess H+
Sulfonation of benzene
Sulfuric acid (H2SO4) and sulfer trioxide (SO3) create complex ion
- Benzene acts as a nucleophile and reacts with ion
- Regenerates sulfuric acid
Friedel-Crafts Alkylation of benzene
Lewis acid and complimentary lewis base (Haloalkane) form complex ion
- Benzene acts as nucleophile
- Regenerates Lewis acid and HX
- Forms polyalkylated benzenes
- Rarely used in synthesis
Friedel-Crafts acylation of benzene
Acyl choloride and lewis acid form coordiantion complex then acylium ion
- Benzene reacts with ion and regenerates lewis acid and HX
- Often used in synthesis
- NH2, -NHR, -NR2
+M>-I strongly activating (1 reactive)
-OH, -OR
+M>-I strongly activating (2 reactive)
-NHCOR, -OCOR
+M>-I activating (3 reactive)
-Ph, -CH-CH2
+M, +I Activating (4 reactive)
-R
+I weakly activating (5 reactive)
-Cl, -Br, -I
-I>+M deactivating (6 reactive)
-CHO, -COR
-M, -I deactivating (7 reactive)
-CO2H, -CO2R
-M,-I deactivating (8 reactive)
-SO3H
-M,-I strongly deactivating (9 reactive)
-NO2
-M,-I strongly deactivating (10 reactive)
Regioselectivity of activating groups
Increased electron density at 2,4 positions
Where do halogens direct groups?
2,4 position
Regioselectivity of deactivating groups
Increase electron densitiy at 3 position
why is 2,4 more stable for +M groups?
Produces another resonance form (more disperse charge on intermediate)
Para
4
Ortho
2
Meta
3
NO2 -> NH2
Reduction - Sn/HCl
COR -> CH2R
Reduction - Zn/Hg/HCl
CH3 -> CO2H
Oxidation - KmNO4
Solution to Friedel-Crafts alkylation
Friedel-Crafts acyaltion and then Clemmensen reduction (Zn/HCl/Hg)
Amide -> amine
NaOH, H2O, heat
Sulfuric acid -> H
H2SO4, H2O, heat
Aldehyde
R-CO-H
Ketone
R-CO-R
Carboxylic acid
R-CO-OH
Acyl CHloride
R-CO-Cl
Acid anhydride
R-CO-OCOR
Ester
R-CO-OR
Amide
R-CO-NH2
Addition of strong nucleophile to carbonyl
Forms alcohol
Addition of weak nucleophile to carbonyl
Carbonyl is a weak base - protonate with H+ to form strong electrophile
- weak nucleophile reacts
- Forms alcohol
What groups can a negatively charged nucleophile substitute out of a carbonyl?
Cl, OCOR, OR, NR2
What groups can a neutral nucleophile substitute out of a carbonyl?
Cl, OCOR
What groups can a weak nucleophile substitute out of a carbonyl?
OH, OR, NR2
-ly charged nucleophile substitution of carbonyl
creates a substituted carbonyl and forms X-
- X- more unstable than Nu-
- But C-X (and C-O in intermediate) weaker than C=O
Neutral nucleophile substitution of carbonyl
Carbonyl must be strong electrophile
- Et3N/pyridine required to deprotonate weak nucleophile in intermediate
- creates a substituted carbonyl and forms X-
Weak nucleophile substitution of carbonyl
Carbonyl initialy protonated (acid catalysis)
- Forms strong electrophile
Forms XH (seperates in solution) and substituted carbonyl
Alpha-substituted reaction of a carbonyl
- base removed H from alpha position
- Forms enolate ion
- More stable resonance forms has - on O (strong nucleophile)
- Reacts with electrophile
Why are aldehydes generally more reactive than ketones?
- Nucleophile can approach aldehydes more readily and trans state is less crowded
- Carbon in ketone less electrophilic
Reduction of carbonyl
Sodium borohydride (NaBH4) (weaker) or lithium aluminium hydride (LiAlH4) (stronger)
Reduction of carbonyl
- Produced Alkoxide ion
- Workup
Why are tertiary alcohols not easily oxidised?
Because a C-C bond needs to be broken
Oxidation of a 2’ alcohol forms….
Ketone
Oxidation of a 1’ alcohol forms…
Aldehyde
Further oxidation of a 1’ alcohol forms…
A carboxylic acid
Oxidizing agent to form a ketone
CrO3 and H+ Jones reagent
Oxidizing agent to form an aldehyde…
PCC
Oxidizing agent to form carboxylic acid…
CrO3 and H+ Jones reagent/KMnO4
What is an organometallic?
Organic group bonded to metal R-M
organometallic acting as a nucleophile
forms primary alcohol and metal oxide
Grignard reagent
R-MgX
Formation of grignard reagent
- Anhydrous
- N2
- Will ready react with O2 and water
Grignard + aldehyde
2’ alcohol and HOMgX
Grignard + ketone
tertiary alcohol + HOMgX
Wittig reaction
Phosphonium Ylide and carbonyl
Hydration of carbonyl
reversible forms hydrate
- Eq determined by stability of carbonyl relative to hydrate
Addition of an alcohol to carbonyl
forms hemiacetals
acid catalyst
Hemiacetal + 2nd eq of alcohol
Acetal
why are acetals useful?
Act as protecting groups for aldehydes (do not react w bases, redox reagents and nucleophiles)
How to reverse acetal formation
H+ catalyst and remove H2O
Addition of primary amine to carbonyl
reversible, forms imine
pH of formation of imine
4.5 - below and amine becomes protonated and above theres not enough H+ to protonate the -OH in hemiaminal
Reduction of imine
NaBH4 to amine
Ester + nucleophile
nucleophilic acyl substitution
Carboxylic acid + Nucleophile
competitive deprotonation
Best leaving groups
- neutral
- stable
- for an anion - low pKa for conjugate acid indicates A- is relatively stable
Why are ketones and aldehydes more reactive than etsers
C is more + in a/k
OR is +M
Relative reactivity of carboxylic acid derivatives
acyl chloride, acid anhydride, ester, amide
Why are acyl chlorides so reactive?
-I stronger than +M
why are acid anhydrides so reactive?
-I>+M - lp on O is shared
Why are esters less reactive?
+M>-I
why are amides the least reactive?
+M»-I
Esterification of carboxylic acid
Weak nucleophile with acid catalyst - produces ester
Reversible - alcohol and dehydrating agent to force equilibrium (like MgSO4)
Carboxylic acid + ammonia
acid base reaction
room temp
RCO2- +NH4 salt formed
Carboxylic avid Et3N/pyridine
forms salts
Carboxylic + SOCl2
Acyl chloride + SO2 + HCl
alternatives to SOCl2
Phosphorus trichloride/pentachloride
Hydrolysis of acyl chloride
Cl- is the leaving group
carboxylic acid
Alcoholysis of acid anhydride
ester + RCO2-
What nucleophiles do esters react with?
Strong and weak (w catalyst)
Why do amides undergo few nucleophilic substitutions?
carbonyl carbon not electrophillic
Reduction of ester
LiAlH4 (NaBH4 not strong enough)
1’ alcohol
Base hydrolysis of an ester
saponification carboxylic acid and ROH
Ester + Grignard reagent
3’ alcohol
Acyl chloride + ammonia (2 eq.)
Primary amide + Cl-
Hydrolysis of amide
- heating in conc. aq acid or hydroxide ion
- carboxylic acid + NH4+
What is an enol?
a C(OH)=R group
a structural isomer of a carbonyl
What is keto-enol tautomerism?
The interconversion between keto and enol forms of a carbonyl
Acid catalyst tautomerism
- Protantates O of C=O
- regenerates acid at end
Base catalysed tautomerism
- Forms enolate ion
- -OH regenerated
Why is the keto form more stable?
- Combined enthalpy of bonds higher than enol
- However enol stabilised if C=C is conjugated with a second pi bond and if -OH is involved in intramolecular H-bonding
What molecules are prone to enolisation?
Aldehydes and ketones (not esters and carb acids)
Are enols nucleophiles or electrophiles?
Nucleophiles
Reaction of enols with bromine
- Acid cat.
- After acid cat. tautomerism Br- introduced at alpha pos. of ketone (extremely weak base, more likely that H2O acts as base in this step)
Why will a brominated enol resist further bromination?
due to +I effect of Br
Why are H atoms in the alpha positions of carbonyls acidic
the -I and -M effects of carbonyls stabilise the enolate ion
Enolate ion + electrophile
- 2 diff nucleophilic sites due to resonance
- major product is substitution at C
Aldol condensation
- OH- catalyst
- Rapid and reversible
- product both aldehyde and alcohol
What is the equilibrium of aldol condensation?
- Aldehyde eq. lies to aldol
- Ketone eq. lies to ketone
What configurational isomer do enals favour?
E - more stable than Z
