OSMS1_2025_J
Organic Synthesis: Methods and Strategy 1
Table of content
Lecture 1: Chapter 23 ..............................................................................................................2
Lecture 2: Chapter 23—Part 2 Protecting group ...................................................................... 10
Chapter 9: Organometallic reagents—Regioselectivity ........................................................ 14
Lecture 3: Chapter 22— Conjugate addition and nucleophilic aromatic substitution ................ 17
Lecture 4:.............................................................................................................................. 22
Lecture 5: Chapter 36—Rearrangements ................................................................................ 26
Lecture 6: Chapter 26 Condensation non, stereochemical principles ...................................... 32
Lecture 7: Chapter 27—Sulfur, Silicon, and phosphorous........................................................ 37
Lecture 8: Chapter 27--Silicon chemistry ............................................................................... 42
Lecture 9: Chapter 27—Phosphorous ..................................................................................... 49
Lecture 10: Aza-enolates , enamines...................................................................................... 54
Lecture 11: Chapter 35—Pericyclic reactions ......................................................................... 58
Lecture 12: Chapter 35: sigmatropic ...................................................................................... 67
15.4 Electrocyclic reactions ............................................................................................... 76
15.2.3 Frontier Molecular Orbital (FMO) theory ................................................................ 79
1
,OSMS1_2025_J
Lecture 1: Chapter 23
Synthesis
- Structure → functional groups FG (R, A, X)
- Reactivity → C—C, redn, oxidn, …, C—X
- Reagents
Selectivity
➢ Chemoselectivity: Which functional group will react
➢ Regioselectivity: Where will it react
➢ Stereoselectivity: How will it react
Bromination
Various positions available: ortho, meta, para
Bromination at the para and ortho positions
o Ortho position: there are 2 of them, and they are both available
▪ They are much more sterically hindered than the para position
o Para position: there is only 1 para position
▪ it is less sterically hindered, therefore it will be present in a slight
excess.
Ortho/para directing group
Normally nitrogen is considered a strong EDG, however, due to the competing resonance
stabilization of the carbonyl, the methoxy group is a stronger EDG.
Hydrolysis
Hydrolysis occurs at the ester since the nitrogen is stabilized by resonance to the carbonyl.
Stronger electron donation towards the carbonyl, therefore less δ+, and therefore less
accessible.
o Regioselectivity
2
,OSMS1_2025_J
Paracetamol
If we compare the phenolic ester to the methyl ester, the phenolic ester is easier to cleave due
to its ability to stabilize the negative charge in the phenolic ring.
Resulting in phenol being a very good LG
Reactivity towards nucleophile
To determine which carbonyl is more reactive relies on the δ+ & δ-.
Lone pair stabilization decreases the reactivity of the ester carbonyl.
o Ketones are more reactive than esters
Chemoselectivity: Which functional group will react
The primary alcohol is more Bromine is better LG compared to
reactive than the secondary. chlorine, therefore, the nucleophile
attacks at this carbon.
3
, OSMS1_2025_J
Reduction
This can be done with H2, H-
o Most important reduction agents
LiAl4
o Requires inert conditions no H2O/H+
o Use THF or Et2O as solvent
o In principle, it can transfer 4 hydride molecules
Na+BH4-
o MeOH or EtOH as solvent, not easily protonated
o Will reduce only in protic solvents or in the presence of electrophilic metal
cations such as Li+ or Mg2+
o Essence: transfer a hydrogen atom with 2 electrons → hydride transfer
➢ Reduction ester → formation of alcohol
o LiAlH4 is often used
o Safer alternative: LiBH4
▪ Selectivity for esters over acids and amides
▪ NaBH4 reduces esters only very slowly
o Mechanism
4
Organic Synthesis: Methods and Strategy 1
Table of content
Lecture 1: Chapter 23 ..............................................................................................................2
Lecture 2: Chapter 23—Part 2 Protecting group ...................................................................... 10
Chapter 9: Organometallic reagents—Regioselectivity ........................................................ 14
Lecture 3: Chapter 22— Conjugate addition and nucleophilic aromatic substitution ................ 17
Lecture 4:.............................................................................................................................. 22
Lecture 5: Chapter 36—Rearrangements ................................................................................ 26
Lecture 6: Chapter 26 Condensation non, stereochemical principles ...................................... 32
Lecture 7: Chapter 27—Sulfur, Silicon, and phosphorous........................................................ 37
Lecture 8: Chapter 27--Silicon chemistry ............................................................................... 42
Lecture 9: Chapter 27—Phosphorous ..................................................................................... 49
Lecture 10: Aza-enolates , enamines...................................................................................... 54
Lecture 11: Chapter 35—Pericyclic reactions ......................................................................... 58
Lecture 12: Chapter 35: sigmatropic ...................................................................................... 67
15.4 Electrocyclic reactions ............................................................................................... 76
15.2.3 Frontier Molecular Orbital (FMO) theory ................................................................ 79
1
,OSMS1_2025_J
Lecture 1: Chapter 23
Synthesis
- Structure → functional groups FG (R, A, X)
- Reactivity → C—C, redn, oxidn, …, C—X
- Reagents
Selectivity
➢ Chemoselectivity: Which functional group will react
➢ Regioselectivity: Where will it react
➢ Stereoselectivity: How will it react
Bromination
Various positions available: ortho, meta, para
Bromination at the para and ortho positions
o Ortho position: there are 2 of them, and they are both available
▪ They are much more sterically hindered than the para position
o Para position: there is only 1 para position
▪ it is less sterically hindered, therefore it will be present in a slight
excess.
Ortho/para directing group
Normally nitrogen is considered a strong EDG, however, due to the competing resonance
stabilization of the carbonyl, the methoxy group is a stronger EDG.
Hydrolysis
Hydrolysis occurs at the ester since the nitrogen is stabilized by resonance to the carbonyl.
Stronger electron donation towards the carbonyl, therefore less δ+, and therefore less
accessible.
o Regioselectivity
2
,OSMS1_2025_J
Paracetamol
If we compare the phenolic ester to the methyl ester, the phenolic ester is easier to cleave due
to its ability to stabilize the negative charge in the phenolic ring.
Resulting in phenol being a very good LG
Reactivity towards nucleophile
To determine which carbonyl is more reactive relies on the δ+ & δ-.
Lone pair stabilization decreases the reactivity of the ester carbonyl.
o Ketones are more reactive than esters
Chemoselectivity: Which functional group will react
The primary alcohol is more Bromine is better LG compared to
reactive than the secondary. chlorine, therefore, the nucleophile
attacks at this carbon.
3
, OSMS1_2025_J
Reduction
This can be done with H2, H-
o Most important reduction agents
LiAl4
o Requires inert conditions no H2O/H+
o Use THF or Et2O as solvent
o In principle, it can transfer 4 hydride molecules
Na+BH4-
o MeOH or EtOH as solvent, not easily protonated
o Will reduce only in protic solvents or in the presence of electrophilic metal
cations such as Li+ or Mg2+
o Essence: transfer a hydrogen atom with 2 electrons → hydride transfer
➢ Reduction ester → formation of alcohol
o LiAlH4 is often used
o Safer alternative: LiBH4
▪ Selectivity for esters over acids and amides
▪ NaBH4 reduces esters only very slowly
o Mechanism
4
