CHM243H5S

Overview of the course

1
Textbook

ISBN: 0199270295

Paperback
or
Kindle editions

2
Lectures/Tutorials

Mon, 12-1PM in IB-120

Wed, 12PM-1PM in IB-120
Fri, 11-NOON in DV-2074

3
 Badges

Bring them to class

every Friday

4
 depict mechanisms. At the end of the course, you
should feel increased confidence to attempt
mechanistic explanations for almost any
circumstance in organic chemistry.

Marking Scheme* Mid-Term Dat

Practicals 20 % Mon 27 Feb
WASPS* 15 % Last Drop Dat
SUABC* 10 × ½ = 5 % Sun 12 Mar
MTWT* 20 % Final Exam
FWE* 40 %
Details to be
announced.
TOTAL 100 %
The Final Exam
* See overpage for more details about period is 6-22 Ap
each component of the mark scheme.
* See course outline for further details.
Topics
5
 Students may choose to
replace their MTWT mark
with their FWE mark.

6
CHM243H5S

Week 1
Bonding

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CHM243H5S

Week 1
Nucleophilic addition to
carbonyl
39
125

Nucleophilic attack at carbonyl 40

126

Nucleophilic attack at carbonyl 41

126

Should say pi

Nucleophilic attack at carbonyl 42

127

Nucleophilic attack at carbonyl 43

127

Nucleophilic attack at carbonyl 44

128

Nucleophilic attack at carbonyl 45

128

Nucleophilic attack at carbonyl 46

128

Nucleophilic attack at carbonyl 47

128

Synthetic example

Nucleophilic attack at carbonyl 48

130

Nucleophilic attack at carbonyl 49

 Burnie - Dernitz angle

Nucleophilic attack at carbonyl 50

Nucleophilic attack at carbonyl 51
135

Hydration of aldehydes and ketones

Nucleophilic attack at carbonyl 52

134

Nucleophilic attack at carbonyl 53

135

Nucleophilic attack at carbonyl 54

136

Nucleophilic attack at carbonyl 55

136

Nucleophilic attack at carbonyl 56

CHM243H5S

Week 2
More nucleophilic additions
to carbonyls
1
139

Synthetic examples using cyanide

Don’t worry about the second steps in these transformations just yet,
but revisit this slide later, when you are revising.

Nucleophilic attack at carbonyl 2

134

Hydrating carbonyls with water

Nucleophilic attack at carbonyl 3

135

How much hydrates form depends on accessibility

and electrophilicity

0.001 2000

electronic argument: electro

1.06 withdrawing capacity of
groups

1.2E6

2280
electronic argument from the
steric argument fluorine
Nucleophilic attack at carbonyl 4
134

Nucleophilic attack at carbonyl 5

135

How much hydrates form may also depend on

other factors

Think of the strained ring

as “spring-loaded.”

Nucleophilic attack at carbonyl 6

136

Nucleophilic attack at carbonyl 7

136

Attacking carbonyls with alcohols instead of water

Nucleophilic attack at carbonyl 8

136

Attacking carbonyls with intramolecular alcohols

Nucleophilic attack at carbonyl 9

130

Attacking carbonyls with hydride?

Instead, attack carbonyls with hydride donors

Nucleophilic attack at carbonyl 10

131,132

Synthetic examples using sodium borohydride

1
change double bond O to OH and add a
H

2 OH H 4

3 5

don't worry about Bromine

Nucleophilic attack at carbonyl 11

132

LiAlH4 is stronger than NaBH4 but keep it dry!

Nucleophilic attack at carbonyl 12

132

Attacking carbonyls with organometallic reagents

Nucleophilic attack at carbonyl 13

184

Nucleophilic attack at carbonyl 14

185

How to make organolithium reagents

Nucleophilic attack at carbonyl 15

133

RLi produces secondary alcohols from aldehydes

and tertiary alcohols from ketones

Nucleophilic attack at carbonyl 16

133

Much like LiAlH4 organometallic reagents are

destroyed by moisture

Nucleophilic attack at carbonyl 17

133

Grignards (RMgX) work the same way

Making a Grignard

Nucleophilic attack at carbonyl 18

185

Common solvents used for these reactions

Nucleophilic attack at carbonyl 19

186

Complications to watch for…

Nucleophilic attack at carbonyl 20

187

Sometimes the metal might exchange…

Nucleophilic attack at carbonyl 21

187

…and that can be useful

Nucleophilic attack at carbonyl 22

188

One more thing…

Nucleophilic attack at carbonyl 23

139

Bisulphite can also add to a carbonyl

Nucleophilic attack at carbonyl 24

139

How to make cyanohydrins and stay alive

Nucleophilic attack at carbonyl 25

CHM243H5S

Week 2
Nucleophilic substitution at
the carbonyl group
26
197

The concept of the leaving group

Nucleophilic attack at carbonyl 27

198

Why are hemiacetals base sensitive?

Base

Nucleophilic attack at carbonyl 28

198

Compare the situation between a Grignard and an ester

Nucleophilic attack at carbonyl 29

198

leaving groups

Nucleophilic attack at carbonyl 30

199

Synthetic examples

Nucleophilic attack at carbonyl 31

199

Mechanism for nucleophilic substitution of acid chlorides

Nucleophilic attack at carbonyl 32

199

Acid anhydrides behave the same way…

Nucleophilic attack at carbonyl 33

199

Archetypal mechanism for nucleophilic substitution at

carbonyl

Nucleophilic attack at carbonyl 34

200,201

Me (-) leaving group is wierd, a terrible leaving group and acid

chloride is better leaving

group than ethoxide
Nucleophilic attack at carbonyl 35
203

Converting acyl chlorides to amides

Nucleophilic attack at carbonyl 36

203

mechanism

Nucleophilic attack at carbonyl 37

203

Synthetic example
O
Me
N

ME

Nucleophilic attack at carbonyl 38

203

Synthetic example

Nucleophilic attack at carbonyl 39

204

amide is most stable of all

carbonyls
Converting esters to amides

Nucleophilic attack at carbonyl 40

204

Synthetic example

O O

N
H

Nucleophilic attack at carbonyl 41

204

Nucleophilic attack at carbonyl 42

206

also would get R1 OH

Nucleophilic attack at carbonyl 43

206

𝜋 donation raises the C=O LUMO ‘out of reach’

Nucleophilic attack at carbonyl 44

206
Moiety: In organic chemistry, a moiety is a part of a molecule which is typically given a
name as it can be found within other kinds of molecules as well.

Trend in electrophilicity at carbonyl moieties

In chemistry, delocalized electrons are electrons in a molecule, ion or solid metal

that are not associated with a single atom or a covalent bond. ... In quantum
chemistry, this refers to molecular orbital electrons that have extended over
several adjacent atoms.
chloride has very week delocalization
2p
3p

Nucleophilic attack at carbonyl 45

207

Carboxylic acids do not form amides directly…

act as a base, not a

nucleophile
…unless you drive off water with heat

Nucleophilic attack at carbonyl 46

CHM243H5S

Week 3
Catalyzing nucleophilic
substitution at C=O
1
208

Addition of acid catalyzes nucleophilic attack

more posotive sp encourages a nucleophile

Nucleophilic attack at carbonyl 2

209

Synthetic examples O

Nucleophilic attack at carbonyl 3

209

All the steps in esterification are reversible

you make the carbonyl more attractive to

the nucleophile
water would more the reaction to the right, not good for making an ester

Nucleophilic attack at carbonyl 4

209

Transesterification

need acid conditions

Nucleophilic attack at carbonyl 5

210
in the WASPS

Alkaline hydrolysis of esters is irreversible

quench with HCl

only to make things reversible is in acidic contions. must lower the ph.

Nucleophilic attack at carbonyl 6

212

Acid hydrolysis of amides

Nucleophilic attack at carbonyl 7

 213

Alkaline hydrolysis of amides

boiled for 3 hours

incorrect mechanism produces NH-, this is a terrible leaving group. the conjugate acid of NH2 is
ammonia (NH3)

Nucleophilic attack at carbonyl 7

213

this is what really happens

Strong bases can force the departure of NH2–

THis is just like alkaline hydrolyses of amides

+ Me2NH

Ph OH

These tertiary amides are

more difficult to hydrolyse

Nucleophilic attack at carbonyl 8

213
maybe exam question

In fact, there is an alternate mechanism that

forces a choice between NH2– and O2–

to make it work, take a second proton off

makes a di-anion

Nucleophilic attack at carbonyl 9

CHM243H5S

Week 3
Some related interconversions

10
213
since mechanism is not shown, you don't need to know

Dehydrating amides to make nitriles

Nucleophilic attack at carbonyl 11

214

Hydrating nitriles to make carboxylic acids

Nucleophilic attack at carbonyl 12

214,215
don't worry about this slide
Making acyl chlorides from carboxylic acids (1)

Sn2 displacement

produces 2 gases. super entropicly

favoured
Nucleophilic attack at carbonyl 13
215
don't worry about this slide

Making acyl chlorides from carboxylic acids (2)

use phosphuroous or sulpfur when need to do hard
chemistry

thermodynamically favoured

Nucleophilic attack at carbonyl 14

215 print this slide

R1CO2- H2o SOCl2 or PCl5

H2o

R1OH H20 Acid or base

R1OH
acid only

NH2 R1OH, H+

NH2 H2O

strong acid or strong base

Nucleophilic attack at carbonyl 15

CHM243H5S

Week 3
Making ketones from esters

16
216
Exam question
think yo uget a key tone but yuo get a tertiary alcohol
How do we control a organometallic addition?
keytone is more reactive thatnthe ester, any
future reaction will satrt with keytstone first. this
produces the alcohol

The product of 1 is more reactive than the starting material!

Nucleophilic attack at carbonyl 17

217

Lithium aluminium hydride also cannot stop…

Nucleophilic attack at carbonyl 18

218

avoid delviereing 2 r groups. use an acid chloride. it will arget teh aid over the ester
acid is more reactive than ester.
the ketone would then get attacked not the ester
Method 1: Make the target C=O more reactive

Nucleophilic attack at carbonyl 19

219

Method 2: Use a carboxylic acid excess organolithium

carbolic acid are nomaly immune to attack. if yo uuse lithium it iwll

conatin the charge, so they methyl cann attack the more neutral
Synthetic example acoboxylica acid

OH

Et

Nucleophilic attack at carbonyl 20

219

Exam questuon!!!!
Method 3: Use a Weinreb amide

this is weird. its called a

weinreb amide

Nucleophilic attack at carbonyl 21

219

Using a Weinreb amide use this with grignar to delvier a methyl group.

stable with magenisum can come and coordiante the

2 oxygens in a 5 membered ring. sits until you decide
to quench it. it replaces the metal with proton. whole
thing will collpase and you get the keytone

Nucleophilic attack at carbonyl 22

219

Me

Nucleophilic attack at carbonyl 23

CHM243H5S

Week 3
Miscellaneous related
reactions
24
220

to make
1 Using
aldehydes
DMF to make aldehydes

this shows up again in aromatic

chemistry

Nucleophilic attack at carbonyl 25

 220

es to 2make
Using
ketones
nitriles to make ketones
uses pi * orbitals. should behave the same was if it
were a ketone

prof would put NMgBr, instead of charges

imines would hydrolyse into keytones

Nucleophilic attack at carbonyl 26

CHM243H5S

Week 4
Nucleophilic attack at C=O
with loss of carbonyl oxygen
1
222

Nucleophilic reactions at C=O, so far…

Nucleophilic attack at carbonyl 2

222

Nucleophilic reactions at C=O, where the O is lost

has to be a primary amine this is called

could be an aldehyde an imine

Nucleophilic attack at carbonyl 3

223

Review of hemiacetal formation

Nucleophilic attack at carbonyl 4

224
acetyl formation

Making acetals from aldehydes

important to understand

assited leaving. methenol does not cuase the displacement. not

enough time. what actauly ahppenes the neighoring brown
oygen comes in and causes the the disturbance. ths makes the
Nucleophilic attack at carbonyl oxonium postive and reactive 5
225

Examples of oxonium ions, where oxygen has 3 bonds

Nucleophilic attack at carbonyl 6

227

Synthetic examples
OMe

Me

OMe

O O

temporary hide a keytone

protection chemistry
Nucleophilic attack at carbonyl 7
227

Synthetic examples of acetal hydrolysis

dilute acid, this is how you unhide

MeCHO + 2 BuOH

CHO

+ 2MeOH

Nucleophilic attack at carbonyl 8

228

Cyclic acetals form even more easily

protects carbonyls

sulfur chem is 3rd year stuff

Nucleophilic attack at carbonyl 9

228

Mechanism of cyclic acetal (dioxolane) formation

could put +- H+ instead of the

arrows

quenches the + cahrge. + migtrets to incoming oxygen

one of the harder ones to have to learn

Nucleophilic attack at carbonyl 10

228

Protecting C=O with dioxolanes

not possible, because it would begin to

attack itself

first protect the keytone on the left

this will allow you to work on bromine without a cross reaction

Nucleophilic attack at carbonyl 11

230

Replacing carbonyl oxygen with nitrogen

for i inies a goldylokcs of ph of 4-6 is required!

Nucleophilic attack at carbonyl 12

230

Synthetic example proton hop not shown

Ph Ph
N

Ph H
Ph

Imine

proton hop, should +-H+

Nucleophilic attack at carbonyl 13

231b

Synthetic example

Nucleophilic attack at carbonyl 14

231,232

Imines are easily hydrolysed

if you wet an imine it will go backwards, so you are able to push it in either direction

Nucleophilic attack at carbonyl 15

232a

Some types of imines are stable

Nucleophilic attack at carbonyl 16

233

primary are more reactive than secondary alcohols

Secondary amines produce enamines

condense it with a carbonyl

hemieamanyl

this tiem there is no proton to remove from

nirtogen, to solve this lose a prton lose a proton
from neigboirng carbon. this moves the double
bond. this will produce a tortamer
Nucleophilic attack at carbonyl 17
234

Imines and enamines are in equilibrium all the time

Nucleophilic attack at carbonyl 18

CHM243H5S

Week 4
Usefulness of imines:
Reductive amination
19
234

Reductive amination

wont touch a but twil lreduce a

keytone or lithium

keytone to an amine
first rpdouce an imine, then reduced it to an amine

Nucleophilic attack at carbonyl 20

235

Reductive amination

attacking the iminium here

Nucleophilic attack at carbonyl 21

235

Reductive amination using hydrogen and nickel

this will come back again

Nucleophilic attack at carbonyl 22

236

Reduction to amines with lithium aluminium hydride

destroy acid chloride to amine. LiAlH4 is like mike tyson of reducers. will
always give you an amine when there is a nitrogen

Nucleophilic attack at carbonyl 23

CHM243H5S
difrent reactions covered so far: acetly formation 1 then iminie formation 2

Week 4
The Wittig reaction 3

24
237

Nucleophilic attack at carbonyl 25

237

Wittig reaction, Step 1 we want to make alkenes

SN2 substitution

like a tertiary amine

Nucleophilic attack at carbonyl 26

237

Wittig reaction, Step 2

add very strong base

base can deprotnate the methyl group

Nucleophilic attack at carbonyl 27

238

Wittig reaction, Step 3

this is strreacnge, makes a 4 mebered ring. it is highly

strained.

the 4 ring collapses to prodcude the product we want.

thermodynamic sink because P

and O love eathother. thnk DNA

Nucleophilic attack at carbonyl 28

CHM243H5S

Week 4
Dithianes

29
238

Dithianes are the sulphur analogues of acetals

shoud be able to do the mechianism for this !!!!

or BF3

Reaction reversal can be achieved with

mercury salts and aqueous acid

Nucleophilic attack at carbonyl 30

662

Synthetic example

Nucleophilic attack at carbonyl 31

CHM243H5S

Week 4
Formation and reactions of
enols and enolates
32
450

Reactions of enolates 33
449,450

should be heavily on the right suggested from NMR

this is the signal we see in the
NMR

Reactions of enolates 34
450

Keto-enol tautomerism
not resonance structure we are moving protons around the
molecule instead

Reactions of enolates 35
452

Acid catalyzes enolization …

Reactions of enolates 36
452

And so does base …

Reactions of enolates 37
453

In base, enolates are formed that are stabilized

can be vervy potent nuclephi;es

Reactions of enolates 33
CHM243H5S

Week 5
Formation and reactions of
enols and enolates
1
453

asymetric alyl anion

biggest is on the carbon.

carbon will be the neulceophilic
end

Reactions of enolates 2
454

Highly polarized electrophiles (such as acyl chlorides)

tend to favour nucleophilic attack by enolate oxygen
(the ‘hard’ end)

hard attack

samll orbital is hard end

large orbital is soft end. caob will attak a soft end

1 quation on exam about htis

Reactions of enolates 3
454

But otherwise nucleophilic attack occurs through

the enolate carbon instead (the ‘soft’ end)
most likely going to attack from carbon

Reactions of enolates 4
454

Reactions of enolates 5
454

here enoliszation is not possible

Reactions of enolates 6
454

Take care when enolizing esters: always use the

matching alkoxide salt as the base to avoid hydrolysis
if ethoxide then would scarmble ester. chose
base to match the ester.

Reactions of enolates 7
455

For enolizing acyl chlorides: use a hindered base

to avoid making unwanted amides

uses a hindered base. just a big base, that preents from being a good nucleophile. they
alwasys just grab protons

Reactions of enolates 8
455

Carboxylic acids cannot easily be enolized because

they are readily deprotonated to form carboxylates
that are poor nucleophiles

red is most acidic proton

cannot make enalotes from carboxili acids. id you want yo uwill need to use
strnger acid

Reactions of enolates 9
455

Carboxylic acids can, however, form ‘ene-diols’

under acid conditions either make an enoalte or en-ol

Amides are difficult to form enolates from …

Reactions of enolates 10
458

Enols are favoured in 1,3-dicarbonyl compounds

Reactions of enolates 11
459

Some enols are very stable indeed double bond next door to
hydorlyxl group makes it an
enol

Reactions of enolates 12
459
conjsugation is a srouce of stability

Unconjugated systems won’t stay that way

carbon naeigbiering any carbonyl is the alpha carbon

Reactions of enolates 13
460

Enantiomers at the alpha carbon will racemize

Reactions of enolates 14
461

Halogenation of ketones in acid

gave a proton receoverd a prton

Reactions of enolates 15
461

Synthetic example
asymetric, but only one enol is possible.

Reactions of enolates 16
462

Synthetic example

quesiton on midterm, maybe?

Reactions of enolates 17
462

Halogenation of ketones in base

get a runway reaction

hapnes a gain

happens again

Reactions of enolates 18
463

a test for methyl keytones

Reactions of enolates 19
463

Basis of the iodoform test same process as previous slides

Reactions of enolates 20
463

More control over last few slides

Acid catalyzed halogenation alternates location

Reactions of enolates 21
464

Nitrosation of enols
keytone oxime keytone

the process to step 2

very
shove 2 protons on
strong
elctrophile

convert ketone into enol from to reaect, since ketone is elctrophile it wont react this tautomerises to
step 2
Reactions of enolates 22
465

Synthetic example

O
O

NOH O

Reactions of enolates 23
CHM243H5S

Week 5
Stable alternatives to enolates

24
466

cheat for making an enol- enolate suregates

oxygen likes to hang out with silicon. most of earths crust is

O. in form of silicate

Reactions of enolates 25
466

Making lithium enolates and silyl enol ethers

diisopropyl

SN2 sub
get hindered base

Reactions of enolates 26
466

Making silyl enol ethers from lithium enolates

TMS: trimethylsilylclorate

Reactions of enolates 27
467

… and back again

Reactions of enolates 28
467

Alkylating enols at oxygen to make enol ethers

oxygen is hard end
carbon would be soft
end

want to avoid this

Reactions of enolates 29
467

Making enol ethers a better way …

Reactions of enolates 30
468

skipped this slide

Enol ethers hydrolyse easily in dilute acid

Reactions of enolates 31
468
skip

Reactions of enolates 32
469
skipped might be worth looking at using proteiction chem with enol
ethers
Acetals made from DHP are a good way of
protecting alcohols

Reactions of enolates 33
469

Hydrolysis of silyl enol ethers goes slightly differently

Reactions of enolates 34
469

We can use lithium enolates and silyl enol ethers as

a source of kinetic enolates

kinetic enolate

Reactions of enolates 35
CHM243H5S

Week 5
Alkylating enolates

36
584
Carbonyls react two ways…

Reactions of enolates 37
584

Leading to the problem of cross-reaction

enol attacks itself

aldehyde and alcohol

Reactions of enolates 38
585

Two ways around the problem: FIRST OPTION

(less convenient, multistep)
add the keytone to the base first. this way base is in excess. so it will alwasy form the enolate

convert 100% to second step

Reactions of enolates 39
585

SECOND OPTION (more convenient, ‘one pot’)

Reactions of enolates 40
585
question on exam

Approach 1: Use nitriles as less electrophilic

alternatives to carbonyl compounds

Reactions of enolates 41
585,586

Synthetic examples of monoalkylation

propyl bromide

just write base

N PH

base CN

Ph O

Reactions of enolates 42
586

Double alkylation is also possible with 2 eq. base

should write 2 eq instead of x 2

Reactions of enolates 43
587

Approach 2: Use nitroalkanes as less electrophilic

alternatives to carbonyl compounds

Reactions of enolates 44
587

Synthetic example

NO2

Reactions of enolates 45
587

Choosing the alkylating electrophile

know the steps for each

very tricky to do

Reactions of enolates 46
588
intense focus on this. know this!!!

Approach 2: Alkylations with lithium enolates

Reactions of enolates 47
588

Synthetic example

O
Me

OEt

Reactions of enolates 48
589

Cross-reacting problem with esters

Reactions of enolates 49
589

Solutions for alkylating esters: (i) add the ester to

the solution of LDA, and (ii) use a bulky ester group

Reactions of enolates 50
589

Alkylating carboxylic acids requires two

equivalents of base

act as base act as base

Here, BuLi can be used because it won’t attack –CO2Li

(apparently)

Reactions of enolates 51
590

Aldehydes are too cross-reactive to use lithium

enolates, so avoid them! never use lithium reagents like Lda with aldehydes.
us LDA with ketones or esters

You can't deprornate fast enough with LDA, so

yo ustill get cross reaction

Reactions of enolates 52
591

Approach 3: Enamines as alternatives to aldehydes

this is a keytone not an aldehyde...

Reactions of enolates 53
592

Handy secondary amines for making enamines

giveaway for enamine type synthesis

Reactions of enolates 54
592

It is important to use reactive alkylating reagents

with enamines

could attack from nitrogen instead

Reactions of enolates 55
593

Approach 4: Aza-enolates

Reactions of enolates 56
594

Synthetic example

synthesized by cyclohexanone with primary amine O

SnBu3

Check notebook for full

mechanism

Reactions of enolates 57
595

How to alkylate with tertiary alkyl halides

Ti could pull it off the halogen

Reactions of enolates 58
CHM243H5S

Week 6
Stabilized enolates and kinetic
versus thermodynamic control
1
596

Useful 1,3-dicarbonyl compounds

Reactions of enolates 2
596

Malonic ester and acetoacetic ester syntheses

base matches the type of ester

SN2 reaction

Midterm or Exam quesrtions !!!!

Reactions of enolates 3
597

How do we do this?

Na+ -O2C
NaOH HCl, Heat

H2O

Reactions of enolates 4
599

Regioselectivity with enolates

Reactions of enolates 5
599

Conjugation can favour one enolate over another

Reactions of enolates 6
599

Kinetic enolates convert to thermodynamic

enolates—given half the chance!

Reactions of enolates 7
600

Silyl enol ethers favour the thermodynamic

enolate—we can make them selectively like this…

This is true unless you made the lithium enolate first

and then added TMSCl to trap out the kinetic
product.

Reactions of enolates 8
600

We use low temperatures and strong bases like

LDA to selectively prepare kinetic enolates

Reactions of enolates 9
601

Synthetic example

Ph

Reactions of enolates 10
601

Reactions of enolates 11
601

Preparing kinetic enolates for 1,3-dicarbonyls—

making a double anion

Reactions of enolates 12
CHM243H5S

Week 6
Reactions of conjugated enones
— Michael-type addition
13
603

Michael addition—attacking 1,4 to a conjugated

carbonyl compound and generating an enolate

Reactions of enolates 14
603

lithium cuprates—adding alkyl groups 1,4 to

carbonyls

Reactions of enolates 15
604

Synthetic example

Reactions of enolates 16
605

Reactions of enolates 17
605

Reactions of enolates 18
605

Reactions of enolates 19
606

Reactions of enolates 20
606

Reactions of enolates 21
607

Reactions of enolates 22
607

Reactions of enolates 23
607

Reactions of enolates 24
607,640

Ring closures

The Darzens condensation

Reactions of enolates 25
608

Reactions of enolates 26
609
Last page before midterm

Reactions of enolates 27
CHM243H5S

Week 6
Reactions of enolates with carbonyl
compounds: the aldol and Claisen
28
615

The basis of the aldol condensation

aldahide and
alcohol

electro an nucleophole from same compiound

Reactions of enolates 29
616

Dehydration is common with stronger bases

micheal type acceptor

Reactions of enolates 30
616

Elimination is E1cB neither E1 nor E2

cB means conjusgate base

if in base

hydroxide leaves (dehydration). this is the special

the proton goes first case of E1cB

Reactions of enolates 31
616

The aldol reaction occurs in acid, too…

Reactions of enolates 32
616,617

…and elimination of water is even easier, but

goes E1

comparison
with base

dehydration

Reactions of enolates 33
617

Directing the aldol reaction

Reactions of enolates 34
617

no alpha protons
on this side

Reactions of enolates 35
618

an aldol instead of clyzen, what is a clyzen?

Reactions of enolates 36
618

Synthetic example

crossed aldol

Reactions of enolates 37
619

the mechanism from previous slide example

Synthetic example

Reactions of enolates 38
619

can only be deprotonate

the target on the Me
group

enolate formation, but this doest actauly happen

Reactions of enolates 39
620

runaway reaction

Reactions of enolates 40
620
maybe on exam

This mechanism is reminiscent of base-catalyzed hydrolysis of amides.

Reactions of enolates 41
CHM243H5S

Week 7
Summarizing alkylations
609

Summary of alkylation approaches

primary secondary tertiary

lithium enolates YES YES NO

silyl enol ethers* YES YES YES

enamines** YES NO NO

aza-enolates YES YES NO

* Use a Lewis acid such as titanium (IV) chloride or tin (VI) chloride

** Use reactive alkylators such as allyl and benzyl halides, or an α-halo carbonyl

Reactions of enolates 2
A
CHM243H5S

Week 7
The Mannich Reaction

1
621
profs favorite reaction...

Reactions of enolates 2
621

Products of the Mannich reaction can be

conveniently eliminated to form alkenes

Reactions of enolates 3
622

Reactions of enolates 4
625

Directing aldol condensations

Reactions of enolates 5
626

Synthetic examples

Reactions of enolates 6
629

Knoevenagel condensation

Doebner modification: add pyridine,

decarboxylate

Reactions of enolates 7
641

Reactions of enolates 8
643

Reactions of enolates 9
CHM243H5S

Week 7
Delocalization and
conjugation
10
141

Aromatic substitutions 11
142

Aromatic substitutions 12
142

Aromatic substitutions 13
143

Aromatic substitutions 14
144

Aromatic substitutions 15
146

Aromatic substitutions 16
146

Aromatic substitutions 17
146

Aromatic substitutions 18
147

Aromatic substitutions 19
159

Aromatic substitutions 20
160

must be sp2 carbons

Aromatic substitutions 21
160

anti aromatic (4n always gives

you anti aromatic)

6 energy lvls 8 energy lvls

Aromatic substitutions 22
161

Aromatic substitutions 23
162

Cyclopentadienyl anion is remarkably stable

Aromatic substitutions 24
162

Aromatic heterocycles

Aromatic substitutions 25
CHM243H5S

Week 8
Electrophilic aromatic
substitution
26
473

Naming relative positions around a benzene ring

Aromatic substitutions 27
474

Benzene is unreactive compared to alkenes

Aromatic substitutions 28
474

When reactions do happen they proceed by

substitution

Aromatic substitutions 29
475

Aromatic substitutions 30
476

nitronium best
electrophile

Aromatic substitutions 31
476

Benzene sulphonation
sulphuric acid reacts with itself

deprotonation

Aromatic substitutions 32
478
maybe exam question

remaniscent of Sn1 reaction

Aromatic substitutions 33
478

Aromatic substitutions 34
CHM243H5S

Week 8
Directed electrophilic
aromatic substitution
1
479

Phenol has an activated benzene ring

Aromatic substitutions 2
479

Substitution proceeds at ortho & para positions

Aromatic substitutions 3
D 480

Cooling such reactions can limit the extent of

substitution

Aromatic substitutions 4
480

Mesomeric donation of a lone pair into the ring

activates the ortho & para positions towards
electrophiles this is in pi orbitals

oxygen is donating, normaly it is taking

polarisaiton of sigma bonds is the inductive effect

Aromatic substitutions 5
481

Nitration of phenol proceeds more quickly than

for benzene

36%
25%

Aromatic substitutions 6
481

Synthetic example

paracetomol

Aromatic substitutions 7
481

Synthetic example

Aromatic substitutions 8
482

Rivers doesnt beleive this

Aromatic substitutions 9
482

becuase nitrogen i=is less elctro negative than

oxy, it is better at donating elctrons so it
Nitrogen donates even better than oxygen
doesnt stop the reaction

Aromatic substitutions 10
483
mechanism for lab 7

We can take control by diverting the nitrogen

lone pair

Aromatic substitutions 11
483

Steric effects favour formation of the para product

Aromatic substitutions 12
484

Alkylated rings are activated

mesomeric donation

60% 35% 5%

Aromatic substitutions 13
484

Alkylated rings direct to ortho and para positions

caiton stablisyse by alkyl ubstiuent

Aromatic substitutions 14
485

No stabilization for meta positions

Aromatic substitutions 15
485

Synthetic example

don't worry about this part

Aromatic substitutions 16
486

Synthetic example

Aromatic substitutions 17
487

Conversely, withdrawing groups are meta-

directing
N doest have a lone pair. this will drwa elecotnrs out of benzene ring

Aromatic substitutions 18
487

Why? Because the intermediate’s cationic charge is

least exposed to the withdrawing group

Aromatic substitutions 19
487

Attack at ortho or para positions places cationic

charge on the ipso carbon—not good!

Aromatic substitutions 20
488

Nitro groups are deactivating and direct meta

3 hilgy electro elemests N and O so highly withradwing. very deactiavted so it iwll go meta

Aromatic substitutions 21
488

Synthetic example
in WASPS

Aromatic substitutions 22
493
dont use unless you are sure it acualty works

Avoid Friedal Crafts alkylation

Aromatic substitutions 23
493

Use Friedal Crafts acylation instead

amalgum?

HCL is to rpovide porotns

Aromatic substitutions 24
494

Acid anhydrides can also be used

Aromatic substitutions 25
494

Synthetic possibilities

Reduction and oxidation 26

495

Turning a withdrawing (deactivating) group into a

donating (activating) group

Reduction and oxidation 27

495

Aromatic amines can be made into diazonium

salts with nitrous acid (HNO2)

Aromatic substitutions 28
CHM243H5S

Week 8
Nucleophilic aromatic
substitution
29
514

Nucleophilic SN2 attack cannot normally occur

on an aromatic ring

Aromatic substitutions 30
515

SN1 departure of the leaving group is unlikely

Aromatic substitutions 31
515

An addition–elimination type mechanism can

occur, however

Aromatic substitutions 32
516

Addition–elimination goes like this…

Notice we need an electron withdrawing group

Aromatic substitutions 33
516

Synthetic examples

Aromatic substitutions 34
517

A more complex example

Aromatic substitutions 35
518

Aromatic substitutions 36
518

Why is fluoride so good?

Aromatic substitutions 37
519

Useful withdrawing groups that promote

nucleophilic attack on aromatic rings

Aromatic substitutions 38
519

Synthetic examples

Aromatic substitutions 39
520

Aryl cations: they do exist!

Aromatic substitutions 40
521

Mechanism of diazotization

Aromatic substitutions 41
522

Useful reactions of diazonium salts

Aromatic substitutions 42
523

The benzyne mechanism

Aromatic substitutions 43
523

Aromatic substitutions 44
524

Synthetic example

Cl2

Aromatic substitutions 45
525

Nucleophilic attack can be directed

Aromatic substitutions 46
CHM243H5S

Week 9
Selective reduction and
oxidation
1
529

Reduction and oxidation 2

529

Reduction and oxidation 3

529

Making use of relative reactivity

Reduction and oxidation 4

530

Taking control: selective reductions

keytone
alcohol

NaBH4

Reduction and oxidation 5

530

Reducing aldehydes and ketones with NaBH4

NaBH4 pass on hydride

NaBH4

still reducing agent

so it can react
multiple times

Reduction and oxidation 6

531

more stable so need to use stringer reducing agent

Reducing esters and amides with LiAlH4

Reduction and oxidation 7

531

Reduction and oxidation 8

531

Lithium borohydride can provide additional

selectivity

Reduction and oxidation 9

531

Reducing carboxylic acids with borane

Reduction and oxidation 10

532

Borane also reduces amides to amines

Reduction and oxidation 11

533

Reducing esters and amides to aldehydes with

diisobutylaluminium hydride (DIBAH)

Reduction and oxidation 12

533
Using DIBAH for controlled reduction

Reduction and oxidation 13

534

Synthetic example

Reduction and oxidation 14

534

Using LiAlH4 at low temperatures gives control

Reduction and oxidation 15

534
know this table

slecitive for imines

Reduction and oxidation 16

535

Selectively reducing alkenes with hydrogen

Reduction and oxidation 17

535

Reduction and oxidation 18

536

Synthetic example

Reduction and oxidation 19

537

on final exam
Luche reduction uses a lanthanide

will get runaway reaction

Reduction and oxidation 20

537

Selectively reducing benzene rings

Reduction and oxidation 21

537,539

Selectively reducing alkynes to alkenes

Reduction and oxidation 22

537

Reducing acid chlorides to aldehydes: Rosenmund

reaction

Using barium salts is the key to this controlled reduction

Reduction and oxidation 23

538

Reductive amination: reducing imines

You can also use NaB(CN)H3

Reduction and oxidation 24
538

Reducing nitro groups: hydrogenation has

advantages over using Sn/HCl

Reduction and oxidation 25

530

Removing benzyl groups by hydrogenation

NaBH4 H2

LiAlH4

Reduction and oxidation 26

538

Removing benzyl groups by hydrogenation

Reduction and oxidation 27

540

Removing unwanted functional groups

Rainy Nickel

Reduction and oxidation 28

540

The Clemmensen reduction (acid conditions)

Reduction and oxidation 29

540

base conditions

The Wolff–Kishner reduction (acid conditions)

Zn, conc, HCl

?
check textbook

Reduction and oxidation 30

544

Some oxidations

Reduction and oxidation 31

544,545

Reduction and oxidation 32

544

Reduction and oxidation 33

545

Reduction and oxidation 34

545

How to stop at aldehydes

Use an organic solvent like DCM to avoid water

and the generation of hydrates

Reduction and oxidation 35

545

Oxidation with TPAP

Reduction and oxidation 36

545

The Dess-Martin oxidation

Reduction and oxidation 37

545

The Swern oxidation

Reduction and oxidation 38

546

Going all the way (to acids) with KMnO4

Reduction and oxidation 39

CHM243H5S

Week 10
Protection chemistry

1
546

Using conditions to direct reactions in compounds

with multiple functional groups

Protecting groups 2
548

Chemoselectively targeting one functional group

over another by exploiting relative reactivity

use protection chem (see next slide)

Protecting groups 3
548

Reversing the order requires protection chemistry

should say omgbr

Protecting groups 4
549

Problem #1

How do we make this

target molecule?

Protecting groups 5
549

Hiding carbonyls by protecting them with acetals

OMrBr

Protecting groups 6
549

Hiding carbonyls by protecting them with acetals

Protecting groups 7
549

Problem #2

Protecting groups 8
550

Hiding alcohols by protecting them with silyl ethers

Protecting groups 9
551

Hiding alcohols by protecting them with silyl ethers

Protecting groups 10
550

Hiding alcohols by protecting them with DHP

Protecting groups 11
551

Hiding alcohols by protecting them with DHP

Protecting groups 12
551

Hiding alcohols by protecting them with benzyl

groups

Protecting groups 13
552

Hiding alcohols by protecting them with benzyl

groups

repsentaion of r substiution. dont konw which positon its attached to,

othro meta para

Protecting groups 14
CHM243H5S

Week 10
Peptide synthesis

15
553a

Coupling amino acids to make peptides

Protecting groups 16
553

Protecting groups 17
553

Protecting groups 18
556

Hiding carboxylic acids by protecting them with

t-butyl esters

Protecting groups 19
556

Hiding carboxylic acids by protecting them with

t-butyl esters

Protecting groups 20
556

Hiding amines by protecting them as carbamates

Protecting groups 21
557

Hiding amines by protecting them as carbamates

Protecting groups 22
557

Hiding amines by protecting them as carbamates

Protecting groups 23
558

Hiding amines by protecting them with Boc

Protecting groups 24
558

Hiding amines by protecting them with Boc

Protecting groups 25
559

Hiding amines by protecting them with Boc

Protecting groups 26
559

Hiding amines by protecting them with Fmoc

Protecting groups 27
559

Hiding amines by protecting them with Fmoc

Protecting groups 28
559

Hiding amines by protecting them with Fmoc

Protecting groups 29