Nu sub at C=O (Lent Organic) Flashcards
four types of reagents that undergo Nu sub at a C=O
hydride reducing agents
organometallic reagents
water
alcohols
name the hydride reducing agent and product for reaction with acid chlorides and anhydrides
NaBH4, reduces them to alcohols
name the hydride reducing agent and product for reaction with esters
LiAlH4 (slightly stronger than NaBH4 required because esters are less reactive than acid chlorides/anhydrides)
or LiBH4
reduced to alcohols
name the hydride reducing agent and product for reaction with carboxylic acids
Borane
reduced to alcohols (all CA derivs are reduced to alcohols except amides)
name the hydride reducing agent and product for reaction with amides
LiAlH4
reduced to AMINES (the only one not reduced to an alcohol)
general mech for acid chloride / anhydride / ester w Hydride reducing agent
Nu attack –> tetrahedral int
good lg kicked –> aldehyde
x2 Nu attack –> alcohol
general mech for carboxylic acid and borane
x3 CA + BH3 - 3H2(g) –> triacylborate intermediate
+BH3 –> alc
no more detail needed
amide to amine reduction by hydride mech
Nu attack of -AlH4 –> tetrahedral int
-NR1R2 NOT a good leaving group
AlH3 lewis acid bond O-, kicked by N lp
for iminium ion
attack x2 –> amine
what do organometallic reagents react with aldehydes/ketones to form?
alcohols
what do organometallic reagents react with acid halide / anhydrides to form?
SINGLE addition: forms ketone
DOUBLE addition: forms alcohol (ie. ketone continues to react)
can stop because acid chloride/anhydride MORE reactive than ketones
reactions of organometallics with esters
CANNOT stop at the ketone - bc ketone more reactive than ester
add XS to produce alcohol
if only 1eq, major product is the double addition alc, with half the starting material remaining
Grignard + CO2
forms carboxylic acid
Nu attack into C=O of CO2
-MgBr fragment attacks to -O, replaced with H upon workup with H3O+
carboxylic acid with Grignard
MgBr or Li replaces H at -OH
what Is produced when carboxylic acid derivatives are hydrolysed?
carboxylic acid
condition dependent though
how and why do the conditions of hydrolysis vary with each carboxylic acid?
consider strength of Nu (H2O, unchanging), reactivity of C=O and leaving group ability (decreases)
acid chlorides: v reactive, good lg = fast @ 20˚C
anhydrides: slow @ 20˚C
esters: only on heating with acid/base catalyst
amides: only on prolonged (-3hrs) heating w strong acid / base
how does acid-mediated hydrolysis of esters and amides work?
protonates 1. the carbonyl O and 2. the leaving group (lower pKa, better LG) via a proton transfer
note: 1eq acid used for amide, hence NOT catalytic in acid
how does base mediated hydrolysis of esters and amides work?
being/creating -vely charged Nu
deprotonating the carb acid product, pulling equilibrium over (irreversibly) toward products (requires 1eq base, not catalytic)
what do the reactions of CA derivatives with alcohol produce?
esters
EXCEPT difficult to produce esters from amides even with acid/base
conditions for producing esters from each CA derivative
acyl chlorides: fast at 20˚C
anhydrides: slow at 20˚C
carb acids: heat + ACID catalyst
ester: transesterification on heating w acid/base catalyst
amide: does not occur
conditions to push the carboxylic acid – ester equilibrium
toward ester: XS alcohol w acid cat
toward carb acid: XS H2O w acid cat
(they’re basically reverse reactions of each other)
common mistake producing ester from carboxylic acid and why it does not work
base mediated / basic conditions do NOT work - only acid mediated
carb acid would deprotonate in preference to the alcohol (lower pka) forming unreactive carboxylate anion unreactive to further attack by alkoxide
FGI (retrosynthesis)
functional group interconversion
no C-C bonds broken, one functional group simply converted to another
disconnection (retrosynthesis)
C-C bonds are broken
acid chloride retrosynthesis
SM: carboxylic acid (FGI)
using thionyl chloride as reagent SOCl2
carboxylic acid retrosynthesis
FGI: from acid halides, acid anhydrides, esters or amides
by hydrolysis, various conditions
OR disconnection: CO2 and Grignard reagent
ester retrosynth
FGI: from any CA derivative EXCEPT amides
by reaction w/ alcohol
amide retrosynthesis
FGI: acid halides, anhydrides and esters
w/ amine, Nu sub @ C=O
NOT Carboxylic acids!! amine would deprotonate CA to form amine carboxylate salt.
ketone retrosynthesis
FGI: from acetals, hemiacetals and hydrates
disconnection: acid chloride / anhydride and organometallic (1eq)
1˚ alcohol retrosythesis
from aldehydes, acid halides, acid anhydrides, esters or carboxylic acids
with the right reducing agents
NOT amides! they reduce to amines
2˚ alcohol retrosynthesis
FGI: ketone + NaBH4
Disconnection: aldehyde + organometallic (1 eq)
3˚ alcohol retrosynthesis
disconnections of two of the same groups: acid halides, anhydrides, esters + organometallic (2 eq)
double Nu attack
amines retrosynthesis
amides + LiAlH4
