Chemistry Y5: Organic synthesis Flashcards
Where do curly arrows start from?
A lone pair/ bond that will break/ negative charge
If a curly arrow leads to 5 pairs on an atom what must you do?
Add another curly arrow to break one of the bonds
Rank the reactivity of these carbonyl groups:
Aldehyde, Ester, acid chloride, Ketone, amide, anhydride
- A C
- Anhydride
- Aldehyde
- Ketone
- Ester
- Amide
Is a carbonyl more reactive if it is electron withdrawing or electron donating?
More electron withdrawing
What are the 4 ways to react carbonyls?
- Nucleophilic addition
- Nucleophilic addition/ elimination
- Nucleophilic addition/ elimination/Nucleophilic addition
- Interconverting carbonyl groups having different OX states
What is an example of Nu addition of carbonyls
Aldehyde to secondary Alcohol
*Me-MgBr then quench
What is an example of Nu Addition- Elimination in carbonyls
Acid chloride to Amide
*R-NH2 (LP on N attack C)
-RNH3
*R-NH2 attacks again (LP attacks H)
-Cl
In the Nu Addition-Elimination of Acid chloride to amide what is happening to the electropholicity (reactivity)
It is decreasing
What is essential for the Nu Addition - elimination reactions of carbonyls
A good LG
What is a reaction scheme for Nucleophilic addition/ elimination/ addition of an ester?
Ester -(ADD)- (ELIM)->
Aldehyde -(QUENCH/ ADD) -> primary alcohol
H3Al+-H- is the Nu
2 lots of H- attack
How do you get from an Aldehyde to a carboxylic acid?
CrO3, H+ (Jones reagent)
How do you get from a carboxylic acid to an Ester
- MeOH
- Cat. H+
-H2O = LG
How do you get from a primary alcohol carboxylic acid
CrO3. H+ (Jones Oxidation)
How do you get from an Ester to a primary alcohol
- LiAlH4
- H2O
How do you get from a primary alcohol to a Ketone
PCC, Cl-CrO3⁻
* Ketone is quite reactive so LiAlH4 isn’t needed
How do you get from an Aldehyde to a primary alcohol
LiAlH4
or
NaBH
How do you get from a secondary alcohol to a ketone?
CrO3 + ACID (H+, H2SO4, HCl)
How do you make acid chloride from carboxylic acid?
C. acid —(SOCl2) –> Acid Chloride
:O(H) of C. Acid attacks S of SOCl2
:B attacks H (making e.g. HCl)
Products = Cl- , SO2 (g) bubbles off, AC
What are organometallics and what are they used for?
They’re Nu’s, and strong bases (Lewis Base)
They are good for C-C bonding
R- M+ (ionic)
The more E+ve the metal the more reactive the Nu
CH3-Li
CH3-MgBr
How do you make R-MgBr? What are the conditions?
R-Br + Mg (s) —(Et2O DRY) –> R-MgBr
*Solvent must be DRY as OrganoMg reacts with water -> ACID
*Mg should get reduced in this reaction (shd get warm)
why is Et2O a v good solvent?
It has 2 LPs
What are Alkynyl Grignard reagents?
R - = - MgBr
How do you make Alkynyl Grignard reagents?
R - = - H + H3C-MgBr ->
R - = ⁻ + MgBr⁺ + CH4. <—> R - = - MgBr
H3C-MgBr is a waste product so should be used sparingly
What are the possible reactions with organomagnesium?
- Nu addition
- Nu addition/ elimination/ addition
- Nu addition/eliminaiton
Nu Addition with organoMg
- Formaldehyde -> 1. Alcohol
- Aldehyde -> 2. Alcohol
- Ketone -> 3. Alcohol
Reagents:
1. R’‘MgBr
2. H2O
Nu Addition/elimination/ addition with organoMg
Ester -> Ketone -> 3. Alcohol
Nu addition/ elimination with organo Mg
Acid chloride -> Ketone (1eq)
AC -> ketone -> 3. Alcohol (2eq)
(eqs of R’‘MgBr)
How do you make organoLi
R-Br + 2Li —(EtO2 DRY)–> R-Li, Li-Br
R⁻Li⁺
If you want to make a ketone using organoMg what should you start with?
Acid chloride and 1eq of R’‘MgBr
Not Ester as you will get a mixture of Ketone, 3. Alcohol and ester
What is the structure of Et2O
H3C-C(H2)-O-C(H2)-CH3
What are the 3 types of selectivity?
- Regioselectivity
- Stereoselectivity
- Chemoselectivity
What is stereochemistry?
The biological and physical properties of organic molecules depend largely on stereochemical arrangement of functional groups
What is the definition of stereoselectivity?
And give an example we need to know
preferential formation of 1 stereoisomer over another in a chemical reaction
-Conjugate addition
in the conjugate addition of a Me group onto an aromatic ring where the stereochemical arrangement is 98% TRANS favoured what organometalic compound should be used as a reagent?
- Me2CuLi
- Followed by H+/H2O
Me Taken from Me2CuLi and added to aromatic in Meta position (98% TRANS) due to steric hinderence)
Enols and ketones are (——-) of each other?
Tautomers
Enols tautomerise to ketones
How do you make Organocopper reagent?
2MeLi + CuBr ——> Me2CuLi +LiBr
What does it mean is a reaction is stereospecific?
If the starting materials differ only in their configuration are converted into stereoisomeric products
e.g Dehydroxylation of alkenes
-Products always the same just isomers of each other
How can you control chemoselectivity?
- Number of eqs
- Time
- Chemoselective agents
What is an example of a chemoselective agent?
NaBH4
Sodium Borohydride is less reactive than LiAlH4, it reduces both ketones and aldehydes NOT esters
Why is NaBH4 not as reactive as LiAlH4?
Na is not as e+ve as Al
Not as reactive
Not as strongly ionic
What would the reagents be to convert:
O =[ Benzene] - Ester
to
HO-[Benzene]-OH
- LiAlH4
- Et2O
- H2O
*Both groups get reduced
What would the reagents be to convert:
O =[ Benzene] - Ester
to
HO-[Benzene]-Ester
- NaBH4
- Et2O
- H2O
- Ketone reduces
*Ester unaffected
What would the reagents be to convert:
O =[ Benzene] - Ester
to
O=[Benzene]-C(H2)-OH
Use protecting groups
*Ketone unaffected
*Ester reduced
Why do we need to protect functional groups?
In order to react ONLY the least reactive group
What makes a good PG?
- Easy to install
- Resists conditions that could damage functionality
*Easy to remove under mild and specific condictions- that don’t affect other groups - Cheap + sustainable
Why do PGs reduce atom economy?
They don’t appear in the final product
What are orthogonal sets used to remove PGs?
- Acid (HCl, HC3COOH)
- Base (OH-, RO-)
- Hydrogenation (H2, pd/c)
- Fluoride ions (F-)
Ideally PGs only belong to 1 Orthogonal set
What is the PG for Aldehydes and ketones?
2eqs of R’‘OH, which forms an acetal + H2O
-Diols are often used otherwise acetal formation is entropically unfavourable
What is the mechanism for Protection of an Aldehyde or ketone using 2 eqs R’‘OH
- Protonate ketone
- react with OH = Nu attack
- Proton transfer
- Lose H2O
- React with 2nd OH
- Lose H+
State the reagents requires to protect and deprotect a ketone whilst reducing an ester functional group?
- Diol + Cat. H+
- LiAlH4 + H2O
- H2O + Cat.H+
What are the 3 things were trying to protect with PGs
- Ketones and aldehydes
2.Hydroxyl groups (alcohols+Phenols) - Amines
What PG do we need to protect hydroxyl groups?
PGs belonging to the orthogonal set: ACID
What are the Hydroxyl PGs?
- THP
- benzyl (Bn)
- Acetyl (Ac)
- (TBS)
What do THP protected alcohols resist to?
Ox agents, Hydrogenation, Bases, Nu (grignards reagents), fluorides
what are the conditions to protect and deprotect a:
primary alcohol <-> Acetal
Protect: Dihydropyran
Deprotect: H2O, Cat. H+
What are the conditions to protects and deprotect a:
Primary alcohol <-> Ether
Protect: “BnBr”
Deprotect: H2, pd/c
PG = ‘Bn”
What are the conditions to protect and deprotect a:
Primary alcohol <-> Ester
Protect: “AcCl”
Deprotect: Cat. NaOMe (base), MeOH (solvent)
PG =”Ac”
What do Bn protected alcohols resist?
*Ox Agents
*Most Nu, Electrophiles and bases
*Fluorides
What do Ac protected alcohols resist?
*Ox Agents
*Mild acids
*Electrophiles
*Fluorides
*Hydorgenation
What are Ac PGs removed by?
Mild bases and Nu’s (Grig, Org.Li, LiALH4)
What are the conditions to protect and deprotect a:
Primary alcohol <-> Silyl ether
protect: “TBS-Cl”
Deprotect: F- or H+
PG= TBS
What do TBS protected alcohols resist?
*Ox agents
*Hydrogentation
*Electrophiles
*Most Nu’s
What are TBS PGs removed by?
Flourides:TBAF (Tetrabutylammoniumfluoride)
Acid: TFA (CF3COOH)
(Trifluoroacetic acid)
What do the reagents BU4, NF deprotect?
TBS
What does the reagent H3O+ deprotect?
THP and TBS
What do the reagents Cat. NaOMe and MeOH deprotect?
Ac
What do the reagents H2 and pd/c Deprotect?
Bn
what are good PGs for Amines, and why?
Carbamates,
*Easy to install
* Lp conjugated to carbonyl (Not Nu)
*Carbamates are not v reactive towards Nu’s
*Can be converted back to amines
What would be a way to show why carbamates aren’t good Nu’s?
Show the resonance structure
-Lp Ends up in a +ve and -Ve charge on the molecule
What are the conditions to protect and deprotect a:
Primary amine <-> “CBZ” carbamate
Protect: “Cl-cbz” , Na2CO3, H2O
Deprotect: H2, pd/c, MeOH
PG= cbz
What do CBZ carbamates resist to?
*Ox agents
*Most E’s
*Acids
*Bases
*Most Nu’s (NOT grig, orgLi, LiAlH4)
*Fluorides
What are the conditions to protect and deprotect a:
Primary amine <-> “BOC” carbamate
Protect: BOC, NaOH, H2O
Deprotect: Acid- TFA (CF3COOH)
what do BOC carbamates resist to?
*Ox agents
*Most E’s
*Hydrogenation
*Bases
*Most Nu’s (NOT Grig, orgLi, LiAlH4)
*Fluorides
Why is the deprotection of BOC and CBZ carbamates irreversible?
The bi-product CO2(g) will bubble off
What are proteins?
polymers of AAs linked via peptide bonds
What is the basic structure of all AAs?
Glycine
H2N-C-C(=O) - OH
The C next to the amine group is always chiral
All Have primary amines (except Proline which is 2nd)
What is the C and N terminus of a peptide?
C = Carboxyl end
N = Amino end
Why does peptide synthesis require PGs?
*If not an Acyl chloride would form (V. reactive and it would self react)
*Or a zwitterionic complex would form = No LP on the N = Not soluble in organic solvents
SO,
Any ‘R’ groups with any functionality must be protected
* If all reactive groups are protected then a peptide bond will form and HCl will be removed
What coupling method is best for peptide sythesis?
DCC (need to know method)
-I think will come up on exam!
* Forms urea as side product
When making an acid chloride why can’t BOC be used?
Because the conditions required also generate HCl
-ACID = no boc
what conditions would you use to deprotect CBZ and ph and make a peptide?
H2, pd/C
How would you protect analine’s N terminus
boc2O and NaOH
How would you protect glycine’s C terminus
H-O-Bn and NaOH
What is DCC
Its the combination of the BOC protected analine + Bn protected glycine
How would you deprotect DCC?
CF3COOH (TFA), H+ and then H2, pd/c
What is retreosynthesis?
Disconnect bonds you know how to make (e.g. esters) continues until you reach starting materials
-Working backwards
What conditions do you need to go from Bn- C(H2)-Br to ph-C(H2)- MgBr
- Mg
- Et2O
What conditions do you need to go from ph-C(H2)- MgBr to ph-C(H2)-C(CH3₂)-OH
- acetone (H3C-C(=O)-CH3)
- H2O ‘QUENCH”
What conditions do you need to go from ph-C(H2)-C(CH3₂)-OH to
ph-C(H2)-C(CH3₂)-O-C(=O)-CH3
- Acid chloride
- Pyridine (weak base added to trap HCl generated during ester formation)
where do you disconnect in retrosynthesis?
At branching points and remove chains from rings if possible
* Look for symmetry
In the forward step what must you remeber to mention
QUENCH
what size of compound should you try break down into
7 carbons or less
-Only 1 functional group
What is a synthon
A generalised and frequently imaginary fragment produced by a disconnection
Synthons and their synthetic equivalents
1. R+
2. R-
3. 2nndary alcohol cation
4. R-C(+)=O
- RBr/ RI
- RMgBr/ RLi
- ketone
- Acid chloride
