Organic Synthesis Flashcards
Which elements can never have more than four pairs (full octet)?
2nd row elements
e.g. B, C, N, O, F
How can you check the octet rule when drawing a mechanism?
If the arrow you’re drawing would lead to 5 pairs (on a 2nd row element), you must draw another arrow to move away one of its bonds/pairs
Where does the reactive of carbonyls come from?
The electronegative O and the electropositive C
In carbonyls, what is the O subject to attack by?
The electronegative O is subject to attack from electrophiles
In carbonyls, what is the C subject to attack by?
The electropositive C is subject to attack from nucleophiles
What is the order of reactivity of electrophiles (descending order)?
Most reactive
Acid chloride
Anhydride
Aldehyde
Ketone
Ester
Amide
Least reactive
How does the electron withdrawing ability of the connected X group for carbonyls influence reactivity?
The more electron withdrawing X is, the more reactive the carbonyl group is.
For example, acid chlorides are the most reactive, as Cl (X) is very electron withdrawing
Why do esters and amides have low reactivity?
Because they have lone pairs (from the attached N/O) that can be donated to reduce electrophility
What carbonyl groups undergo nucleophilic addition, and what is the product?
Ketones and aldehydes undergo electrophilic addition, when subjected to Me-MgBr. The product is an alcohol
How is aldehyde/ketone nucleophilic addition quenched?
By addition of water, which will stop the reaction by turning O- to OH
What carbonyl groups undergo nucleophilic addition/elimination?
Esters, anhydrides, acid chlorides and amides
Why do the prior mentioned groups undergo nucleophilic/addition reactions, and ketones/aldehydes not?
Because the R/H groups of aldehydes/ketones are poor leaving groups, whereas other groups like Cl and O are good leaving groups
How do you get from an ester to a primary alcohol?
LiAlH4 and H2O
How do you get to a carboxylic acid from a primary alcohol/aldehyde?
Jones oxidation:
CrO3, H+ (H2SO4) and acetone solvent
How do you get from a carboxylic acid to an ester?
MeOH in presence of H+ catalyst
How do you get from alcohol to aldehyde/ketone?
PCC oxidation:
Cl-CrO3- and Ar-N+-H
What is the advantage of PCC oxidation?
It can oxidise alcohols to ketones/aldehydes, without fully oxidising all the way to carboxylic acid
How do you get from an aldehyde/ketone to an alcohol?
LiAlH4 or NaBH4
Upon addition of R-MgBr and H2O (quench), what do the following become:
Aldehyde
Ketone
Ester
Acid chloride
Carbon dioxide
Aldehyde -> Secondary alcohol
Ketone -> Tertiary alcohol
Ester -> Tertiary alcohol with 2 identical groups
Acid chloride -> Ketone
Carbon dioxide -> Carboxylic acid
How many R-MgBr equivilants are required to turn ester -> tertiary alcohol?
2 eq. or more
How many R-MgBr equivilants are required to turn acid chloride -> ketone?
1 eq.
What is orthogonal protection?
A strategy of organic synthesis that allows groups to be removed independent of each other
How can protecting groups be classified orthogonally?
Protecting groups can be classified according to the conditions used for removing them
What are the 4 different ways of removing protecting groups (deprotecting)?
- Acid
- Base
- Hydrogenation
- Fluoride
What is the protecting group for aldehydes/ketones?
Acetal
How do you turn a ketone/aldehyde into an acetal?
2 eq. of R”OH (catalysed by H+)
What alcohol is often used to turn ketones/aldedehydes into acetals and why?
Diols, as otherwise acetal formation is entropically disfavoured
What does transforming a ketone/aldehyde into an acetal protect from?
It will reduce nucleophiles (including hydride reducing agents like LiAlH4) and oxidising reagents
How do you turn acetal back into a ketone/aldehyde?
(Excess) H2O, catalyst H+
When are hemiacetals stable?
When they are cyclic
When can you skip a step in the mechanism?
When all that is changing is the position of a H+. This is known as proton transfer
If you wanted to reduce an ester to an alcohol on a molecule which also contained a ketone, why is this a problem and how can it be overcome?
It is a problem because ketones are more electrophilic (so more susceptible to reduction) than esters.
This can be overcome by turning the ketone into acetal, and then reducing, as acetal is not susceptible reduction
How do you make a grignard reagent from a bromoalkane?
Mg, Et2O
Why do we need to protect alcohols?
- Alcohols are nucleophilic (especially when converted into alkoxides by a base)
- Primary and secondary alcohols are easily oxidised
- Alcohols react with very strong bases, e.g. Grignards, organolithium reagents or LiAlH4
What does THP stand for, and what is it?
THP stands for tetrahydropryranyl.
It is one possible protecting group for alcohols
How do you get from an alcohol to THP?
Dihydropyran and H+ catalyst
How do you turn THP back to R-OH?
H2O and H+ catalyst
What is the advantage of turning alcohol to THP group?
It allows you to do other chemistry on the rest of the molecule, without affecting the OH group.
Once the intended chemistry is done, THP can be converted back to OH
What do THP protected alcohols resist?
- Oxidising agents
- Hydrogenation
- Bases
- Nucleophiles (incl Grignards, organolithiums and LiAlH4)
- Fluorides
What is functional group is a THP?
An acetal
What is Bn, and what is its purpose?
It stands for benzyl, and is a protecting group for hydroxyls
What is the structure of Bn?
It is a benzene with an attached methyl group
What does Bn transform hydroxyl into?
An ether, with structure
R-OBn
How do we make Bn?
Benzyl bromide (BnBr) and a strong base (e.g. NaH)
What is the role of the strong base (NaH) in forming a Bn protecting group?
NaH takes H+ away from the R-OH, forming an alkoxide R-O-
What happens in Bn protection, after the alkoxide (R-O-) is formed?
The negative O- attacks the delta positive C on BnBr, losing the Br, and forming the Bn protection group.
This happens via Sn2
What reagents are required to turn Bn protected back to an alcohol/hydroxyl group, and what is the product?
H2 and Pd/C, the product is the original alcohol, and toluene (benzene ring-CH3)
How can you protect alcohol using Ac?
Acetyl chloride reacts with an alcohol to form a protecting ester
What are the reagents for forming Ac protecting group?
The alcohol you want to protect + Acid chloride (AcCl)
How do you turn an Ac protected group back to the original alcohol?
MeOH (solvent) and NaOMe cat
What is the Ac protecting group resistant against, and what is it no resistant against?
Resistant against:
- Oxidising agents
- Mild acids
- Electrophiles
- Hydrogenation
- Fluorides
Not resistant against:
- Mild bases
- Nucleophiles (e.g. Grignards, organolithiums, LiAlH4)
What does the TBS group help protect?
Hydroxyls
What is the structure of TBS?
It is Si, with two sticks at the top and one 3 pronged stick out the bottom left side
What are the reagents to form a TBS protected group for alcohol?
R-OH
TBS-Cl
Strong base (Et3N)
What functional group is TBS protecting group?
It is an ether (R-O-TBS)
What are the reagents for deprotection of TBS?
F- from TBAF
or
H+ from TFA
Which protecting group/s can you use under acidic conditions?
Bn or Ac both are resistant to acidic conditions
THP and TBS will turn back into alcohols under acidic conditions
Are amides good protecting groups for amines, why / why not?
No they are not, as they are too difficult to hydrolyse back to amines
What are carbamates?
Protection groups for amines; there a difference types, but they all have the structure O=C-O-R
What is benzyl carbamate also known as?
Cbz or Z or O=C-O-Bn
What is benzyl carbamate?
It is a carbamate (O=C-O-R), with the R group being benzyl
How do you form a Cbz protected amine?
Primary/secondary amine + Chloro-Cbz
In the presence of Na2CO3 & H2O
How do you deprotect a Cbz amine?
H2 + Pd/C + MeOH
What is Cbz not resistant to?
Cbz is not resistant to:
Grignards
Organolithiums
LiAlH4
Fluorides
How do you form a Boc protected amine?
Primary/secondary amine + Boc
In presence of NaOH & H2O
What does Boc stand for?
tert-Butyl carbamate
How do you deprotect Boc?
Strong acid (e.g. CF3COOH)
What are the the two possible protecting groups for carboxylic acids?
Methyl ester (Me)
Benzyl ester (Bn)
What are the reagents for protection of carboxylic acid to methyl ester?
MeOH, cat H+
OR
MeOH & SOCl2
What are the reagents for deprotection of methyl ester (back to original carboxylic acid)?
NaOH, H2O
THEN
H+
What are the reagents for protection of carboxylic acid to benzyl ester?
BnOH, cat H+
OR
BnOH & SOCl2
What are the reagents for deprotection of benzyl ester (back to original carboxylic acid)?
NaOH, H2O
THEN
H+
OR
H2, Pd/C
What do both methyl and benzyl esters not protect against?
Midle bases, and nucleophiles (Grignards, organolithiums, LiAlH4)
