SMILES REARRANGEMENT [REACTION AND MECHANISM]Shikha Popali
THE SMILES REARRANGMENT IS THE PROCESS OF REARRANGING OF ELEMENTS OF THE STRUCTURE, WHERE IN THIS PRESENTATION HOW TO REARRANGE IS EXPLAIN WITH ITS MECHANISM
SMILES REARRANGEMENT [REACTION AND MECHANISM]Shikha Popali
THE SMILES REARRANGMENT IS THE PROCESS OF REARRANGING OF ELEMENTS OF THE STRUCTURE, WHERE IN THIS PRESENTATION HOW TO REARRANGE IS EXPLAIN WITH ITS MECHANISM
A first-order reaction can be defined as a chemical reaction in which the reaction rate is linearly dependent on the concentration of only one reactant.
A second kind of second-order reaction has a reaction rate that is proportional to the product of the concentrations of two reactants
Nucleophilic Substitution reaction (SN1 reaction)PRUTHVIRAJ K
Attack of nucleophile at a saturated carbon atom bearing substituent, known as leaving group results in Substitution reaction.
The group that is displaced (leaving group) carries its bonding electrons.
The new bond is formed between nucleophile and the carbon using the electrons supplied by the nucleophilic agent.
The compound on which substitution takes place is called “substrate.”
The substrate consists of two parts, alkyl group and leaving group.
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
THE IMPORTANCE OF MARTIAN ATMOSPHERE SAMPLE RETURN.Sérgio Sacani
The return of a sample of near-surface atmosphere from Mars would facilitate answers to several first-order science questions surrounding the formation and evolution of the planet. One of the important aspects of terrestrial planet formation in general is the role that primary atmospheres played in influencing the chemistry and structure of the planets and their antecedents. Studies of the martian atmosphere can be used to investigate the role of a primary atmosphere in its history. Atmosphere samples would also inform our understanding of the near-surface chemistry of the planet, and ultimately the prospects for life. High-precision isotopic analyses of constituent gases are needed to address these questions, requiring that the analyses are made on returned samples rather than in situ.
2. 1.Aliphatic Nucleophilic Substitution and types
2.Mechanisms- introduction
3.The SN2 Mechanism
4.Evidences for the SN2 mechanism:
5.The SN1 Mechanism
6.Evidences for the SN1 Mechanism
7.THE SET Mechanism (single-electron
transfer).
8.The SNi Mechanism
9.Mixed SN1 AND SN2 Mechanism
10.Nucleophilic Substitution at an Allylic
Carbon
11.Nucleophilic Substitution at an Aliphatic
Trigonal
12.Carbon Nucleophilic Substitution at a Vinylic
Carbon
3. ALIPHATIC
NUCLEOPHILIC
SUBSTITUTION
SUBSTITUTION-
• replacement of an atom or group of
atom by any other atom or group of
atom.
NUCLEOPHILE-
At least one unshared pair of
electron
Lewis base
Attracted towards positively
charged species.
May be neutral or negatively
charged.
Example: Cl¯, Br¯, I¯, CN¯, OH¯,NH₃,
RNH₂, H₂O, ROH, etc.
4. General reaction-
R- X + Y: R-Y + X:
Nucleophile Y: may be neutral or negatively
charged.
Substrate may be neutral or positively
charged.
substrate nucleophile substituted
product
Leaving
group
5.
6. SN2
MECHANISM
SN2 stands for
substitution nucleophilic
bimolecular.
BACK SIDE ATTACK
SINGLE STEP.
Direct displacement.
NO INTERMEDIATE
FORMATION
INVERSION OF
CONFIGURATION
The energy necessary to
break the C-L bond is
supplied by simultaneous
formation of the C-Nu
bond.
GENERALLY YIELD SINGLE
PRODUCT
7. Evidences for the SN2 mechanism:
1.Kinetics:
• rate expression,
Rate=
k[substrate][nucleophile]
• If a large excess of
nucleophile is present (i.e.
solvolysis) –
Rate= k [substrate]
such kinetics are called
pseudo-first order.
8. 2. Stereochemistry:
3. No substitution at
bridgehead carbon
• Not be able to react by this
mechanism, since the nucleophile
cannot approach from the rear
• REQUIREMENT FOR SN2:
• SN2 mechanism requires the
backside attack by the nucleophile,
inversion of configuration and co
planarity of three no-reacting
groups in the transition state .
• REASON: prevented at the bridge
head carbons due to rigid cage like
structures
9. SN1
MECHANISM
SN1 mechanism (substitution
nucleophilic unimolecular)
TWO STEP PROCESS
The first step is a slow
ionization of the substrate and
is the rate-determining step
The second is a rapid
reaction between the
intermediate carbonation and
the nucleophile
The ionization of a leaving
group to form the carbocation
is always assisted by the
solvent, since the energy
necessary to break the bond is
largely recovered by solvation
of CATION and of LEAVING
GROUP.
10. EVIDENCES FOR THE SN1 MECHANISM:
1. kinetics
• first-order reaction
following the rate law:
RATE= k [RX]
• solvent is necessary to
assist in the process of
ionization, it does not enter
the rate expression,
because it is present in
large excess.
11. 2. STEREOCHEMISTRY
The stereo chemical
evidence for the SN1
mechanism is less clear-
cut than it is for the SN2
mechanism.
First-order substitutions
do give complete
racemisation, many
others do not. Typically
there is 5–20% inversion.
• Some of the products
are not formed from
free carbocations but
rather from ion pairs.
12. • Role of ion pair:
Here is an intimate, contact, or tight ion pair; a loose or solvent-separated ion pair
and the dissociated ions (each surrounded by molecules of solvent) are formed.
The reaction products can result from attack by the nucleophile at any stage.
• Nucleophilic attack by a solvent molecule on tight ion pair thus leads to inversion.
Attack on solvent separated ion pair leads to racemisation.
3. Formation of rearranged products:
13. 4. NO substitution at
bridgehead carbons
• Not be able to react by this
mechanism, since the nucleophile
• REQUIREMENT:
SN1 proceed through carbocations
which must be planar.
• REASON:
Because of rigid cage like structure,
bridgehead carbon atom cannot
assume planarity, hence
heterolysis leading to formation
of carbocation is prevented.
THE SET MECHANISM (single-
electron transfer).
• In some nucleophilic reaction, sn1 is
highly probable.
• Esr detection of intermediate- free
radicals are involved.
• Carbocation- good electron
acceptor
• Nucleophile- good electron donor.
• Mechanism- SET mechanism. For
example, the reaction between the
triphenylmethyl cation and t-
butoxide ion:-
• Ph₃C⁺ + t-BuO¯ Ph₃C° + t-BuO°
t-BuOCPh₃
14. Mixed SN1 AND SN2 MECHANISM:-
• Some reactions of a given
substrate under a given set of
conditions display all the
characteristics of –
: INTERMEDIATE BEHAVIOUR- GIVEN BY
SNEEN –
• mechanism that is neither ‘‘pure’’ SN1 nor
‘‘pure’’ SN2, but some ‘‘in-between’’ type.
• all SN1 and SN2 reactions can be
accommodated by one basic mechanism
(the ion-pair mechanism).
• The substrate first ionizes to an
intermediate ion pair that is then
converted to products-
RX R⁺X¯ PRODUCT
• If k1>k2 then mechanism is SN2, if
• k2> k1 then mechanism is SN1
• Borderline behaviour is found where
the rates of formation and destruction
of the ion pair are of the same order of
magnitude (k1=k2).
2: simultaneousoperation:
• no intermediate mechanism at all, and
borderline behaviour is caused by
simultaneous operation.
• in the same flask, of both the SN1 and
SN2 mechanisms; that is, some
molecules react by the SN1, while
others react by the SN2 mechanism.
SN1 SN2IN BETWEEN-
TWO THEORIES
intermediate
behaviour
simultaneous
operation
K1 K2
15. • Among the experiments that have been cited for the viewpoint that
borderline behaviour results from simultaneous SN1 and SN2 mechanisms
is the behaviour of 4-methoxybenzyl chloride in 70% aqueous acetone.
4-methoxybenzyl chloride
in 70% aqueous acetone.
conversion to 4-methoxybenzyl
alcohol occurs by an SN1
mechanism.
alcohol is still a product, but now
4-methoxybenzyl azide is another
product.
increases the rate of ionization
but decreases the rate of
hydrolysis, (SN2 MECHANISM-
FOR AZIDE FORMATION)
16. The Sni
Mechanism
(substitution nucleophilic internal)
In a few reactions, nucleophilic
substitution proceeds with retention of
configuration, even where there is no
possibility of a neighboring-group
effect.
Follows second order kinetics
RARE
The reaction between alchols and
thionyl chloride has been studied
exclusively.
Example- α –pehnyl alchol and
thionyl alchol
•It was found that product is formed
with complete retention of
configuration on the starting
alcohol.
•The reaction proceeds with the
formation of a chlorosulphite ester
which collapes with elimination on
SO2.
•The chlorosulphite ester could form
the product by SN2 with inversion,
and SN1 with racemisation.
17. MECHANISM OF Sni
on the basis of experimental
fact-
First step- formation of
chlorosulphite
(intermediate).
Second step- dissociation
of the chlorosulphite
ester to form an ion –pair
(not dissociated).
Because of the geometry
of the ion pair, the
chlorine atom is forced to
attach the carbonium ion
from the side as original
C-O bond of the alchol
(internal attack).
18. If (S)-1-phenyl ethanol and SOCl2 react in presence of a tertiary amine
such as pyridine, the product is (R)-1-phenylethylchloride is obtained, i.e.
Inversion of configuration occurs.
The pyridine reacts with the HCl, produced in the first step of the
pyridinium hydrochloric acid and Cl¯ being an effective nucleophile,
attacks the alkyl chlorosulphite from the back via SN2 reaction.
Thus we can say in prescence of pyridine, reaction follows the SN2
mechanism and withoput it follows the SN1 mechanism.
RATE OF REACTION- both reactant plays crucial role in reaction. Therefore,
RATE= k[ROH] [ SOCL₂].
19. Nucleophilic
Substitution at an
Allylic Carbon
• Reason-
Two products are formed because an
allylic type of carbocation is a
resonance Hybrid so that C-1 and C-3
each carry a partial positive charge
and both are attacked by nucleophile
resulting in the formation of two
products:
• This mechanism has been called the
SN1’mechanism.
Allylic substrates rapidly undergo
nucleophilic substitution reactions .
usually accompanied by a certain
kind of rearrangement known as an
allylic rearrangement.
When allylic substrates are treated
with nucleophiles under SN1 conditions,
two products are usually obtained: the
normal one and a rearranged one.
R-CH=CH-CH₂⁺ R-C⁺H-CH=CH₂
20. • Nucleophilic substitution at an
allylic carbon can also take place
by an SN2 mechanism, in which
case no allylic rearrangement
usually takes place.
• In which the nucleophile attacks
at the γ carbon rather than the
usual position. This mechanism
is called SN2’ mechanism and is
an allylic substitution. The SN2’
mechanism takes place under
SN2 conditions where α
substation sterically retards the
normal SN2 mechanism.
If equilibrium
reached Not
reached
stable product
(thermodynamically
controlled product)
less stable
product
(kinetically
controlled
product)
Greater
amount
Greater
amount
21. • When a molecule has in an
allylic position a nucleofuge
(leaving group) capable of
giving the SNi reaction, it is
possible for the nucleophile to
attack at γ the position instead
of the a position. This is called
the SNi’ mechanism and has
been demonstrated on 2-
buten-1-ol and 3-buten-2-ol,
both of which gave 100% allylic
rearrangement when treated
with thionyl chloride in ether.
Ordinary allylic rearrangements
(SN1’) or SN2’ mechanisms
could not be expected to give
100% rearrangement in both
cases.
22. Nucleophilic Substitution at an Aliphatic
Trigonal Carbon
• The compounds containing a
trigonal carbons, especially
when the carbon is double
bonded to an oxygen, a
sulphur, or a nitrogen undergo
nucleophilic substitution
through tetrahedral
mechanism, often reaction
follows the second order called
addition-elimination.
• In tetrahedral mechanism first
the nucleophile attacks to give
a tetrahedral intermediate and
then the leaving group
departs.
23. • As expected, this reaction is catalysed by acid because,
protonation decreases the electron density at the carbon
undergoing substitution, which facilitates the attack of
nucleophile:
24. Nucleophilic Substitution at a Vinylic Carbon
Concerned with the nucleophilic substitution at unsaturated carbon such
as vinylchloride (CH₂=CHCl).
Nucleophilic substitution at a vinylic carbon is difficult under normal
condition and is extremely slow compared to substitution at saturated
carbon. The Vinyl chloride are essentially inert towards nucleophiles.
Reason-
1. Vinyl C-X bond (x= halogen, oxygen, nitogen) is stronger than the alkyl C-X
bond because of a resonance interaction between the double bonds and an
unsaturated pair on X. This interaction also weakens and polarizes the pi
bond, which is why such compounds are reactive towards the
electophilic addition.
25. 2. The sn2 transition state as
well as sn1 intermediate (a
vinyl cation) are too high in
energy to be readily
accessible.
It takes 16-18 kcal more
energy to break a C-X bond in
vinyl halide than
corresponding alkyl halide.
• Thus the rate determining step
involves the breaking of C-X bond.
The bond in vinyl halide is harder to
break and reaction is slow.
• After a lot of reserch,
• The vinylic cation can readily made
through by solvolysis of the SN1 kind
if two conditions are met:
1. The leaving group is extremely good
one.
2. The vinylic group contains electron
releasing substituents.
Most commonly used for this purpose is
the super leaving group – trifluro
methanesulfonate (-OSO2CF3)
WHICH is known as TRIFLATE.
26. The powerful electron withdrawing F- ATOM( through dispersial of negative
charge) help to stabalise the triflate anion, and makes the parent acid
CF3SO2OH one of the strongest LOWRY- BRONSTED ACID known, much
stronger than known H2SO4 AND HClO4.
27. REFRENCE-
1. Advanced organic chemistry: reaction mechanisms and
structure by Jerry March; McGraw Hill
2.Advanced organic chemistry by Dr. Jagdamba singh and Dr.
L.D.S.Yadav; pragati prakshan
3.Organic reactions and their mechanisms ( second edition) by
P.S. KALSI
4. REACTION MECHANISM in organic chemistry by S.M.
Mukhrjee and S.P. Singh and Macmillan.