20

rganic Synthesis
Table 6.2: Effect of Substituents on Electrophilic Aromatic Substitution

Ortho-Para Directors Meta Directors

TH

Strongly Activating Moderately Deactivating 6.8

-N H2-N HR,-NR2 -C=N

-SO3H
Acis
-C0 2H,CO2R the
-CHO,COR

Moderately Activating Strongly Deactivating

Fo
-N HCOCH3,-N HCOR -NO2
A
-NR3
-9 CHg,-9R
-CF3,-CCl3

Weakly Activating
CH3.-C2Hs,-R
-CgHs
Weakly Deactivating

6.8 One Group C-X Disconnections

One group disconnection is a fundamental approach to synthetic design. It involves the disconnection of
only one functional group which we need to recognise to know that we can make the disconnection e.g, in
case of ethers, amides and sulphides the position of disconnection is easily decided, we disconnect a bond
joining carbon to the hetero atom O, N or S. Also in case of aromatic compounds the position o
disconnection needed no decisic
The corresponding reactions are mostly ionic and involve nucleophilic hetero atoms as in alcohols (ROH),
amines The disconnection will therefore yield a cationic carbon synthon (I).
(RNH2) or thiols (RSH). The
reagent for (1) will usually have a good leaving group attached to R(2). Thus the reaction is a substitutionof
some kind and the reagents will be alkyl halides, acylchlorides and the other like reagents which undergo
substitution most readily

R RY Y Br, OTs , etc.

(1) (2)
 The Disconnection Approach
21
6.8.1 Carboxyl Derivatives
R-C-X

Acid derivatives are easily disconnected so we prefer to choose the bond between the carbonyl group and
rhe hetero atom for our first disconnection (i)

R-C +X C-X R--Y XH ..(1)

For example the ester (G) can be disconnected in this way.

Analysis

CH2
CH2 ester
Ph OH Ph
Ph O Ph
(3)

Synthesis
CH2 PhCOCl
TM(3)
Ph OH Pyridine
The synthesis can be carried out is a number of ways; but the use of acid chloride (Y =CI) is the easiest; with
pyridine as catalyst and solvent. Acid chlorides are the most reactive of all acid derivatives and can be made
from the acids themselves with PCls or SoCl2

Propanil (4)is an amide; it can be disconnected to an amine (5) and an acid chloride. Further
disconnection of the aromatic amine (5) follows from our earlier discussion.
Analysis

NH
NH2

amide

Cl C
(4) NO2 (5)

CN
Nitration
CI
CI
Cl Cl
 22
Organic Synthesis
The orientation for nitration is correct; stearic hindrance will prevent formation of much
1, 2 ,
trisubstituted compound.
Synthesis
NO2 NH2

HNO3 H Et COCl
TM (4)
H2S04 Pd.C
CI
CI

CI CI Cl
(5)

6.8.2 Alcohols, Ethers, Alkyl Halides, and Sulphides

One group C-X disconnection in aliphatic compounds (RX) gives nucleophile XH and an electrophilie
a

carbon species (R*) usually represented by an alkyl halide, "tosylate (ROTs) or mesylate
(ROMs). These
compounds can all be made from alcohols and as alcohols can be made by C-C bond formation, so we
shall treat the alcohol as the central functional group.
Analysis
RX R +XH
RBr or ROTs or ROMs

Synthesis
TsCl
ROTs
Pyridine
RBr PBr3
or ROH
HBr MsCl
ROMs
EtgN

Synthesis of aliphatic compound from alcohols (Table 6.3)

R'OH
R'SH base ROR Ethers
RSR
base Suphides
ROH RX
1. (NH2)2 CS
RSH Thiols
2. HO/Hgo
Hal R-Hal
X=halide, OTs, OMs Alkyl halides
Nu RNu Other derivatives

Tosylate=toluene p-sulphonate; Mesylate=a methane sulfonate

 The Disconnection Approach|
23
Condition for synthesis are to be chosen to suit the structure of the molecules. e.g., Methyl and primary
allv derivatives react by SN2 mechanism so powerful nucleophiles and non-polar solvents are effective;
uhereas tertiary compounds react even more easily by the S mechanism via stable carbonium ions (6)
generated directly from alcohols, alkyl halides, or even alkenes. Powerful nucleophiles are of no help here
but polar solvents and catalysis (usually acid or Lewis acid) help by making the OH a better leaving group.

R1-
R3
R2

R- OH R1- RI-
R3 -R3 R3
R2 R2 R2

6)
Polar
solvent
Rl- Br
R3 37976
R2

The nitro compound (7) and the azide (8)-examples of other derivatives in the above table are easily made
from the corresponding bromides by SN2 reactions as they are both primary alkyl compounds.

Br NaNO2 NO2
Urea
DMSO
(7)

,N3
Ph Br NaN3 ph
(8)

Allylic (9) and benzylic (10) derivatives react easily both by S and SN mechanisms so conditions are not
so important here. However secondary alkyl derivatives are most difficult to make and so conditions need
to be rather harsh in these cases.

Br Nu Nu

(9)
Nu
Br Ar Nu
Ar
(10)
 24
Organic Synthesi
The
6.8.3 Ethers and Sulphides Synthes
Ttis very obvious depending
TM for first disconnection
to choose
either side of the reactivin on
Vity (oa
the
lackof itd eg p-methoxy toluene (11) used as wall flower perfume has a reactive side (Me, bySNg )and.
unreactive (Ar) side so disconnection is easy.
The sa
Analysis ionise a

0 Mc sp carl

ether +MeY

Me Me
For exa
(11)
alkyl ra
Synthesis
OH Analys

MeS04
NaOH TM (11)
Me

In anocher example compound (12) ie, benzyl isopentyl ether (used as gardenia perfume)
disconnection may takes place on either side as both involve primary alkyl halides. The benzyl haide s
te CI

reactive but the decisive point in favour (b) is that route (a) might wellead to
ofroute elimination.
Analysis Synth

Ph OH

Ph
(12) +HO
Ph
Synthesis: This is SN2 again, so base catalysis helps.
6.
base
Ph C So ta
HO 0 TM (12)
disc
If there is no obvious preference, it is more helpful to write both fragments as alcohols and decide lad disce
elseu
which to convert into an electrophile the ether (13) i.e. benzyl isopentenyl ether both
e.g, in
sides
reactive so we write the wo alcohols. The ether can be made
by either of the routes, although tne 6.
shown is less ambiguous. (Baldwin et al 1970)
Analysis Wh
ace

Ph C one

Ph sho
ether OH HO
(13) (di-
 The Disconnection Approach
25
Synthesis
Base TM (13)
HO PhCH2Br

The same principles apply to sulphide (R s R) synthesis. The reaction 1s even easier by SN2 as thiols
ionise at a lower pKa than alcohols, the anion (14) is softer than RO and thus more nucleophilic towards
sp3 carbon.

R-S-R2 =R's+ Ry
(14)
For example chlorbenside (15) (used as acaricide ie., killing mites and ticks) is first disconnected on the
alkyl rather than the aryl side.
Analysis
Cl
S Cl
S CS
Sulphide
CI

Cl
(15)

Synthesis SH C

Cl
O NaOEt
ErOH
TM (15)

(15)

6.9 Two Group C-X Disconnections

So far we have used 'one group' disconnection ie. we have recognised a single functional group and the
disconnection corresponded to a reliable reaction to make that functional group. The rwo group c-X
disconnection stands for the disconnection where one functional group is used to help disconnect another
elsewhere in the molecule.

6.9.1 1, 1-Difunctionalised Compounds

When both the functional groups are linked to the same carbon, it is denoted as 1,1-difunctionalised e.g
acetals (or ketals). In these compounds one carbon atom marked i n (16) has tuwoCO bonds, we can use

one oxygen atom to help disconnect the other, thus finding the compound as an acetal. Both C-0 bonds
should therefore be disconnected and we can label the operation '1, 1-dix' to show that it is a two-group

(dix) disconnection.
 26
Organic Synthesis
The Disconnect
R OMe R R
R2
ôMe O+ MeOH
Analysis

CoMe R2

(16)
H2
Likewise there is another example of an acetal (17), it is easily recognised and its synthesis is straioh.
forward.
Analysis Synthesis
OMe
Ph 1, 1-dix Ph CHO + 2MeOH
acetal
OMe
6.9.2 1, 2-E
(17)
Synthesis 6.9.2.1 Alco
Nu
MeUH
Ph CHO
H TM (17) (22)
Acetals are examples of general type of molecule (18) in which two hetero atoms are
a Nu
same carbon atom. This C-atom (in 18) both joined to the
is then at the oxidation level of
molecule is made from a carbonyl a
carbonyl group and the (23)
compound and two nucleophiles.
Nu
HX
=0 +
HY Nu
(18)
Now if one of the hetero atoms is
present as OH group then only one nueleophile is involved and molecules
such as cyanohydrin (19) can be
made from carbonyl Another com
compound and HCN.
The chlorine
ÖMe
Analysis
-
= OH - =0 + HCN

(19)
when both atoms have been
The synthesis of a-amino acid
replaced by other groups, 1, 1-disconnections
(20) is an important may be more difficult to spot.
one heteroatom
and nitrogen as the example to illustrate
this disconnection with cyanide a
other,
synthesis (Strecker synthesis) the amino disconnection gives an aldehyde, ammonia and cyanide. In
in acid or base. cyanide (21) is made in one step from the the Amine (28
aldehyde and hydrolyscu of readily a
(The Disconnection Approach 27

Analysis
R
RCHO
FG 1,1-dix

HN coH HaN CN NH3 HCN

(20) (21)

Synthesis
(NH4)2CO3 NaOH, H20
RCHO (21) TM (20)
HCN or H H20

6.9.2 1, 2-Difunctionalised Compound

6.9.2.1 Alcohols
Nu Compounds such as (22) and (23), consist of hetero atoms on adjacent C-atoms
and are most helpfully considered as derivatives of alcohols. Disconnection gives
(22)
the synthon (24), the reagent for which is the epoxide (25), the compound you
Nu
Cl would get if you tried to make (24) itself.
(23)

Nu
OcOR
(22) Nu
Nu OH Nü +
C
OH %
(23) (24) (25)
Another compound (26), having physiological activity such as anti tumor activity is one of p-chloro amines.
The chlorine atom must come from alcohol (27) which is clearly an epoxide adduct of amine
(28).
Analysis

C OH

(26) (27) (28)

Amine (28) is also an ester so we have an obvious disconnection to (29), another epoxide adduct, this time
of readily available
anthranilic acid.
 Organic Synthesis (Th-
28
Analysis 2 Chlo
H atom
NH2
N OL requi
C
esler 1,2dix Anot
CO>H CO2H deriva
O (29)
Anal
The synthesis turns out to be easier than expected as treatment of anthranilic acid with an excess
ot
ethylene oxide gives (27) directly, POClg was used instead of the more usual Socla to make the chloride.

NH2
excess

O
(27) POdl3, TM (26)
cO2
Synth
6.9.2.2 Carbonyl Compounds
A carbonyl compound such as (30) undergo 1, 2-dix disconnection and yields the electrophilic synthon ie.
a-carbonyl cation (31), a very unstable species. The best reagents for this synthon are the a-halo carbonyl
compounds, which can be easily made and readily attacked by nucleophiles.

1, 2-dix Hal
Nu Nk +
R R
(30) (31) 6.9
For example the 1, The
2-dix disconnection of a herbicide 2,4-D' (32)[a-(2,4 dicloro phenoxy) acetic acid] has
been illustrated below, leading to a phenol. other

Analysis an ur

cyani
O2H
OH
1, 2-dix C COH
Cl Cl
(32) C

Amir
OH
turn|

O Phenol
ROH
Anal
Synthesis OH
OH
1. NaOH
Fe TM (32)
2. CICHCO2H
C
 (The Disconnection Approach

Chlorination of phenol can be

controlled to give mostly the
L2 29

atom decreases the reactivity of the 2, 4-dichloro compound, as each chlorine

molecule towards further
required for the substitution to form TM (32). chlorination. The anion of the phenol will be
Another example of disconnection of certain
esters (33) shown
derivatives of liquid carboxylic acids for below illustrates a way of
making crystalline
purification, identification and protection.
Analysis
O

R
1, 2-dix Br

Br
Br
(33)
(34)
Synthesis
O

Br

Br
RCOH
NaHCO3
TM (33)

(34)

6.9.3 1, 3-Difuctionalised Compounds

The compounds such as (35) possessing carbonyl function
a
other may be and
nucleophile at 1, 3 position to each
a
disconnected at the carbonyl oxidation level, thus
an unsaturated
compound (37). This is the Michael reaction,producing synthon (36) whose reagent is
a

cyanides, nitro compounds etc. and most effective for all carbonyl
nucleophiles. compounds,
Nu R
Nu R R

(35) (36)
Amines such as (38) may be (37)
produced by from cyanides (39) through reduction and the
FGil
turn by the Michael
reaction. Base catalysis is required in this cyanides in
ROH synthesis as RO" is a
better nucleophile than
Analysis
RO NH2 FGI
reduction
RO RO+
CN CN
(38) (39)