Nu sub at C=O (Lent Organic)

Question 1

four types of reagents that undergo Nu sub at a C=O

Answer 1

hydride reducing agents
organometallic reagents
water
alcohols

Question 2

name the hydride reducing agent and product for reaction with acid chlorides and anhydrides

Answer 2

NaBH4, reduces them to alcohols

Question 3

name the hydride reducing agent and product for reaction with esters

Answer 3

LiAlH4 (slightly stronger than NaBH4 required because esters are less reactive than acid chlorides/anhydrides)
or LiBH4

reduced to alcohols

Question 4

name the hydride reducing agent and product for reaction with carboxylic acids

Answer 4

Borane
reduced to alcohols (all CA derivs are reduced to alcohols except amides)

Question 5

name the hydride reducing agent and product for reaction with amides

Answer 5

LiAlH4
reduced to AMINES (the only one not reduced to an alcohol)

Question 6

general mech for acid chloride / anhydride / ester w Hydride reducing agent

Answer 6

Nu attack –> tetrahedral int
good lg kicked –> aldehyde
x2 Nu attack –> alcohol

Question 7

general mech for carboxylic acid and borane

Answer 7

x3 CA + BH3 - 3H2(g) –> triacylborate intermediate
+BH3 –> alc

no more detail needed

Question 8

amide to amine reduction by hydride mech

Answer 8

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

Question 9

what do organometallic reagents react with aldehydes/ketones to form?

Answer 9

alcohols

Question 10

what do organometallic reagents react with acid halide / anhydrides to form?

Answer 10

SINGLE addition: forms ketone

DOUBLE addition: forms alcohol (ie. ketone continues to react)

can stop because acid chloride/anhydride MORE reactive than ketones

Question 11

reactions of organometallics with esters

Answer 11

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

Question 12

Grignard + CO2

Answer 12

forms carboxylic acid
Nu attack into C=O of CO2
-MgBr fragment attacks to -O, replaced with H upon workup with H3O+

Question 13

carboxylic acid with Grignard

Answer 13

MgBr or Li replaces H at -OH

Question 14

what Is produced when carboxylic acid derivatives are hydrolysed?

Answer 14

carboxylic acid
condition dependent though

Question 15

how and why do the conditions of hydrolysis vary with each carboxylic acid?

Answer 15

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

Question 16

how does acid-mediated hydrolysis of esters and amides work?

Answer 16

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

Question 17

how does base mediated hydrolysis of esters and amides work?

Answer 17

being/creating -vely charged Nu
deprotonating the carb acid product, pulling equilibrium over (irreversibly) toward products (requires 1eq base, not catalytic)

Question 18

what do the reactions of CA derivatives with alcohol produce?

Answer 18

esters

EXCEPT difficult to produce esters from amides even with acid/base

Question 19

conditions for producing esters from each CA derivative

Answer 19

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

Question 20

conditions to push the carboxylic acid – ester equilibrium

Answer 20

toward ester: XS alcohol w acid cat
toward carb acid: XS H2O w acid cat

(they’re basically reverse reactions of each other)

Question 21

common mistake producing ester from carboxylic acid and why it does not work

Answer 21

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

Question 22

FGI (retrosynthesis)

Answer 22

functional group interconversion

no C-C bonds broken, one functional group simply converted to another

Question 23

disconnection (retrosynthesis)

Answer 23

C-C bonds are broken

Question 24

acid chloride retrosynthesis

Answer 24

SM: carboxylic acid (FGI)
using thionyl chloride as reagent SOCl2

Question 25

carboxylic acid retrosynthesis

Answer 25

FGI: from acid halides, acid anhydrides, esters or amides
by hydrolysis, various conditions

OR disconnection: CO2 and Grignard reagent

Question 26

ester retrosynth

Answer 26

FGI: from any CA derivative EXCEPT amides
by reaction w/ alcohol

Question 27

amide retrosynthesis

Answer 27

FGI: acid halides, anhydrides and esters
w/ amine, Nu sub @ C=O

NOT Carboxylic acids!! amine would deprotonate CA to form amine carboxylate salt.

Question 28

ketone retrosynthesis

Answer 28

FGI: from acetals, hemiacetals and hydrates

disconnection: acid chloride / anhydride and organometallic (1eq)

Question 29

1˚ alcohol retrosythesis

Answer 29

from aldehydes, acid halides, acid anhydrides, esters or carboxylic acids

with the right reducing agents

NOT amides! they reduce to amines

Question 30

2˚ alcohol retrosynthesis

Answer 30

FGI: ketone + NaBH4

Disconnection: aldehyde + organometallic (1 eq)

Question 31

3˚ alcohol retrosynthesis

Answer 31

disconnections of two of the same groups: acid halides, anhydrides, esters + organometallic (2 eq)

double Nu attack

Question 32

amines retrosynthesis

Answer 32

amides + LiAlH4