C[-] synthon
O=C-C[-] synthon
O=C[-] synthon
HO(C=O)[-] synthon
C[+] synthon
HO-C[+] synthon
O=C[+] synthon
HO-C-C[+] synthon
O=CCH2C[+] synthon
HO(O=)C[+] synthon
Direct N-Acylation
Amide bond formation
N-acylating agents
N-acylation mechanism
N-acylation needs
N-acylation base can cause problem by…
Stop base reacting with acylating agents by…
Biphasic acylation reactions to make amides using amines and acid chlorides are known as
N acylation using acid anhydrides often use lewis base catalysts such as
N acylation strategies all the same for
O acylation makes
Common acylation agents are
Protecting groups are
Amine protecting groups abbreviations
Cbz means
Cbz add (to amines only) with…
Cbz protects against aka DOES NOT react with…
Cbz removal using
Cbz synthesis using
Cbz are super useful because
Cbz are orthogonal to
Benzyl pg add to alcohols OR amines OR carboxylic acids with
Benzyl pg protects against
Benzyl pg remove with
Benzyl pg removal mechanism
PMP and benzyl groups are related - both removed with
PMP is basically a benzyl PG with an added para group
Fmoc pg means
Fmoc addition using
Fmoc useful in solid phase protein synth because
Fmoc addition mech
Fmoc are stable to
Fmoc removed using
Fmoc removal mechanism
Fmoc orthogonal to
Fmoc pka is approx
Boc pg means
Boc pg addition
Boc pg removal
Boc pg stable to
Boc pg orthogonal to
Also protect Amines with TsCl and NsCl known as
Protecting groups for carboxylic acids
Methyl ester pg installed using
Methyl ester pg removal using
tert Butyl ester protecting group for carboxylic acids add to using
tert Butyl ester pg protects against
tert Butyl ester pg removal use
Potassium carbonate pka
Triethylaminium pka
Pyridinium pka
Phenol pka
Thiophenol pka
Thiophenol pka acidity lower than phenol because
Piperidinium pka
Imidazolium pka
DMAP ium pka
K2CO3 with methanol makes
K2CO3 potassium carbonate useful base as it
K2CO3 in water dissociates into
Cs2CO3 similar to K2CO3 however the Cs makes it more
Carbonyl ketone and aldehyde protecting groups
Primary alcohols selectively protected over secondary alcohols using
Methyl ether phenol or alcohol pg deprotection
Amide bond formation in Peptide coupling requires Coupling reagents because
Peptide coupling reagents are…
Two main types of amide coupling reagents are…
DCC stands for…
Other carbodiimides are…
Coupling reagents work by…
Coupling reagent mechanism
Catalytic lewis bases =
Catalytic lewis bases are used to…
Common catalytic lewis bases =
Coupling reagents can also be used to make….
Disadvantage of coupling reagents is
EDCI is advantageous because
HOBt attacks via
Heteroatom Alkylation is useful as
Oxygen and Sulfur nucleophiles are often…
Want to have oxygen or sulfur nucleophiles deprotonated to react with..
Electrophile structure effects rate of substitution because…
Secondary Chloride, Ethyl Chloride, Me-Cl, Benzyl Cl, PhC(=O)CH2Cl order of Sn2 rate…
Why is PhC(=O)CH2Cl fastest at reacting with nucleophiles…
Conjugation of antibonding orbital ie sigma* and pi* orbitals increases rate of substitution by…
Leaving group ability depends on…
Water H2O or HOH has its conjugate base of HO[-] so is a…
Acidity of halides increases from…
Therefore the leaving group ability of halides increases from…
In Nucleophilic aromatic substitution F is the best leaving group because
As HO[-] is a poor leaving group need an activating group such as…
Nosyl groups are
Trifyl groups are
With nitrogen Ts, Ns, Tf, Ms groups bond to N and…
Triflic acid pka = Super Acid
Hydrogen iodide pka
Nosyl groups very useful [avoids overalkylation :)] for secondary amine synthesis by…
Trifyl groups bound to oxygen are useful as…
Ammonia with Alkyl-halides is problematic because
Sodium Azide-alkyl halide synth combo'd with Staudinger reduction used to synthesise…
Azide-amine synth uses…
Staudinger reduction used to…
Staudinger reduction uses reagents…
Gabriel synthesis also used to synthesise…
Gabriel synthesis involves using…
The alkyl-Phthalimide then is de-protected using
Secondary and tertiary amines are made using…
Reductive amination is also known as
Reductive amination is the process of…
Reductive amination is an alternative too…
Direct alkylation can happen multiple times per amine however…
Adding a carbonyl to an amine occurs best under…
Mildly acidic conditions best because…
Imine or protonated iminiums can be reduced using…
How does the reactivity of NaBH3CN over NaBH4 compare…
What is the significant benefit to using NaBH3CN over NaBH4...
NaBH3CN does not react with
Reductive aminations are run as…
Reductive aminations used to synthesise…
Why is a onepot approach to reductive amination useful?
Reductive amination mechanism…
Care must be taken with NaBH3CN why?
Nucleophilic aromatic substitution involves the reaction of….
Nucleophilic aromatic substitution involves what two steps?
Nucleophilic aromatic substitution reactions are known by what shorthand?
Typically SnAr reactions involve three features…
SnAr reactions never have the electron withdrawing group in what position relative to the LG
SnAr reactions can occur frequently with other species such as…
Typically a base is equired in SnAr reactions to…
The two main requirements for SnAr reactions are…
With SnAr on heterocycles what needs to be considered and why?
In SnAr the nucelophile attacking the ring MUST attack the Carbon joined to the…
Which is the rate determining step in SnAr?
A key feature of SnAr reactions is that the…
Rate of SnAr reactions is therefore NOT dependent upon…
The fastest substiution occurs with the most electronegative halide Fluoride why?
With meta electron withdrawing groups to the leaving group, what happens?
As the position of the leaving group on the ring determines the site of nucleophilic attack…
The trends for SnAr are inverse to that of EAS…
Aryl Fluorides are significantly better leaving groups in SnAr even when…
The negatively charged intermediate in SnAr is known as the
SnAr involves how many steps in its mechanism
Even though breaking the C-F bond is energetically challenging…
In a reaction energy diagram the transition state and intermediates are represented by
The SnAr reaction energy diagram
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