Unit 5 (Lesson 28-33) Flashcards
true/fasle: the alpha hydrogen of the carbonyl compound is significantly more acidic than a typical hydrogen
true
- electron withdrawing effect of the C=O
- resonance stabilization of the resulting negative charge
[keto-enol tautomerization] carbonyl is in equilibrium with it’s enol form when under
- acidic conditions
- due to acidity of alpha hydrogen of carbonyl compound
alpha - halogenation:
acid-catalyzed halogenation of a carbonyl
single halogenation
- under acidic conditions
oxygen of carbonyl has less e- density because of e- withdrawing halogen
multiple halogenation
alpha proton is more acidic because of e- withdrawing halogen
tautomerization
a process where two isomers interconvert in rapid equilibrium
why is the carbonyl isomer (aldehyde or ketone) favored in nearly every case
due to the stability of the C=O
- notable exception is phenol
why do dicarbonyls form a greater amount of enol at equilibrium
due to hydrogen bonding between the enol OH and the neighboring carbonyl oxygen
under acid catalyzed conditions, tautomerization begins with
protonation
under basic conditions tautomerization begins with
deprotoation
alpha hydrogens
hydrogens on the carbon immediately bonded to carbonyl carbon
how many resonance forms do alpha hydrogens have
2
electron donation towards the carbonyl (resonance or induction) increases/decreases alpha hydrogen acidity
decreases
electron withdraw away from the carbonyl (resonance or induction) increases/decreases alpha hydrogen acidity
increases
if the nitrogen of an amide possesses a hydrogen, that hydrogen is more/less acidic than the amides’ alpha hydrogen
more
what makes LDA a poor nucleophile
sterics
- if you want something to act as a base only – LDA is a good choice
enolate formation with LDA
LDA is the best base for enolate formation
kinetic conditions for enolate formation (used in alkylation)
- no equilibrium
LEAST SUB CARBON - the carbonyl compound i slowly added to a slight excess of strong base
- reaction carried out at LOW temperature (78 degrees)
- aprotic solvents (THF, ethyl ether) are used
- less substituted double bond
less stable
thermodynamic conditions of enolate formation
- equilibrium
MOST SUB CARBON - the base is slowly added to the solution
- reactions are carried out at higher temperatures
- protic sovlents (ROH) can be added to the reaction
- more substituted double bond
- more stable
aldol addition
–a nucleophilic addition reaction between an enolate and an aldehyde or ketone electrophile, forming a B-hydroxy carbonyl product
–addition to carbonyl group at alpha position of seperate carbonyl group
- rxn is reversivble
- new C-C bond
- efficient for prepartation of B-hydroxy aldehydes and ketones
negative Keq value for enolate equilibrium
reactant favored
positive Keq value for enolate equilibrium
product favored
what happens when you use an alkoxide or hydroxide for enolate formation
only a small amount of enolate is generated - carbonyl is favored
for a di-carbonyl system, is it generally reactant or product favored if you use an alkoxide or hydroxide
product favored
- irreversibly favor enolate formation
alpha halogenation occurs on what
aldehydes and ketones
what can an alpha-halogenated product be treated with to forma a beta-unsaturated product
a big bulky strong base
what kind of ketone allows you to create either a kinetic or thermodynamic product
non-symmetrical ketone
how to get a kinetic enolization
use light excess of LDA (1.05 eq) at a cold temp (-78 degrees)
how to get a thermodynamic enolization
use a slight deficiency of LDA (0.95 eq) at a warmer temp (0 degrees)
- kinetic enolate forms first, but reacts with the 0.05 starting material in an acid base reaction to create the thermodynamic enolate
- can add 0.05 methanol to increase yield o f thernodynamic enolate
self aldol addition
occur when an aldehyde or ketone is reacted under basic conditions at room temperatue
what is an aldol condensation
a nucleophilic addition reaction between an anolate and an aldehyde or ketone electrophile, followed by a E1CB dehydration to form an alpha-beta-unsaturated carboyl product
- kicks off OH, makes c=c bond
what purpose does heat have when you see a ketone or aldehyde with a strong base and water
heat is the key that it is a dehydration mechanism and not a regular aldol addition
controlling products of crossed aldol addition
if one component has no acidic alpha hydrogens, the second carbonyl compound can be added slowly to solution, giving mostly one product
steps for a crossed aldol addition
form desired enolate first using LDA, then slowly add the second carbonyl compound (so it doesn’t react with itself)
type 1 crossed aldol addition
- both aldehydes and ketones possess enolizable alpha hydrogens
- enlolate nucleophile prepared with LDA, then desired electrophilic aldehyde/ketone is added slowly
- acid workup required
type 2 crosses aldol addition
- one species lacks alpha hydrogen
- enlolate cannot be generated from an aldehyde/ketone that lacks alpha hydrogens – this aldehyde/ketone will serve as the electrophile
steps for type 2 crossed aldol addition
- species lacking alpha hydrogens is first dissolved in basic solution
- then aldehyde/ketone is added slowly - molecule will then enolize and attack the species lacking
claisen condensation
- similar to Aldol condensation, but with esters
- efficient method for preparing B-keto esters
- same ester and alkoxide(reagent) must be used to prevent transesterification of the ester
Ex:
1.) NaOCH3, HOCH3
2.) H2O, HCl (no heat)
why are claisen condensations irreversible
due to the increased acidity of the alpha hydrogen
what relationship do you need to have to undergo the loss of CO2 upon heating
alpha-beta relationship to make carboxylate
what leads to an alpha-beta unsaturated carbonyl compound undergoing a 1,2 addition
kinetic product aka direct addition
- strong nucleophiles
RMgX
RLi
NaBH4
LiAlH4
what leads to an alpha-beta unsaturated carbonyl compound undergoing a 1,4 addition
thermodynamic product aka conjugate addition
- weak nucleophiles
CH3OH
H2O
RNH2
Cl-
Br-
-CN
CHSH
Michael Reaction
1,4 addition of stabilized carbon nucleophiles to alpha-beta unsaturated carbonyl compounds
- conjugate addition of stabilized anions (enolates) forms new carbon-carbob bonds
- formation of a 1,5 di-carbonyl
What does michael addition work well with
- stabilzed carbon nucleophiles
- they add like weake bases -CN, -Br, etc
- when you see a beta compound ***
robinson annulation
- a michael reaction followed by an aldol addition then dehydration
- hallmark indicator of a Robinson annulation is the FORMATION OF A 6-MEMBERED RING
- often product is an alpha-beta unsaturated ketone
dieckmann condensations
- an intramolecula nucleophilic acyl substitution between an enolate and an ester electrophile, cyclizing to form a cyclic beta-ketp carbonyl
1,6 dieckmann condensation
forms 5 membered ring
- 1 attacks 5
1,7 dieckmann condensation
1 attacks 6
forms 6 membered ring
robinson annulatio indicator
base/heat/carbonyl with alyene
malonic ester synthesis
- synthetic route to prepare a carboxylic acid with a desired chain length
malonic ester starting material
- diester
- matching alkoxide
- RX
- H2O, HCL, heat
acetoacetic ester synthesis
- ketoeter
- matching alkoxide
- RX
- H2O, HCl, heat
acetoacetic ester synthesis
- makes ketones
how to recognize an Aldol addtition
NaOH, H2O, 0 degrees
