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1. Rabia Aziz
Organic Synthesis: The Disconnection
ApproachOneGroupC-CDisconnection of
Alcohol and Alkene
BS-IV Organic Chemistry
VIII-Semester
Jinnah University For Women
Karachi
Assignment
11/8/2018

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C-C Disconnections:
C-C disconnections are more challenging because organic molecules contain many C-C bonds.
OCFC-Chap3 2
 Disconnection and Synthons
radical
ionic
pericyclic
(homolytic)
(heterolytic)
CC CC
CC ..
+
CC CC
nucleophilic
Nu:
electrophilic
E+
Formation of C-C Bonds: the
Principles
Common Acceptor Synthons
Synthon Synthetic equivalent

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Common Donor Synthons
Derivedreagent
Synthetic
equivalentSynthon
Alternating Polarity disconnection
• The Question of how one chooses appropriate carbon-Carbon bond disconnections is related
to functional group manipulations since the distribution of formal charges in the carbon
skeleton is determined by the functional group(s) present.
•The Presence of a heteroatom in a molecule imparts a pattern of electrophilicity and
nucleophilicity to the atoms of the molecule.
•The concept of alternating polarities or latent polarities (imaginary charges) often enables one
to identify the best positions to make a disconnection within a complex molecule.
Wurtz Reaction:
Alkane can be synthesised by the catalytic hyrogenation (reduction) of alkene and alkyne; by
alkyl halide reaction with Zn and HX; and by hydrolysis of Grignard reagent. The retrosynthesis
of the alkane achieve by FGI.
An etheral solution of n alkyl halide is treated with sodium which removes the halogen of alkyl
halide and the two alkyl radicals join together to form an alkane.

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Hydrocarbons by coupling of alkyl halides.
2RX + 2Na → R-R + 2NaX
The coupling of alkyl halides upon treatment with a metal for example elemental sodium to
yield symmetrical alkanes can be prepared by the Wurtz-Fittig reaction that is the coupling of
aryl halides with alkyl halides.
Retrosynthesis:
Friedel-Crafts Alkylation:
We could disconnect BHT 13 ('Butylated Hydroxy-Toluene') at either bond b to remove the
methyl group or bond a to remove both t-butyl groups. There are various reasons for preferring
a. para-Cresol 15 is available whereas 14 is not. The r-butyl cation is a much more stable
intermediate than the methyl cation—and r-alkylations are among the most reliable. Finally the
OH group is more powerfully ortho-directing than the methyl group.
We have a choice of reagents for the /-butyl cation: a halide with Lewis acid catalysis, and r-
butanol or isobutene with protic acid catalysis. The least wasteful is the alkene as nothing is
lost. Protonation gives the r-butyl cation and two r-butyl groups are added in one operation
/-butylbenzene
Analysis

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Synthesis:
One Functional Group C-C Disconnection:
Disconnection close to the functionalgroup (path a) leads to substrates (SE) that are readily
available. Moreover, reconnecting these reagents leads directly to the desired TM in high yield
using well-known methodologies. Disconnection via path b also leads to readily accessible
substrates. However, their reconnection to furnish the TM requires more steps and involves
two critical reaction attributes: quantitative formation of the enolate ion and control of its
monoalkylation by ethyl bromide.
1. Synthesis of Alcohols:
Disconnections of Simple Alcohols:
Alcohol compounds are an important class of compounds in organic chemistry. Any compounds
possessing the group ‘R-OH, where R is alkyl group’ comes under the category of alcoholic
compounds or its derivatives. The different kind of alcohols includes primary alcohols,
secondary alcohols and tertiary alcohols (Figure 1). Alcohols have wide applicability in our daily
life. They are useful as synthetic intermediates, cleansers, cosmetics, fuels, alcoholic beverages,
etc. The synthetic and retrosynthetic analysis of alcoholic compounds are required for their
utility.

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Synthesis of alcoholic compounds by 1,1 C-C disconnections:
The C-C disconnections of alcohols are more challenging because of their vast numbers and it
becomes very difficult to identify, which C-C bond to disconnect for carbocation and
carboanion. However, there are reagents available for the generation of carbanion like RMgX
and carbocation like RBr.
For example, 2-methyl-2-propanol (1) can be made from acetone (4) and methyl magnesium
bromide (5).
Retrosynthetic Analysis:
The retrosynthetic pathway of 2-methyl-2-propanol (1) is given in figure 3. The C-C bond
adjacent to oxygen has been disconnected to give cation (2) and anion (3) as synthons. The
reagent for the cation (2) is acetone (4) and reagent for carbanion 3 is Grignard reagent, methyl
magnesium bromide (5).
Synthesis:
The synthetic pathway of 2-methyl-2-propanol (1) is given in figure 4. The reaction of methyl
bromide (6) with magnesium in the presence of dry ether gives Grignard reagent, methyl
magnesium bromide (5). The reaction of methyl magnesium bromide (5) with acetone (4) gives
the target molecule (1).

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1. Synthesis of branched side chain alcohol:
Retrosynthetic analysis:
The retrosynthetic pathway of branched side chain alcohol, 2,3-dimethylbutan-2-ol (7) is given
in (Figure 5). The C-C bond adjacent to oxygen has been disconnected to give cation (8) and
anion (3) as synthons. The reagent for the cation (8) is 3-methylbutan-2-one (9) and reagent for
carbanion (3) is Grignard reagent, methyl magnesium bromide (5), through path ‘a’. An
alternative and more popular is through pathway ‘b’.
Synthesis:
The synthetic pathway of 2,3-dimethylbutan-2-ol (7) is given in (Figure 6). The reaction of
methyl bromide (6) with magnesium in the presence of dry ether gives Grignard reagent,
methyl magnesium bromide (5) (Figure 4). The reaction of methyl magnesium bromide (5) with
3-methylbutan-2-one (9) gives the target molecule (7). The synthetic method through pathway
‘b’ disconnection approach is given in (Figure 7).
2. Synthesis of unbranched side chain alcohol:
Retrosynthetic analysis:
The retrosynthetic pathway of unbranched side chain alcohol, 2-methylpentan-2-ol (10) is given
in figure 7. Two pathways for the disconnection approach have been shown. The pathway ‘b’ is
more favoured. The C-C bond adjacent to oxygen has been disconnected to give cation 2 and

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anion (12) as synthons. The reagent for the cation (2) is acetone (4) and reagent for carbanion
(12) is Grignard reagent, (13).
Synthesis:
The synthetic pathway of 2-methylpentan-2-ol (10) is given in figure 9. The reaction of
propylbromide with magnesium in the presence of dry ether gives Grignard reagent,
propylmagnesium bromide (13) (Figure 9). The reaction of propylmagnesium bromide (13) with
acetone (4) gives the target molecule (10).
Synthesis of alcoholic compounds by 1,2 C-C disconnections:
Any compound bearing an alcoholic group can also be disconnected at the C-C bond next to the
adjacent bond to the oxygen atom. The retrosynthetic analysis in (Figure 10) shows the C-C
disconnection. The starting materials for these types of compounds are epoxide and Grignard
reagent (Figure 11).
Let us consider an example, 1-phenyl-2-butanol (14) can be made from 2-ethyloxirane (15) and
phenyl magnesium bromide.
Retrosynthetic analysis:
The retrosynthetic analysis of 1-phenyl-2-butanol (14) is given in figure 12.

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Synthesis
Using the above disconnection approach synthesis of 1-phenyl-2-butanol (14) is given in figure
13. The reaction of 1-butene (but-1-ene, 16) with peracid leads to the formation of epoxide at
the position of double bond, known as 2-ethyloxirane (15). The reaction of 2-ethyloxirane (15)
with phenyl magnesium bromide gives the target molecule (14).
COMPOUNDS DERIVED FROM ALCOHOLS
2. Alkene Synthesis:
Disconnections of Simple Olefins:
1. Synthesis of Alkenes by Elimination Reactions
Alkenes can be made by the dehydration of alcohols 2, usually under acidic conditions, the
alcohol being assembled by the usual methods. This route is particularly good for cyclic alkenes
3 and those made from tertiary and/or benzylic alcohols as the E1 mechanism works well then.
The same alkene is formed from 2 regardless of which side eliminates but 4 gives a 76% yield of
an 80:20 mixture of 5and 6.

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When Zimmermann and Keck wished to study the photochemistry of a series of alkenes of the
general structure 7 they could have put the OH group at either end of the double bond but they
chose the branchpoint 8 because dehydration of the tertiary benzylic alcohol should be very
easy and there is no ambiguity in the position of the alkene whatever R may be. They used the
Grignard method and dehydrated 8 with POCI3 in pyridine.
Eliminations on alkyl halides follow essentially the same strategy except that the reaction is
now done by the E2 mechanism with a strong hindered base to avoid SN2 reactions. This
approach is good for terminal alkenes 10 as the elimination is successful on primary halides.
The alcohol 12 can be made by any method.
So a typical synthesis might involve treating the alcohol 10 with PBr3 to make the bromide and
eliminating with t-BuOK. There is again no ambiguity in the position of the alkene.
Dienes can be made by this elimination strategy if vinyl Grignards are used as the vinyl group
blocks dehydration in that direction and makes the cation intermediate in the E1 reaction
allylic. An interesting example is the four-membered ring compound 13, disconnected via the
allylic alcohol 14 to cyclobutanone 15.
Cyclobutanone 15 is available, and also very electrophilic, so addition of the vinyl Grignard and
dehydration with the rather unusual reagent iodine gave the diene 13. This diene will be used
in a Diels-Alder reaction in chapter 17.
2. Alkene Synthesis by the Wittig Reaction
The most important method of alkene synthesis is now the Wittig reaction which gives full
control over the position of the double bond and some control over its geometry. A phosphine,

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usually triphenyl phosphine PI13P, reacts with an alkyl halide in an SN2 reaction to give a phos-
phonium salt 18. Treatment with base, often BuLi, gives the phosphoniumylid 19. An ylid is a
species with positive and negative charges on adjacent atoms. Reaction with an aldehyde gives
the alkene, usually the Z-alkene 20 if Rl is an alkyl group, and triphenylphosphine oxide 21.
The mechanism for the formation of the alkene is open to discussion especially as there is no
agreement on the source of the stereoselectivity. We suggest that the carbanion end of the ylid
adds to the aldehyde 22 and the 'betaine' then cyclises 23 to the four-membered ring which
fragments to give the products 24. There is no doubt about intermediate 24 nor that its
decomposition must be stereospecific. So the Z-alkene 20 is formed from the cis
oxaphosphetane 24.
As the Wittig reaction forms both 7t and a-bonds, the disconnection is right across the middle
of the alkene giving a choice of starting materials. So with the exo-cycYc alkene 26, very
difficult to make by elimination methods, we could use formaldehyde or cyclohexanone as the
carbonyl component with either phosphonium salt 25 or 28. It is a matter of personal choice
whether you draw the ylid, the phosphonium salt or the alkyl halide at this stage.
Wittig did this synthesis with the iodide 29, which he made himself, to give 26 in low yield
(46%) but higher yields are routinely obtained nowadays: Vogel reports 64% from the
commercially available bromide 30 using the sodium salt of DMSO as base.
Trisubstituted alkenes 32 are no trouble as either a secondary halide 35 or a ketone can be
used. As both 33 and 35 are available we choose them.
The synthesis is straightforward but does produce a mixture of geometrical isomers.

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This is another case where dehydration, even of the tertiary alcohol 36, would probably give a
mixture of positional (and geometrical) isomers.
Wittig Reactions with StabilisedYlids
The unstable aspect of the ylid is the carbanion: phosphonium salts are stable compounds so
any substituent that stabilises the anion also stabilises the ylid and this reverses the
stereoselectivity to favour the E-alkene. Even benzylic ylids give f-alkenes as in the reaction with
the anthracene 37 that gives a good yield of crystalline 38 having a coupling constant between
the two marked Hs of 17Hz. One possible explanation is that the formation of the betaine or
oxaphosphetane is reversible if the ylid is stabilised and only the faster of the two eliminations
occurs to give the E-alkene.
Applications of the Wittig Reaction
An excellent application of the distinction between stabilised and unstabilisedylids is in the
synthesis of leukotriene antagonists. The intermediate 39 (R is a saturated alkyl group of 6, 11
or 16 carbon atoms) was needed and disconnection of the Z-alkene with a normal Wittig
reaction in mind followed by removal of the epoxide exposed a second alkene with the E
configuration that could be made from the aldehyde 43 and the stabilisedylid 42
This ylid is so stable that it is commercially available and reacts cleanly with 43 to give only £-
41. Epoxidation under alkaline conditions gives the trans epoxide 40 and a normal Wittig on an
unstabilisedylid gives 39: the yield depends on R.
When the substituent becomes very anion-stabilising, as in 42, the ylid may not react with
ketones and anions of phosphonate esters are usually preferred in the Homer-Wadsworth-

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Emmons (HWE) variant. The reagent triethylphosphonoacetate 46 is made by combining a
phosphite (EtO)3P instead of a phosphine, with ethyl bromoacetate. Displacement of bromide
44 gives a phosphonium ion that is dealkylated by bromide 45.
Barrett used the reaction at the start of his synthesis of an antibiotic. The HWE reaction with
the enal 47 gives the diene ester 48 and by reduction with DIBAL, the dienol 49.
The 'optical brightener' Palanil 50—it makes your clothes look 'whiter than white' and your T-
shirts fluoresce in UV light—can be disconnected by the Wittig strategy to two molecules of the
phosphoniumylid 51 and one of the dialdehyde 52. The availability of the dialdehyde, used in
the manufacture of terylene, makes this route preferable to the alternative.
As the ylid 51 is stabilised by the nitrile as well as the benzene ring, the phosphonate ester 54 is
preferred in the manufacture and the reaction is strongly trans selective. The by-product is the
anion of dimethyl phosphate 55 which is water-soluble and very easy to separate from the
product 50. By contrast, triphenylphosphine oxide is insoluble in water and can be difficult to
separate from the alkene.
Many insect pheromones are derivatives of simple alkenes. Disparlure 56, an attractant for the
gypsy moth, is an epoxide derived by stereospecific epoxidation from the Z-alkene 57. As
neither substituent is anion-stabilising, a simple Wittig should give the right geometry.
The synthesis was carried out this way, though no doubt the alternative combination would
also work well. The synthetic material is as attractive to the moth as the natural pheromone.

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Dienes by the Wittig Reaction
Conjugated dienes are needed for the Diels-Alder reaction and Wittig disconnection 61reveals
that the choices here are more important. The easily prepared enals 62 would react with an
unstabilisedylid 63 to give a Z-alkene but the conjugated allylic ylid 60 might give the E-alkene.
The mono-substituted butadiene 66 was needed with a trans alkene in the middle. So discon-
nection 61a looks good and the allyl phosphonium salt 65 did indeed give £-66 though in poor
yield. These low molecular weight hydrocarbons are difficult to isolate as they are volatile.
Diarylbutadienes 69 can be made by method 61b as the ylid from 68 is conjugated and will give
one £-alkene while the other comes from an aldol condensation used to make the enal.
Though the Wittig is the most important, there are many other ways to make alkenes using a
variety of elements in the periodic table keeping the same disconnection.
3. Use of Acetylenes (Alkynes)
 Acetylene itself is readily available and its first important property is that protons on
triple bonds are much more acidic than most CH protons.
 They are valuable intermediates because disubstituted acetylenes can be reduced at will
to either E- or Z-alkenes by different reducing agents.
 A rather different reaction of acetylenes is the addition of water, usually catalysed by
Hg(II), to give ketones.