1.
C-X DISCONNECTION & C-C DICONNECTION

2.
CONTENT
• Introduction of disconnection approach
• Retrosynthetic analysis FAQs
• C-X disconnection
a) One group disconnection
b) Two group disconnection
• C-C disconnection

3.
DISCONNECTION APPROACH
• An approach for designing organic synthesis which involves
breaking down of target molecule into available starting
material by imaginary breaking of bonds (disconnection)
and/or by functional group interconversion is known as
disconnection approach or retrosynthesis or synthesis
backward.
• This is the process of synthesis design which starts with
product and works backward towards the starting material.
• Retrosynthesis is indicated by using “=>” symbol.

4.
DISCONNECTION APPROACH
The aromatic amide amelfolide is a cardiac antiarrhythmic agent. Because we
see that it is an amide, we know that it can be made quite simply from p-
nitrobenzoyl chloride and 2,6-dimethyl-aniline again, we can represent this
using a retrosynthetic arrow. Mentally breaking a molecule into its component
parts like this is known as disconnection, and it’s helpful to indicate the site of
the disconnection with a wiggly line as we have here.

5.
• These are the few general strategy which are important points introduced which apply to the whole
of synthetic design rather than one particular area. The main choice is between the various
disconnection, even such a simple disconnection as the following alcohol can be disconnected.
• We want to get back to simple starting materials and we shall do if we disconnect the bond which
are:
a) Towards the middle of the molecule thereby breaking into two reasonably equal halves rather than
chopping off one or two carbon atoms from the end and,
b) At a branch as this is more likely to give straight chain fragments and these are more likely to be
available.
• Disconnections very often take place immediately adjacent to, or very close to functional groups in
the target molecule. This is pretty much inevitable, given that functionality almost invariably arises
from the forward reaction.
Retrosynthetic analysis FAQs
How to choose a disconnection?

6.
A good disconnection visibly simplifies the target molecule. Otherwise, the synthesis challenge doesn’t get any
easier.
A good trick here is to consider whether you can draw a resonance form of the synthon which looks more like a
real reactive intermediate. If it does, you’ve clearly made a good choice of polarity, and you’ve most likely gone a
long way to identifying the synthetic equivalent.
How do I recognize a good disconnection?
How do I decide which synthon carries which charge?

7.
See immediately above, and consider also the inherent polarization of the key reactive bonds within your proposed
synthetic equivalent; the synthon is often just an extreme, imaginary version of the real-life situation.
• Recognize the functional group in the target molecule.
• For compounds consisting of 2 parts joined by a heteroatom, disconnect next to the heteroatom.
• Disconnection next to aromatic ring should not be a priority.
• Consider alternative disconnections and choose routes that avoid chemo selectivity problems—often this means
disconnecting reactive groups first
• Disconnection must correspond to known, reliable reactions.
How do I identify the synthetic equivalents of my synthons?
Overall important points for choosing a disconnection

8.
C-X DISCONNECTION
• The C-X disconnection approach is mainly applicable to a carbon chain attached to
any of the heteroatoms like O, N, or S. Here, a bond joins the heteroatom (X) to the
rest of the molecule like a C-O, C-N, or C-S group. This point is good point to
initiate a disconnection. This is called a ‘One-group’ C-X disconnection as one
would need to identify only one functional group like ester, ether, amide etc. to
make the disconnection.
• The corresponding reactions are mainly ionic that involve nucleophilic
displacement by SN1, SN2 or carbonyl substitution with amines, alcohols and
thiols on carbon electrophiles.

9.
C-N AMIDE
DISCONNECTION • The synthesis is very simple. The only
point worth noting is the use of
catalytic hydrogenation for the
reduction rather than the very messy
tin and HCl,
• Industry greatly prefers catalytic
methods with no toxic by-products.
A simple example is the weedkiller propanil used on rice
fields. Amide disconnection gives amine obviously
made from o-dichlorobenzene by nitration and
reduction. All positions around the ring in o-
dichlorobenzene are about the same electronically but
steric hindrance will lead to dichloronitrobenzene being
the major product.

10.
C-O ETHER
DISCONNECTION
We can apply these ideas to the synthesis of the
herbicide 2,4-D (2,4-dichlorophenoxyacetic acid).The
most reasonable disconnection of an ether is the C-O
bond because we know that ethers can be made from
alkyl halides by substitution with an alkoxide anion.
Once the retrosynthetic analysis is
done, we can go back and use our
knowledge of chemistry to think of
reagents corresponding to these
synthons. finish. It isn’t reasonable to
try to predict exact conditions for a
reaction: to do that you would need to
conduct a thorough search of the
chemical literature and do some
experiments.

11.
C-O ESTER
DISCONNECTION
A simple example to explain the disconnection
approach:
This compound is an insect repellent and as a
solvent for perfumery. As it’s an ester, we know
that it can be made from alcohol plus acyl
chloride, and we can represent this using a retro
synthetic arrow.
The analysis reveals two available compounds:
benzyl alcohol and benzyl chloride. Combining the
two pyridine as solvent and catalyst gives the ester.

12.
C-S SULFIDE
DISCONNECTION
Chlorbenside is used to kill ticks and mites.
For compounds consisting of two parts
joined by a heteroatom, disconnect next to
the heteroatom, we can suggest a
disconnection next to the sulfur atom.
Chlorbenside
synthesis:

13.
TWO GROUP C-X
DISCONNECTION
This compound was needed for some
research into the mechanisms of
rearrangements. We can disconnect
on either side of the ether oxygen
atom, but (b) is much better because
(a) does not correspond to a reliable
reaction: it might be hard to control
selective alkylation of the primary
hydroxyl group in the presence of the
secondary one.

14.
TWO GROUP
DISCONNECTION
The Zeneca drug propranolol is a beta-blocker
that reduces blood pressure and is one of the
top drugs worldwide. It has two 1,2-
relationships in its structure but it is best to
disconnect the more reactive amine group first.
The second disconnection can’t make use of an
epoxide, but a simple ether disconnection takes
us back to 1-naphthol and epichlorohydrin, a
common starting material for this type of
compound.
(isoproplyamine)

15.
C-C DISCONNECTION The only functional group is the triple
bond, and we shall want to use the
chemistry of alkynes to show us where to
disconnect. You know that alkylation of
alkynes is a reliable reaction, so a
sensible disconnection is next to the
triple bond.
The disconnections we have made so far have all been
of C–O, C–N, or C–S bonds, but, of course, the most
important reactions in organic synthesis are those that
form C–C bonds. We can analyze C–C disconnections in
much the same way as we’ve analyzed C–X
disconnections.
Consider, for example, how you might make this simple
compound, which is an intermediate in the synthesis of
a carnation perfume.

16.
C-C DISCONNECTION
• In planning the synthesis of phenylacetic acid,
two synthons are identified. A nucleophilic "-
COOH" group, and an electrophilic "PhCH2+"
group.
• Of course, both synthons do not exist per se,
synthetic equivalents corresponding to the
synthons are reacted to produce the desired
product.
• In this case, the cyanide anion is the synthetic
equivalent for the −COOH synthon, while benzyl
bromide is the synthetic equivalent for the
benzyl synthon.
• The synthesis of phenylacetic acid determined by
retrosynthetic analysis is thus:
PhCH2Br + NaCN → PhCH2CN + NaBr
PhCH2CN + 2 H2O → PhCH2COOH + NH3
In fact, phenylacetic acid has been synthesized
from benzyl cyanide itself prepared by the
analogous reaction of benzyl bromide with sodium
An example of C-C disconnection will
allow the concept of retrosynthetic
analysis to be easily understood.

17.
C-C DISCONNECTION With two carbonyl groups, the alkylation
should be particularly straightforward
since we can use a base like methoxide.
The ether disconnection is then
immediately obvious. In the synthesis of
arildone the alkyl iodide was used for the
alkylation.
Arildone is a drug that prevents polio and herpes simplex viruses from
‘unwrapping’ their DNA, and renders them harmless. It has just the
structural characteristic you should be looking for: a branch next to a
carbonyl group.
2-chloro-5-
methoxyphenol
1,6-
dibromohexane

18.
FEW OTHER EXAMPLES
Paracetamol, for example, is an amide that can be disconnected either to amine + acyl chloride or to amine +
anhydride.
Retrosynthesis of propoxycaine

19.
FEW OTHER EXAMPLES
Benzocaine, we see an ester group and known that esters are reliably made from some derivative of
an acid and an alcohol. We should disconnect the C-O ester bond.
Retrosynthesis of ibuprofen

20.
REFERENCE
• ORGANIC. CHEMISTRY SECOND. EDITION.
Jonathan Clayden Nick Greeves Stuart Warren.
• Organic Synthesis: The Disconnection Approach, 2nd
Edition Stuart Warren, Paul Wyatt.