What is a Heterocyclic Compound?
A heterocyclic compound has at least two different elements as a member of its ring.
The most common hetero atoms found on a cyclic ring are Oxygen (O), Nitrogen (N) and Sulphur (S).
Example:
Nucleic Acid that is present in the body responsible for storing and expressing genetic information, is an example of a Heterocyclic compound.
Essential micronutrient, Vitamins is also an example of a heterocyclic compound.
The majority of drugs, pesticides, dyes, and plastics are examples of heterocyclic compounds.
Classification of Heterocyclic Compounds
Based on the electronic arrangement, we can classify Heterocyclic compounds into two types:
Aliphatic Heterocyclic Compounds
Aromatic Heterocyclic Compounds
Aliphatic Heterocyclic Compounds
Aliphatic heterocyclic compounds are those cyclic heterocycles that do not contain any double bond.
The properties of aliphatic heterocyclic compounds are mainly affected due to ring strain.
Examples of aliphatic heterocyclic compounds are Aziridine, Ethylene Oxide, Thiirane, Oxetane, Azetidine, Thietane, Tetrahydrofuran (THF), Dioxane, Pyrrolidine, Piperidine, etc.
Aromatic Heterocyclic Compound
Aromatic heterocyclic compounds, as the name suggests, are cyclic aromatic compounds.
Aromatic Heterocyclic compounds obey Huckels Rule, i.e.
It should be cyclic.
It should be planar.
It should not contain any sp3 hybridised atoms.
It must have (4n+2) đ electrons.
Aromatic Heterocyclic compounds are analogous to Benzene.
Examples: Furan, Pyrrole, Thiophene, Indole, Benzofuran, Carbazole, Quinoline, Isoquinoline, Imidazole, Oxazole, Pyrazole, Pyridazine, Pyrimidine, Purine, etc.
Based on structure, we can classify Heterocyclic compounds into five types:
Three-Membered Heterocyclic Compounds
Four-Membered Heterocyclic Compounds
Five-Membered Heterocyclic Compounds
Six-Membered Heterocyclic Compounds
Condensed or Fused Heterocyclic Compounds
Three-Membered Heterocyclic Compounds
These heterocyclic compounds contain three atoms which may be saturated or unsaturated.
Based on the number of heteroatoms present, we can further classify them into two categories:
Introduction of poly-cyclic compounds, resonance, molecular orbital structure, physical properties, preparation, reaction and uses of napthalene, anthracene, phenanthrene, napthaquinone, napthol, napthylamine, 9,10 anthraquinone and phenanthrequinone.
Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of this group has two remaining bonds that may be occupied by hydrogen or alkyl or aryl substituents. If at least one of these substituents is hydrogen, the compound is an aldehyde.
Heterocyclic chemistry - Fused ring systemsNaresh Babu
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Fused hetero cyclic ring systems like Quinoline, Isoquinoline, Indole, Acridine, Benzimidzole & Phenothiazine - Structure, Aromaticity, Preparations, Acidity-Basicity and characteristic chemical reactions
Embracing GenAI - A Strategic ImperativePeter Windle
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Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Introduction of poly-cyclic compounds, resonance, molecular orbital structure, physical properties, preparation, reaction and uses of napthalene, anthracene, phenanthrene, napthaquinone, napthol, napthylamine, 9,10 anthraquinone and phenanthrequinone.
Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of this group has two remaining bonds that may be occupied by hydrogen or alkyl or aryl substituents. If at least one of these substituents is hydrogen, the compound is an aldehyde.
Heterocyclic chemistry - Fused ring systemsNaresh Babu
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Fused hetero cyclic ring systems like Quinoline, Isoquinoline, Indole, Acridine, Benzimidzole & Phenothiazine - Structure, Aromaticity, Preparations, Acidity-Basicity and characteristic chemical reactions
Embracing GenAI - A Strategic ImperativePeter Windle
Â
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
Operation âBlue Starâ is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
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This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
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Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
⢠The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
⢠The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate âany matterâ at âany timeâ under House Rule X.
⢠The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
How to Make a Field invisible in Odoo 17Celine George
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It is possible to hide or invisible some fields in odoo. Commonly using âinvisibleâ attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
Â
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
Â
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasnât one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Introduction to AI for Nonprofits with Tapp NetworkTechSoup
Â
Dive into the world of AI! Experts Jon Hill and Tareq Monaur will guide you through AI's role in enhancing nonprofit websites and basic marketing strategies, making it easy to understand and apply.
A Strategic Approach: GenAI in EducationPeter Windle
Â
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
1. Oxidation and oxidising agents
KMnO4 and derivative of hexa-valent chromium:
It can be used in acidic, neutral and alkali medium.
KMnO4 soluble in water only.
Many organic compound does not soluble in water.
Few of solvent resistant to the oxidising action of the reagent
like acetic acid, tButanol, dry acetone pyridine.
Mn(VII)
Mn(II)
Mn(IV)
2. CH3
KMnO4, rt
18-crown-6
COOH
78%
KMnO4, PhH, 25o
C
dicyclohexano-18-crown-6
O
COOH
90%
KMnO4, H2O, NaOH,0o
C
PhCH2N+
Me3Cl-
OH
OH
Using of crown ether is very helpful for oxidation with permanganate.
Tetra nbutylammonium permanganate is soluble in organic solvents.
3. Cr (VI) to Cr(III), common oxidising agents are CrO3 and sodium or
pottassium dichromate.
CrO3 is a polymer, exist like (CrO3)n, when dissolve, depolymerisation takes
place.
(CrO3)n+ H2O Cr OH
HO
O
O
Cr(VI) is used in dil. H2SO4, Ac2O, tBuOH or in pyridine.
2HCrO4
- H2O + Cr2O7
--
(CrO3)n + Ac2O Cr
O
O
OCOCH3
H3COCO
(CrO3)n + Me3COH Cr
O
O
OCMe3
Me3CO
(CrO3)n + Cr
O
O
N+
-
O
N
For formyl group
5. Oxidation of hydrocarbon
Need vigorous condition, mixture of product obtained with low yield
In presence of O2, hydrocarbon burn and gives CO2 and H2O.
In absence of activating hydroxyl or amino substituent, benzene rings are only
slowly attack by chromic acid or permanganate.
Used methyl ether or acetyl derivative of ring hydroxy and amino group
respectively. Otherwise they activate the ring and ultimately quinones, CO2
and H2O may be obtained.
Very resistant to oxidation
7. The Ătard reaction is a chemical reaction that involves the direct oxidation of
an aromatic or heterocyclic bound methyl group to an aldehyde using chromyl
chloride.
8.
9.
10.
11.
12.
13.
14.
15. Heterocyclic Chemistry: Quinoline, Isoquinoline and Indole
A benzene ring can be fused on to the pyridine ring in
two ways giving the important heterocycles
quinoline, with the nitrogen atom next to the benzene
ring, and isoquinoline, with the nitrogen atom in the
other possible position.
Indole itself has a benzene ring and a
pyrrole ring sharing one double bond. It
is an aromatic system with 10 electrons,
eight from four double bonds and the
lone pair from the nitrogen atom.
16. Several synthetic antimalarial drugs are based on the quinoline nucleus,
chloroquine is an example. Ciprofloxacin is one of the several 4-
quinolone-based antibiotics in use.
The opium poppy alkaloids papaverine and in more-elaborated form,
morphine are the examples.
17. Quinoline
N
N N
O
NH2
O
O
OR
O
A B
Path - 1
Path - 2
Retero-synthetic disconnection approach:
N NH2
O
O
NH2
+
O
o-aceyl aniline a ketone containing an
ďĄ-methylene group
18. We know formation of C-N bond is easier so we may consider the following
dis-connection approach.
Synthesis of quinoline; path â 1:
Quinoline derivative
N NH2
NH2
O
O
NH2
+
O
H
H
ďĄ,ď˘-unsaturated carbonyl compound
o-aceyl aniline
a ketone or aldehyde containing an
ďĄ-methylene group
19. Friedlander synthesis:
Friedlander synthesis of quinoline derivative involves by using o-aceyl aniline and a
ketone containing an ďĄ-methylene group, the reaction can be carried out in presence
of acid or alkali.
Ph
O
NH2
CH3
O
CH3
+
N
Ph
Et
N
Ph
Me
Me
AcOH, Trace H2SO4
ď
KOH, EtOH
In acid medium the reaction proceeds through the formation of more stable
enol and in base medium the reaction occurs through the abstraction of
more acidic hydrogen atom.
A
B
20. Synthesis of quinoline derivatives through path-A (base catalysed)
Ph
O
NH2
+
H2C
O
Et
NH2
Et
O
Ph
Aldol condensation
and dehydration
N
Et
OH
Ph
H
N Et
Ph
A problem is found that the dimerisation of o-aceyl aniline, so that we should not
take the following compound as starting material.
NH2
O H2N
O
+
N
N
21. Pfitzinger Modification:
The dimerisation problem was solved by Pfitzinger using ISATIN (A) as starting material which in
alkaline medium gives compound B. That compound B will be used as the substrate of quinoline
synthesis.
N
O
O
H
NH2
COO-
O
A B
Synthesis of Isatin: Isatin is commercially available. It may be prepared by cyclicizing the
condensation product of chloral hydrate, aniline and hydroxylamine in sulfuric acid. This reaction is called the
Sandmeyer isonitrosoacetanilide Isatin Synthesis and discovered by T. Sandmeyer in 1919.
N
O
O
H
NH2
Cl
Cl
Cl
OH
OH N
H
Cl
Cl
HO
OH
N
H
N
OH
O
Conc. H2SO4
NH2OH, HCl
H2O
23. Synthesis of quinoline; path â 2:
N N
O
NH2
O
O
OR
O
A B
Procedure - A
Procedure - B
NH2
O
+ Skrup synthesis
NH2
O
O
+
Cambes Syntheisis
Conrod-Limpach
Knoor process
(1, 3-Dicarbonyl)
(ď˘-ketoester)
(ď˘-ketoester)
25. In case of unsymmetrical ketone, we may get two products.
Arylamine and ď˘-ketoester are the substrates.
Conrod- Limpach Synthesis: KCP
Knoor synthesis: TCP
NH2
O
O
OEt
+
N
OH
O
AcOH, 140o
C
N
Me
OH
260o
C
NH2
O
O
OEt
+
N
OEt
O
AcOH, 40o
C
N
OH
Me
260o
C
26. Procedure - B
NH2
O
+ Skrup synthesis
Skraup Synthesis: ďĄ,ď˘-unsaturated carbonyl and aniline
NH2
O
+ Michael type
condensation
N
H
O
N
H
N
[O]
Aromatic electrophilic substitution
in highly activated nuclous
27. Skrup Synthesis for quinoline:
This concept was used by Skrup towards the synthesis of quinoline by heating aniline, glycerol,
nitrobenzene, H2SO4 and FeSO4.
Step-1: Formation of acroline from glycerol by dehydration.
ďĄ,ď˘-unsaturated aldehyde
Step 2: Michael type condensation.
NH2
O
H
+ Michael type
condensation
N
H
OHC
CH2OH
CHOH
CH2OH
CH2OH
CHOH2
CH2OH
C
CH2
CH2OH
OH
-H2O
H
H
CHO
CH2
CH2OH2
CHO
CH
CH2
-H2O
H
H-transfer
H-transfer
28. Step 3: Aromatic electrophilic substitution on highly activated aromatic nucleus.
N
H
N
H
OHC
H2SO4
Dihydroquinoline
Step 4: Oxidation of dihydroquinoline to quinoline.
N
H N
PhNO2
Dihydroquinoline Quinoline
FeSO4 is used to control the violence of the reaction. P-chloranil is the best oxidant. In this
way we can prepare unsubstituted quinoline.
29. NH2
NO2
i. Glycerol, H2SO4, ď
ii. As2O5
NO2
N
MeO
MeO
Various oxidizing agent may be used such as, Fe2(SO4)3, SnCl4, As2O5 etc.
Skrup synthesis is not applicable when acid sensitive groups are present in
the benzene ring. In case of nitroaniline type compound we have to use
another oxidizing agent particularly As2O5.
Synthesis of derivatives of quinoline.
N
Me
N Me
30. N Me
N Me NH2
O
H
+
H3C
O
H
N
Me
N NH2
O
H3C
+
H3C
O
H3C
CH2=O Me2NH
+ +
31. Isoquinoline
N
Disconnection approach: Path-1
NH2
O
O
N N
ď¤+
NH2
ď¤+
ď¤+
A
It is quite impossible to get compound A as it may easily polymerised. For this reason we have
to take a blocked amino aldehyde, i.e. Compound B.
NH2
EtO
EtO
Compound B
OH
Cl2 gas
Cl CHO
Excess EtOH
Cl
OEt
OEt
H2N
OEt
OEt
NH3
32. Synthesis of derivatives of Isoquinoline
CHO NH2
OEt
OEt
N
OEt
OEt
N
C. H2SO4
This reaction is known as Pomernz-Fritsch synthesis of isoquinoline derivative, where
the starting materials are aromatic aldehyde and amino acetal. The reaction can also be
applied when the benzene nucleus contain any type of substituents (electron donating
or withdrawing). Obviously best result will be obtained when e-donating group is
present in the aromatic ring.
CHO NH2
OEt
OEt
N
OEt
OEt
N
C. H2SO4
Br Br
Br
33. N
R
Amino acetal does not react with aromatic ketone. So it is difficult
to get following type of products.
N
N
R R R
NH2
+
O
O
Here also another problem will be arised.
R
NH2
+
O
O
H
H
Ph
R
N
N
Ph
R
R
NH2
O
R
NH2OH
LiAlH4
CHO
EtO OEt
Disconnection approach: Path-2
35. N
NH2
+ O
Cl
Bishlerâs Naperialski Reaction: Synthesis of isoquinoline derivatives
NH2
CN
Br
CH3
NH
O
N
H2N
Ac2O
POCl3
N
ď
[O]
Disconnection approach: Path-3
A phenylethyl amine reacts with carboxylic acid chloride to form an amide,
which can be cyclised with the loss of water to a 3,4-dihydroisoquinoline.
Then it is readily dehydrogenated to isoquinoline derivative. The common
cyclisation agents are P4O10, POCl3, PCl5.
36. Hence the electrophilic character is poor. It will only react with highly activated aromatic
nucleus for the occurrence of the reaction, benzene nucleus should not contain any
electron withdrawing group.
Mechanism:
NH
Me
O
P
Cl
Cl
Cl
O
NH
Me
O
P
Cl
Cl
Cl
-
O
NH
Me
O
P
Cl
Cl
Cl-
O
NH
Me
O
P
Cl
Cl
O
Cl
N
Me
Cl
H
N
H
Cl Me
H
N
Me
-HCl
N
Pd/C
190o
C
37. Benzene ring having e-withdrawing substituent
Benzene ring having e-donating substituent:
NH
R
O
NO2
N
NO2 R
~ 5 %
POCl3
ď
NH
R
O
OMe
N
OMe R
~ 80 %
POCl3
ď
38. Reaction chemistry of quinoline and isoquinoline
Under slightly acidic conditions quinolines and isoquinoline are susceptible
to straight forward electrophilic substitution in the homocyclic ring. Reaction
has been shown to involve the cations and the formal positive charge on
nitrogen makes attack of the hetero ring very difficult.
C-5-substitution occurs, not C-6
N
H
H X
N
H
H X
N
H
H
X
More stable
Isoquinoline behaves like similar way
39. Benzene ring C-protonation, and hence exchange, via N-protonated quinoline,
requires strong sulfuric acid and occurs fastest at C-8, then at C-5 and C-6;
comparable exchange in isoquinoline takes place somewhat faster at C-5 than at C-8.
At lower acid strengths each system undergoes exchange H atom ďĄ to nitrogen,
at C-2 for quinoline and C-1 for isoquinoline. These processes involve a
zwitterion produced by deprotonation of the N-protonated heterocycle.
N
-H
H
N
H
N N
H H
H
H H
40. Nitration: Quinoline gives approximately equal amounts of 5- and 8-
nitroquinolines, whereas isoquinoline produces almost exclusively 5-nitro-
isomer; mechanistically the substitutions involve nitronium ion attack on the
N-protonated heterocycles.
Sulfonation: Sulfonation of quinoline gives largely the 8-sulfonic acid whereas
isoquinoline affords the 5-acid. Reactions at higher temperatures produce other
isomers, both quinoline 8-sulfonic acid and quinoline 5-sulfonic acid are
isomerised to the 6-acid under thermodynamic control.
N N
NO2
N
NO2
+
HNO3, C. H2SO4
0o
C
1:1
N N
SO3H
30% Oleum
90o
C
41. Halogenation: In concentrated sulfuric acid, quinoline gives a mixture of 5- and
8-bromo derivatives; isoquinoline is efficiently converted into the 5-bromo
derivative in the presence of aluminium chloride.
N N N
+
Br
Br
Conc. H2SO4
Introduction of halogen to the hetero-rings occurs under remarkably mild
conditions in which the nitrogen lone pair initiates a sequence by interaction
with an electrophile. Thus treatment of quinoline and isoquinoline
hydrochlorides with bromine produces 3-bromoquinoline and 4-
bromoisoquinoline respectively as illustrated below for the latter.
44. Hydroxylation:
Both quinoline and isoquinoline can be directly hydroxylated with
potassium hydroxide at high temperature with the evolution of hydrogen.
2-Quinolone ('carbostyril') and 1-isoquinolone ('isocarbostyril') are the
isolated products.
45. Indole is an important heterocyclic system because it is built into proteins in the
form of the amino acid tryptophan (Chapter 49), because it is the basis of
important drugs such as indomethacin, and because it provides the skeleton of
the indole alkaloidsâbiologically active compounds from plants including
strychnine and LSD. clayden
Indole
46. Electrophilic substitution: Pyrrole reacts with electrophiles at all positions but
prefers the 2- and 5-positions, while indole much prefers the 3-position.
In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively
unreactive benzene ring standing on one side electrophilic substitution almost always occurs on
the pyrrole ring. But indole and pyrrole differ in one important respect. In indole, electrophilic
substitution is preferred in the 3-position with almost all reagents. Halogenation, nitration,
sulfonation, FriedelâCrafts acylation, and alkylation all occur cleanly at that 3-position. This is,
of course, the reverse of what happens with pyrrole.
An explanation is that reaction at the 3-position simply involves the rather isolated enamine
system in the five-membered ring and does not disturb the aromaticity of the benzene ring. The
positive charge in the intermediate is delocalized round the benzene ring, but it gets its main
stabilization from the nitrogen atom. It is not possible to get reaction in the 2-position without
seriously disturbing the aromaticity of the benzene ring.
3-position
2-position
47. A simple example is the Vilsmeier formylation with DMF and POCl3, showing that
indole has similar reactivity, if different regioselectivity, to pyrrole.
48.
49. Nature is the master of molecular recognition
and so this type of binding is in the heart of
most biological processes.
What is Molecular Recognition?
The specific, non-covalent association between
a receptor molecule and a particular substrate
is primarily called molecular recognition.
Whether it is an enzyme-substrate, antibody-
antigen, or neuroreceptor-neurotransmitter
pair, large molecules bind smaller one tightly
and specifically.
50. K+
SCN-
O
O
O
O
O
O
K+
O O
N
O O
N
O O
I-
Cl-
Li+
O
O O
H3C
CH3
CH3
CH3
H3C CH3
H3C
CH3
CH3
O
CH3
O
H3C
O CH3
Pedersenâs
Model, 1967 Lehnâs Model, 1969
Cramâs Model, 1973
The seminal observation of Pedersen were brilliantly exploited by
other workers most notably by D. J. Cram and J. M. Lehn and three
shared the Nobel Prize in chemistry in 1987.
Crown ether Cryptand
Spherand
51. (2) Supramolecular assemblies, polymolecular entities, which is made by
the spontaneous association of a large undefined number of components
into a specific phase.
The word âsupramolecular chemistryâ has been used in particular for
large multi-protein architectures and organized molecular assemblies.
The term âsupramolecular chemistryâ first used by Professor J.-M.
Lehn, 1978.
Supramolecular chemistry consists of two concerning areas:
(1) Supermolecules, well-defined discrete oligomolecular species that result
from the intermolecular association of a few component based on the
principles of molecular recognition.
What is Supramolecular Chemistry?
52. Molecular Recognition Depends
onâŚâŚ
⢠Hydrogen Bonding Interactions
⢠p-stacking Interactions
⢠Electrostatic Force of Attractions
⢠van der Waalâs Force
⢠Hydrophobic Force
53. Molecular Recognition Depends
onâŚâŚ
⢠Hydrogen Bonding Interactions
Multiple hydrogen bonding a good way
to achieve recognition because of its
strength, directionality and specificity.
54. Molecular Recognition Depends
onâŚâŚ
p-stacking Interactions
Term introduced by E. J. Corey, 1972.
Important in DNA and protein crystal structure.
Face to Face, Edge to Face (T-shaped), slipped stack,
CH-p stack are important.
Slip stacked
T-shaped stacked
Stacked
H
58. The designing PrincipleâŚâŚâŚ
(i) Shape and size complementarities between the host and
guest molecule i.e. convex and concave domains in the
correct location (Host-convergent; Guest-Divergent).
(ii) Large contact area between the receptor-substrate.
(iii) Presence of complementary binding sites such as positive-
negative, charge-dipole, dipole-dipole, hydrogen bonding
donor-acceptor.
(iv) Multiple interaction sites, which increase the association
constant as the number of interaction sites increases.
(v) The medium i.e. the solvent; the chance of hydrogen bond
formation between solvent-substrate will be possible, if
more polar solvent is used.
59. Application of Molecular Recognition:
1. Phase transfer agents.
2. Separation of mixture.
3. Molecular sensors.
4. Switches and molecular machinery
5. Catalyst
6. Pharmaceuticals
6.1 Anti-cancer agents
6.2 Anti-HIV activity
6.3 Drug design etc.
60. Application of Molecular Recognition:
1. Phase transfer agents
3
]
[
L
L
D
D
O NH
Me Me
O
O
Me
O
Me
Me
NH
O
Me Me
O
Valinomycin
K+
+ Cl
-
+
F-
+
F
Cl
K+
[18]-crown-6
CH3CN
KF
Cl
O O
O
O
O
O
O O
O
O
O
O
K+
K+ is complexed by oxygen atom of the antibiotic ester groups and once it is encapsulated
within the macrocycle, it can be transported through the hydrophobic membrane. The
lipophilic membrance will not normally allow charged species to pass through. The enterior
of the K+-valinomycin complex, has peripheral alkyl groups that are âgreasyâ providing the
complex with solubility in the membrane and allowing transport of the metal ion.
On the other hand, KF not soluble in acetonitrile and does not react with benzyl chloride i.e. F-
cannot displace the Cl- atom. But when we use 18-crown-6, the reaction is quantitatively yielded to
completion. The cause behind this is that 18-crown-6 encapsulated K+ and free F- displaces
chlorine.
61. Application of Molecular Recognition:
Chiral separation of mixture
H3C
H3C
O
O
O
O
O
CH3
O
CH3
O
Polymer
(RR)-binapthyl crown ether bound to a polystyrene resin
Cram and coworker have attached chiral crown ethers to polystyrene resin and used the
resulting materials to get chiral chromatographic separations of amino acids and ester salts.
Chiral substrates passing through a column, made of this material, interact with the crown
ethers forming diastereomeric complexes, which have different stability constants. The R-
entiomer forms a thermodynamically more stable complex with the host and is more
strongly bound to the column. Therefore, the S-enantiomer emerges from the column first
and resolution of the enantiomers is achieved. Chiral chromatographic separations are of
great interest to the pharmaceutical industry, which often has to resolve two enantiomers of a
chiral drug, which possess completely different activities
62. Application of Molecular
Recognition:
Molecular sensors
R R
G
G
Fluorescence sensing of chemical and biochemical analytes is an active area of research.
This research is being driven to eliminate radioactive tracers, which are costly to use and to
dispose of. There is a need for rapid and low-cost testing method for a wide range of
chemical, bioprocess and environmental applications.
Sensors should ideally be selective for a particular guest and not only report the presence of
the guest molecule, but should also allow the chemist to monitor its concentration. This
quantitative analysis by fluorescence sensor is medically and environmentally important.
63. Switches and molecular machinery technology use individual molecules for controlling and storing
information, acting as âon-off switchesâ and âlogic gatesâ. If the molecule contain an electron donor
group like amine, then the phenomenon will be more exciting. This phenomenon has been exploited
to develop sensors bound on quenching of polynuclear aromatic hydrocarbons by amines.
The basic idea is that quenching by amines requires that the lone pair is bound to a proton, then
electron transfer is inhibited and the fluorescence is not quenched. Such probes are said to undergo
photoinduced electron transfer from the nitrogen into the aromatic ring. Preventing PET, in similar
way the emission from the anthracene unit is observed. So protons switch on the fluorescence.
H
+
N
O
Cl
No PET
fluorescent
Not fluorescent
PET
N
O
Cl
H+
Moleculplication of Molecular Recognition: ar âon-offâ switch
Switches and molecular machinery
64. Catalyst
+ ADP
2
NH
O
HN
N PO3
NH
O
HN
HN
2
O
P
O
P
O
P
O
adenosine
O O O
O O O
H
O
H
H
H
H
NH
NH
N
NH
NH
O
NH
H
Protonated macrocyclic polyamines can catalyse the hydrolysis of adenosine
triphosphate (ATP) to adenosine diphosphate (ADP). Cyclic hexaammonium cation
strongly binds ATP and an intramolecular transfer of the terminal phosphate to the
sixth nitrogen gives an intermediate, which then loses phosphate ion by reaction
with water.
65. Pharmaceuticals: Anti-cancer agents
HO
HO
OMe
O
O
OMe
O
O
O
O
N
N
N
N
N
OAc
AcO
Gd(III)
Texaphyrin metal complexes of Gd-Tex
Texaphyrin is an expanded porphyrin synthesized by Sessler et al. The
gadolinium complex Gd-Tex is currently undergoing trials for use as a
radiation sensitizer. A cancer patient is exposed to radiation. When Gd-Tex is
exposed to ionising radiation in vivo, it captures an electron and becomes a p-
radical cation.
66. spacer
NH HN
N HN
HN
HN
HN
N
Anti-HIV activity
Bicyclam, a receptor for two transition metal cations, exhibits potent inhibition of
the HIV virous at early stage in its replication cycle. It is possible that this inhibition
is mediated by transition metals.
Linked bicyclam
67. N N
O
O
H H
HO OH
O
H
H
N
N
O O
lle 50' lle 50
Asp 25' Asp 25
Drug design is an iterative process, which begins when a chemist identifies a
compound that displays an interesting biological profile and ends when both the
activity profile and the chemical synthesis of the new chemical entity are
optimized. Traditional approaches to drug discovery rely on a step-wise synthesis
and screening program for large numbers of compounds to optimize activity
profiles. Over the past ten to twenty years, scientists have used computer models
of new chemical entities to help define activity profiles, geometries and reactivity.
Drug design
Inhibitor for HIV protease bound in the enzyme active site