QUIMICA PARA FARMACIA
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QUIMICA PARA FARMACIA


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Indole system
+
Leimgruber synthesis Aminomethylenation of nitrotoluene followed by
hydrogenation yield indole.
N
H
Me
NO2
N
MeO
MeO
N
NO2
+
\u2206 H2
Pd/C
Reactions of indole
Electrophilic aromatic substitution Electrophilic aromatic substitution
of indole occurs on the five-membered pyrrole ring, because it is more
reactive towards such reaction than a benzene ring. As an electron-rich
heterocycle, indole undergoes electrophilic aromatic substitution primarily
at C-3, for example bromination of indole.
N
H
N
H
Br
Br2
FeBr3
+ HBr
The Mannich reaction is another example of electrophilic aromatic sub-
stitution where indole can produce an aminomethyl derivative.
4.7.4 PYRROLE, FURAN AND THIOPHENE: 169
N
H
N
H
Me
Me
NMe Me
H
HCHO
AcOH
+
Similarly, using the Vilsmeier reaction an aldehyde group can be brought in
at C-3 of indole.
N
H
N
H
H
O
H N
O
Me
Me POCl3
H2O
+
Test for indole Indole is a component of the amino acid tryptophan,
which can be broken down by the bacterial enzyme tryptophanase. When
tryptophan is broken down, the presence of indole can be detected
through the use of Kovacs\u2019 reagent. Kovacs\u2019 reagent, which is yellow,
reacts with indole and produces a red colour on the surface of the test tube.
Kovacs\u2019 reagent is prepared by dissolving 10 g of p-aminobenzaldehyde in
150 mL of isoamylalcohol and then slowly adding 50 mL of concentrated
HCl.
4.8 Nucleic acids
The nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA), are the chemical carriers of a cell\u2019s genetic information. Nucleic
acids are biopolymers made of nucleotides joined together to form a long
chain. These biopolymers are often found associated with proteins, and in
this form they are called nucleoproteins. Each nucleotide comprises a
nucleoside bonded to a phosphate group, and each nucleoside is composed
of an aldopentose sugar, ribose or 2-deoxyribose, linked to a heterocyclic
purine or pyrimidine base (see Section 4.7).
O
OHOH
OHOH O
OH
OHOH
1
23
4
5
Ribose
1
23
4
5
2-Deoxyribose
The sugar component in RNA is ribose, whereas in DNA it is 2-dexoyribose.
In deoxyribonucleotides, the heterocyclic bases are purine bases, adenine
and guanine, and pyrimidine bases, cytosine and thymine. In ribonucleo-
tides, adenine, guanine and cytosine are present, but not thymine, which is
replaced by uracil, another pyrimidine base.
170 CH4 ORGANIC FUNCTIONAL GROUPS
In the nucleotides, while the heterocyclic base is linked to C-1 of the
sugar through an N-glycosidic b-linkage, the phosphoric acid is bonded by a
phosphate ester linkage to C-5. When the sugar is a part of a nucleoside, the
numbering of sugars starts with 10, i.e. C-1 becomes C-10, for example 20-
deoxyadenosine 50-phosphate and uridine 50-phosphate.
P
O
O
O N
N
O
OH
O
N N
NH2 P
O
O
O O
OH
O
OH
N N
O
HO
2'-Deoxyadenosine 5'-phosphate
Adenine
Deoxyribose
Phosphate
1'
2'3'
4'
5'
Uridine 5'-phosphate
Uracil
Ribose
Phosphate
1'
2'3'
4'
5'
2'-Deoxyadenosine Uridine
Despite being structurally similar, DNA and RNA differ in size and in their
functions within a cell. The molecular weights of DNA, found in the nucleus
of cells, can be up to 150 billion and lengths up to 12 cm, whereas the
molecular weight of RNA, found outside the cell nucleus, can only be up to
35 000.
Deoxyribonucleic acid (DNA)
Name of the nucleotide Composition
20-Deoxyadenosine 50-phosphate Adenine + deoxyribose + phosphate
Nucleoside is 20-deoxyadenosine, composed of
adenine and deoxyribose
20-Deoxyguanosine 50-phosphate Guanine + deoxyribose + phosphate
Nucleoside is 20-deoxyguanosine, composed of
guanine and deoxyribose
20-Deoxycytidine 50-phosphate Cytosine + deoxyribose + phosphate
Nucleoside is 20-deoxycytidine, composed of
cytosine and deoxyribose
20-Deoxythymidine 50-phosphate Thymine + deoxyribose + phosphate
Nucleoside is 20-deoxythymidine, composed of
thymine and deoxyribose
Ribonucleic acid (RNA)
Adenosine 50-phosphate Adenine + ribose + phosphate
Nucleoside is adenosine, composed of adenine and ribose
Guanosine 50-phosphate Guanine + ribose + phosphate
Nucleoside is guanosine, composed of guanine and ribose
Cytidine 50-phosphate Cytosine + ribose + phosphate
Nucleoside is cytidine, composed of cytosine and ribose
Uridine 50-phosphate Uracil + ribose + phosphate
Nucleoside is uridine, composed of uracil and ribose
4.8.1 Synthesis of nucleosides and nucleotides
A reaction between a suitably protected ribose or 2-deoxyribose and an
appropriate purine or pyrimidine base yields a nucleoside. For example,
4.8 NUCLEIC ACIDS 171
guanosine can be synthesized from a protected ribofuranosyl chloride and a
chloromercurieguanine.
O
OAcOAc
H
AcO
Cl N
NN
N
ClHg
O
NHAc
Ac
N
N
O
OAcOAc
AcO
N
N
O
NHAc
Ac+
-HgCl2
OH- H2O
Guanosine
Nucleosides can also be prepared through the formation of the heterocyclic
base on a protected ribosylamine derivative.
O
OAcOAc
AcO NH2 O
OAcOAc
AcO N
N
O
H
OO
N
H
O
OEtEtO+
(\u2212 2 x EtOH)
OH- H2O
Uridine
2,3,5-Tri-O-acetyl-\u3b2-D-ribofuranosylamine
\u3b2-Ethoxy-N-ethoxycarbonylacrylamide
Phosphorylation of nucleosides produces corresponding nucleotides. Phos-
phorylating agents, e.g. dibenzylphosphochloridate, are used in this reac-
tion. To carry out phosphorylation at C-50, the other two hydroxyl
functionalities at C-20 and C-30 have to be protected, usually with an
isopropylidine group. At the final step, this protecting group can be removed
by mild acid-catalysed hydrolysis, and a hydrogenolysis cleaves the ben-
zylphosphate bonds.
OOH N
N
O
H
O
O O
Me Me
O P OO Cl
Ph
Ph
O P OO O N
N
O
H
O
O O
Me Me
Ph
Ph
H2, Pd
OH P OOH O N
N
O
H
O
OH OH
Dibenzylphosphochloridate
+
Isopyrilidine 
protecting group
H2O, H+
Uridine 5'-phosphate
A nucleotide
172 CH4 ORGANIC FUNCTIONAL GROUPS
4.8.2 Structure of nucleic acids
Primary structure
Nucleotides join together in DNA and RNA by forming a phosphate ester
bond between the 50-phosphate group on one nucleotide and the 30-hydroxyl
group on the sugar (ribose or 20-deoxyribose) of another nucleotide. In the
nucleic acids, these phosphate ester links provide the nucleic acids with a
long unbranched chain with a \u2018backbone\u2019 of sugar and phosphate units with
heterocyclic bases sticking out from the chain at regular intervals. One end
of the nucleic acid polymer has a free hydroxyl at C-30 (the 30-end), and the
other end has a phosphate at C-50 (the 50-end).
The structure of nucleic acids depends on the sequence of individual
nucleotides. The actual base sequences for many nucleic acids from various
species are available to date. Instead of writing the full name of each
nucleotide, abbreviations are used, e.g. A for adenine, T for thymidine, G
for guanosine and C for cytidine. Thus, a typical DNA sequence might be
presented as TAGGCT.
OO Base
O
PO O
O O
O
Base
P OO
Generalized structure of DNA
5'
3'
5'-end
3'-end
Secondary structure: base pairing
The base sequence along the chain of a DNA contains the genetic information.
Samples of DNA isolated from different tissues of the same species have the
same proportions of heterocyclic bases, but the samples from different species
often have different proportions of bases. For example, human thymus DNA
comprises 30.9% adenine, 29.4% thymine, 19.9% guanine and 19.8%
cytosine, while the bacterium Staphylococcus aureus contains 30.8% adenine,
29.2% thymine, 21% guanine