Chemistry Question

Create a reflection essay that describes 4 learning objectives you met while performing this experiment.

a
Virtual Lab Manual
Substitution vs. Elimination
Reactions: Predict the outcome
Synopsis
Have you ever mixed some chemicals and the result was alkynes of trouble? In this
simulation, you will extend your knowledge of nucleophilic substitution and elimination
reactions, and work with which reaction type will be dominant under different reaction
conditions.
Brush up on the reactions
Your main mission in this simulation will be to solve a series of challenges revolving around
substitution and elimination reactions, given by Dr. One, your virtual lab assistant. You will
start by brushing up on your knowledge of the reactions, revisiting the SN1, SN2, E1 and E2
types. You then move to the main lab room, where the chemistry materials you need to solve
the challenges awaits you.
Predict the outcome
The tricky thing with substitution and elimination reactions is that they are often in
competition with each other for specific combinations of reactants. Working with a set of
alkyl halides and nucleophiles/bases, you will be challenged to form and test hypotheses
about which reaction type will be dominant, or which product will be the major one. You can
test your assumptions freely by trying out any conceivable combination of the available
chemicals, and if you don’t get the expected product, you can always just reset the reaction
vessel and try again!
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In the final challenge, Dr. One will simply ask you a series of quiz questions on the topic. You
might already know the answers by then, but if not, you can continue to explore the
reactions using the materials on your workbench.
Solving the puzzle
Only by carefully considering the different reaction conditions will you be able to complete
your mission. Dr. One will, of course, be there to assist you as you move through the
challenges, and you can always head to the theory pages to dive further into the reactions.
Will you be able to figure out how substitution and elimination reactions compete?
Learning Objectives
At the end of this simulation, you will be able to…
● Predict the reaction type and product for reaction conditions that could lead to either
of the SN1, SN2, E1, or E2 type reactions
Techniques in Lab
None
Theory
The SN1 Reaction
An SN1 reaction is a nucleophilic substitution reaction in which the rate-determining step
involves one component. The reaction name derives from S standing for ‘substitition’, N for
‘nucleophilic’ and the 1 denoting the kinetic order of the reaction – or simply the number of
reaction components involved in the rate-determining step.
SN1
reactions
are
two-step, unimolecular reactions and proceed via an
intermediate carbocation. The first carbocation-forming step is the slower of the two and
therefore determines the rate of the reaction. The second step involves the rapid attack of
the nucleophile to the newly-formed carbocation.
Figure 1: General SN1 reaction mechanism.
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Unlike the SN2 reaction – in which we see inversion of stereochemistry in the product – the
SN1 reaction provides a racemic product. Racemization of the stereochemistry takes place
as the nucleophile is able to approach the planar carbocation intermediate from either
side, providing both product stereoisomers.
Factors that affect the SN1 reaction:
●
Solvent Polar, protic solvents usually speed up the rate of an SN1 reaction, as their
large dipole moment helps to stabilize the intermediate carbocation. Polar, aprotic
solvents are not used in SN1 reactions because some of them can react with the
carbocation intermediate and provide unwanted products.
●
Nucleophile Since the nucleophile is not involved in the rate-determining step on an
SN1 reaction, the strength of the nucleophile does not affect the reaction. However,
if you have more than one nucleophile competing to bond with the carbocation, you
could end up with a mixture of products. (Sometimes a solvent can act as a
nucleophile too!)
●
Leaving group The better the leaving group, the faster the SN1 reaction. This is
because the leaving group is involved in the rate-determining carbocation formation
step.
The SN2 Reaction
An SN2 reaction is a nucleophilic substitution reaction in which the rate-determining step
involves two components.
The
reaction
name
derives
from S standing
for
‘substitition’, N for ‘nucleophilic’ and the 2 denoting the kinetic order of the reaction – or
simply the number of reaction components involved in the rate-determining step.
An SN2 reaction arises from the combination of a good nucleophile and a substrate with
an electrophilic reaction center attached to a good leaving group. A good example of this is
the carbon-halogen (C-X)bond you’d find in an alkyl halide.
Figure 2: General SN2 reaction mechanism.
SN2 reactions are one-step bimolecular reactions with concerted – or simultaneous bond-breaking and bond-making steps. Since SN2 reactions proceed in one step, a defining
characteristic of this substitution is that the mechanism does not proceed via a reaction
intermediate. Instead, the nucleophile coordinates to the reaction center to form a bond at
the same time the C-X bond breaks simultaneously. This results in inversion of
configuration at the reaction stereocenter.
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Factors affecting an SN2 reaction:
●
Solvent The rate of an SN2 reaction is significantly influenced by the solvent in
which the reaction takes place. Protic solvents (e.g. water or alcohols with
hydrogen-bond donating ability) decrease the power of the nucleophile due to
a solvation effect. Strong hydrogen-bond interactions between solvent protons and
the highly reactive lone pairs on the nucleophile form a ‘shell’ that prevents the
nucleophile reacting. SN2 reactions are faster in polar, aprotic solvents (e.g. acetone)
that lack hydrogen-bonding capability.
●
Steric effects Since SN2 reactions rely heavily on easy access to the reaction
center, steric effects are one important factor that could impede reaction. By
selecting a less sterically hindered alkyl halide and a strong nucleophile, it’s possible
to favor the SN2 reaction over potentially competing reactions such as the SN1
reaction or elimination reactions.
E1 reaction
Basics of E1 elimination reaction
The E1 elimination is a type of elimination reaction in organic chemistry. It takes place in
two separate steps, but the rate of the reaction is only limited by one of the reactants.
Figure 3 here provides an example of an E1 elimination.
1.
The leaving group – bromide – takes the electrons from the detaches from the main
molecule, which becomes a carbocation. Carbocations are not stable though, so some
further reaction must take place!
2.
A base abstracts a proton from the main molecule, which stabilizes the main molecule via
the formation of a double bond.
Figure 3: Example of the first and second step in an E1 elimination reaction, using
2-bromo-2-methylbutane as the main reactant.
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Important factors that influence E1 reactivity
These factors generally increase reactivity towards an E1 elimination:
● A good leaving group in the main molecule
● Degree of substitution: The more substituted the (potential) carbocation is, the more
stable and therefore likely to form it is. E1 actually almost only occurs at tertiary
carbon atoms!
● Base: A strong base that can pull off that hydrogen. But E1 can actually take place
even with a weak base.
● Temperature: The rate of elimination reactions generally increase with temparature.
When in competition with substitution reactions, adding heat to the reaction will
therefore favor the elimination path.
● The solvent in which the reaction takes place can have a huge effect. How this
affect elimination reactions are beyond this simulation, but you can check out this
page for an overview of how solvents are normally categorized.
Stereochemistry of the reaction product
Because the reaction goes through a planar carbocation intermediate, there is no specific
selectivity towards cis or trans for the product, and usually the result will be a mix of the
two.
E2 reaction
Basics of E2 elimination reaction
The E2 elimination is a type of elimination reaction in organic chemistry. It takes place in
only 1 step, but the rate of the reaction is limited by two of the reactants. Figure 4 here
provides an example of an E1 elimination.
The leaving group takes the electrons and detaches from the main molecule as a base
simultaneously abstracts a proton. Notice there is no intermediate formation of a
carbocation.
Figure 4: Example of an E2 elimination reaction, using 2-bromobutane as the main reactant.
Important factors that influence E2 reactivity
E2 eliminations are for many factors influenced in a similar way for as for the E1 type.
Noteworthy differences are:
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●
●
Degree of substitution: Even though elimination reactions are generally more favored
in highly substituted molecules, E2 reactions can also take place with secondary and
even primary carbon atoms.
It usually requires a strong base.
Stereochemistry of the reaction product
As the E2 reaction takes place in a single step, the reaction product will all have the same
configuration, and the product with trans configuration will be far more dominant. This iis
due to the fact that the leaving group and the base-removed hydrogen will tend to
be antiperiplanar, that is, on opposite sides of the bond of the two carbons that the
involved groups are connected to. This is a special trait of the E2 reaction.
Reaction terminology
Here is a list of terms used in the description of chemical reactions, along with an
explanation of their correct uses.
● Catalyst
A catalyst is a component in a chemical reaction, which increases the reaction rate by
changing the reaction mechanism. A catalyst is not used in the reaction and thus is
often effective in sub-stoichiometric amounts.
● Curly arrow
A curly arrow is a special type of arrow used to denote the movements of the electrons
when describing the reaction mechanism of a chemical reaction.
● Electrophile
An electrophile is a species which will accept donation of electrons to create a new
bond.
● Intermediate
An intermediate, or more precisely a reaction intermediate, is a chemical species which
is formed from the reactants but continues to react to form the product(s) or other
intermediates. Reactions that contain more than one step will also have reaction
intermediates. A reaction intermediate represents a local minimum on a reaction energy
diagram.
● Leaving group
A leaving group is a part of a molecule which breaks away from the substrate during the
reaction, taking with it the electron pair that made up the bond which is being broken.
● Lone-pair
A lone-pair is a pair of valence electrons which do not partake in bonding.
● Nucleophile
A nucleophile is a chemical species which will donate electrons to an electrophile to
form a new bond during a chemical reaction.
● Product
A product is the outcome of a chemical reaction.
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● Reactant
A reactant is the species that is transformed into the product in a chemical reaction. A
reactant is also referred to as a substrate.
● Reaction conditions
The reaction conditions of a reaction include factors like: The temperature at which the
reaction should occur; if any particular atmosphere should be used (for example Argon
or Nitrogen for air-free conditions); the pressure the reaction should run at (if different
from atmospheric pressure); the stirring speed (if important); the reaction time.
● Reagent
A reagent is a substance added to a reaction to cause the chemical transformation of
the reactant(s) to occur, or to test for the presence of a particular compound. A reagent
is consumed during the cause of the reaction, in opposition to a catalyst, which is not
consumed.
● Solvent
A solvent is a chemical substance that dissolved a compound, which is then the solute.
A solvent is usually a liquid, but can also be a gas or a supercritical fluid. Solvents
usually do not partake in a chemical reaction.
● Substrate
A substrate is a chemical species that is consumed during a chemical reaction to give a
product. A substrate can also be referred to as a reactant; however, in catalytic
reactions substrate is the correct term.
● Transition state
The transition state of a chemical reaction represents the highest energy point on the
path from reactants to products. A transition state is not a stable species and cannot
be isolated. A transition state should not be confused with an intermediate!
Correct use of certain terms:
One or more reactants (also referred to as the substrate), dissolved in a solvent, are
transformed into products, either spontaneously or through the action of a reagent or a
catalyst. If the reaction has multiple steps, then intermediates will form after each step,
except for the last one which forms the final product. Every reaction step passes through a
transition state, which represents the highest energy point on the path from reactants to
products.
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Nomenclature of simple hydrocarbons
Simple hydrocarbons are named based on a few straightforward rules. The first part of the
name – the prefix – is determined by the number of carbon atoms in the longest carbon
chain. The second part of the name – the suffix – is determined by whether double or triple
bonds are present. A visual representation of these principles can be seen in Figure 5.
Figure 5: Overview of the nomenclature principles of simple hydrocarbons.
If more than one location is possible for a double or triple bond, a number is added to
indicate its placement on the carbon chain, always counting from one end of the chain and
giving the carbon the lowest number possible.
Chemical nomenclature: Trivial names
A trivial name is a non-systematic name for a chemical substance. Trivial names are not
officially recognized according to the systematic rules of formal IUPAC chemical
nomenclature, but might still be commonly used informally in chemistry. You might come
across trivial (or common) naming in written text, atom labels in chemical structures or in
chemical formulae.
Common/trivial chemical prefixes glossary:
Trivial Prefix
Prefix Expansion
Me
Methan-
or
Notes
Methyl
group
Et
Ethan- or Ethyl group
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Pr
Propan- or Propyl
Bu
Butan- or Butyl group
tert-
tertiary
Tertiary, branched carbon chain.
iso-
isomer
All carbons except one form a continuous
chain. Can also indicate a constitutional
isomer with a trivial name.
n-
‘normal’
Continuous, unbranched carbon chain.
Carbocations
A carbocation is a reactive intermediate that has a carbon atom bearing a positive charge
and three bonds to that carbon instead of four.
Since all carbocations carry a positive charge on a carbon atom – there’s an easy way to
remember this in the name. A cation is a positive ion and the carbo- indicates a carbon
atom. There are different types of carbocations and their structure determines the relative
stability and reactivity of the carbocations.
A primary carbocation is attached to only one other alkyl group. In a general structural
formula you may see the alkyl group denoted as an ‘R’ group.
Figure 6: Primary carbocation general formula and examples of primary carbocations.
In a secondary carbocation the carbon carrying a positive charge is attached to 2 other alkyl
groups. R and R’ represent different alkyl groups which may be the same or different.
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Figure 7: Secondary carbocation general formula and examples of secondary carbocations.
A tertiary carbocation is a positively charged carbon that is attached to 3 alkyl groups. R, R’
and R’’ are alkyl groups and may be the same or different.
Figure 8: Tertiary carbocation general formula and examples of tertiary carbocations.
Alkyl halides
Alkyl halides (also known as haloalkanes) are hydrocarbon compounds in which one or
more of the hydrogen atoms have been replaced by a halogen atom (iodine, bromine,
chlorine or fluorine). Incorporating halogen atoms into a hydrocarbon changes the
compounds’ physical properties – affecting size, electronegativity and bond length and
strength.
Alkyl halides are ideal substrates for reactions that require a good leaving group. The high
reactivity of alkyl halides can be explained in terms of the nature of the C-X bond. The
differences in electronegativity between the carbon and halogen atoms create a highly
polarized bond resulting in a slightly electropositive carbon and slightly electronegative
halogen. This electron-deficient carbon becomes a hotspot for nucleophilic attack, making
alkyl halides excellent substrates for nucleophilic substitution and elimination reactions.
Alkyl halides are classified according to the connectivity of the carbon atom that carries
the halogen atom:
Primary the carbon attached to the halogen is only attached to one other alkyl group
Secondary the carbon attached to the halogen is attached to two other alkyl groups
Tertiary the carbon attached to the halogen attached to three other alkyl groups
In general – due to the steric bulk of three alkyl groups surrounding the halogen in tertiary
alkyl halides – tertiary alkyl halides are far less reactive than the other classes and may
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only participate in elimination reactions. The general reactivity trend across alkyl halides
classes is Primary > Secondary > Tertiary. However – this alkyl halide reactivity trend
is reversed if the rate of a specific reaction (e.g. SN1 reaction) is determined by the
formation of the most stable carbocation. In these situations, tertiary alkyl halides are
highly favored as they would form the most stable reactive intermediate.
Other factors – like which C-X bond you need to break – also contribute to the alkyl halides’
reactivity and the likelihood of a reaction occurring or not.
In selecting the best halide starting material for a reaction – we also need to consider the
strength of the C-X bond we are trying to break. C-F bonds are so strong that fluoroalkanes
very rarely react, so don’t make great starting materials. C-X bond strength falls as we go
down the periodic table, meaning the weakly-bonded iodide is the most willing leaving
group, closely followed by bromide.
Figure 9: Trend in C-X bond strength
Factors that contribute to nucleophilicity
There are four key factors that contribute to a species’ nucleophilicity:
● Charge A nucleophile reacts by donating electrons. This means that the higher the
electron density on a species, the more nucleophilic it is, all other things being
equal. In general, a negatively charged species will be more nucleophilic than its
neutral counterpart.
● Size A nucleophile donate electrons to an electrophile, but to do so it needs to be in
close proximity to the electrophile. This can be hard if the nucleophile is a large and
bulky molecule. In general, a smaller nucleophile is a stronger nucleophile!
● Electronegativity Highly electronegative atoms have a high electron density, but they
also have a high electron affinity, meaning that they attract the electrons strongly. A
nucleophile reacts by donating electrons, which a highly electronegative atom is less
willing to do. Therefore, a less electronegative atom is more nucleophilic, all other
things being equal.
● Solvent Solvents can be either protic or aprotic. A protic solvent can participate in
hydrogen bonding with the nucleophile, which causes the nucleophile to
be cushioned by the solvent. This makes the nucleophile less reactive, than if it was
dissolved in an aprotic solvent.
Leaving groups
A leaving group is a part of a molecule that can break away (leave the molecule) during a
reaction, and in doing so takes with it the electrons that make up the bond that is breaking.
A leaving group can be thought of like a nucleophile working backward: Accepting an
electron pair as a bond is broken – and indeed the second part of a nucleophilic
substitution reaction is the leaving group breaking away.
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The key factor contributing to a species’ suitedness as leaving group is its basicity: The
weaker the baser, the better the leaving group. Read more about the connection between
leaving groups and basicity here.
Halogens are often used as the leaving group, e.g. in alkyl halides. The general order of
“ability to leave” for them is I > Br > Cl > F. But there are exceptions for specific reaction
environments!
Solvent types
Solvents are generally categorized into one of three categories:
● Protic solvents contain an OH, NH or other labile hydrogen (H+ proton)
● Aprotic solvents do not contain any labile protons
● Polar solvents have large dipole moments (aka partial charges). They contain bonds
between atoms with large differences in electronegativity, like oxygen and hydrogen.
Solvents are chosen carefully for their compatibility with specific reactions. For example,
polar solvents are able to dissolve many reagents easily, but can have high boiling points,
making them trickier to remove from reaction products.
Protic solvents are able to stabilize charged intermediates but their ability to hydrogen
bond with charged species can solvate or create a solvent shell around reactive species,
hindering the rate of some reactions. Aprotic solvents are a good choice when designing a
reaction where the rate-determining step relies on the interaction of highly charged
reactive species.
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Virtual Lab Manual
Nucleophilic Addition: explore
the Grignard Reaction
Synopsis
Addition reactions are one of the greatest tools in a medicinal chemists’ toolkit! In this
simulation, you will learn the principles of the nucleophilic addition reaction and put your
knowledge into practice by performing a Grignard reaction to synthesize a potential cancer
drug candidate. You’ll have the chance to make a ground-breaking drug discovery!
Last-ditch drug discovery
Join scientists in a drug discovery team as they investigate one last hunch before the failing
project is shut down. Students will get hands-on in exploring the nucleophilic addition
reaction in a pharmaceutical research lab, and apply their knowledge to help synthesize a
molecule with therapeutic potential. To transform the existing ketone into the target alcohol,
students will develop their practical and theoretical knowledge of the Grignard reaction.
Nucleophilic addition – experiment and explore!
Interact with nucleophilic addition reaction components at a molecular level with our 3D
reaction visualizer. Identify important reaction components before triggering the electron
flow to carry out the reaction before your eyes! Get up close with the mechanistic principles
of nucleophilic addition and better acquainted with molecular-level reactivity considerations.
You’ll also have the chance to give a Grignard reaction a go in a safe and instructive lab
environment. Synthesize your moisture-sensitive Grignard reagent in situ before using it
directly in a Grignard reaction to get one step closer to your target molecule. Prompts from
Dr. One will remind you of the tricky practical aspects to remember for a successful Grignard
reaction!
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Pharmaceutical scale-up
To complete the simulation you’ll investigate factors you’ll need to consider in scaling up the
Grignard reaction to an industrial scale if the drug is shown to be a ‘hit’. Will you be able to
design a synthesis for an effective treatment for breast cancer?
Learning Objectives
At the end of this simulation, you will be able to…
● Demonstrate a detailed understanding of the nucleophilic addition reaction
● Provide an overview and examples of nucleophilic addition to a carbonyl group
● Draw correctly the mechanism for common nucleophilic addition reactions
● Demonstrate a detailed understanding of the Grignard reaction
● Describe the role of each reagent in the Grignard reaction
● Explain the sensitivity of Grignard reaction conditions and be able to make procedural
adjustments
● Gain understanding and practical experience of essential laboratory techniques:
○ Reflux reactions
○ Air-sensitive synthesis
○ Generation and use of reagents in situ
Techniques in Lab
●
●
●
Reflux technique
Air- and moisture-sensitive synthesis
Synthesis and use of Grignard reagents in-situ
Theory
Overview of common functional groups
This image provides you with an overview of the most common functional groups in organic
chemistry. You can read more about each of the functional groups below the image.
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●
Alkane: A hydrocarbon that has no functional groups. Alkanes are named with the
suffix -ane, e.g. butane.
●
Alkene: A hydrocarbon that has at least one C-C double bond. The double bond is
nucleophilic, which makes the alkenes substrates in electrophilic addition reactions.
Alkenes are named with the suffix -ene, e.g. butene.
●
Alkyne: A hydrocarbon that has at least one C-C triple bond. The triple bond is
nucleophilic, which makes the alkynes substrates for electrophilic addition
reactions. If the alkyne is terminal, the proton is slightly acidic and acetylide anions
can be formed. Alkynes are named with the suffix -yne, e.g. butyne.
●
Arene: Also called aromatics, are hydrocarbons that contain at least one phenyl
group. Aromatic rings have a high electron density and are nucleophilic, which makes
them substrates for electrophilic aromatic substitution. Aromatics can contain other
functional groups and are named with the prefix phenyl- or with the suffix -benzene,
e.g. phenylamine and chlorobenzene.
●
Haloalkane: A compound that contains a halogen (main group VII in the periodic
table) substituent. The halogens are more electronegative than carbon, and are good
leaving groups, making haloalkanes good substrates for SN1/SN2 and E1/E2 reactions.
Haloalkanes are named with the prefix halo-, e.g. bromobutane.
●
Aldehyde: A compound that contains a C-O double bond, where one of the
substituents on the carbon atom is a hydrogen atom and the other is a carbon atom.
The C=O bond is polarized towards oxygen, making the carbon atom electrophilic
and thus aldehydes are substrates for nucleophilic addition reactions. Aldehydes are
named with the suffix -al, e.g. butanal.
●
Ketone: A compound that contains a C-O double bond, where both of the
substituents on the carbon atom are carbon atoms. The C=O bond is polarized
towards oxygen, making the carbon atom electrophilic and thus ketones are
substrates for nucleophilic addition reactions. Ketones are named with the
suffix -one, e.g. butanone.
●
Alcohol: A compound with a hydroxy (-OH) substituent to saturated carbon. Alcohols
can be deprotonated to create a good nucleophile, or protonated to transform the
-OH into a good leaving group (OH2), thereby making the alcohols suitable substrates
for SN1/SN2 and E1/E2 reactions. Alcohols are named with the suffix -ol, e.g. butanol.
Note that a hydroxy (-OH) group on an aromatic ring yields the functional
group phenol, which has slightly different reaction properties.
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●
Ether: A compound that contains a C-O-C bond. Ethers are generally not very
reactive and are often used as solvents. Ethers are named with the suffix ether,
e.g. diethyl ether.
●
Amine: A compound that contains an amino substituent. The amine can be primary
(R-NH2), secondary (R-NHR’) or tertiary (R-NR’R”). Amines are alkaline and often used
as bases or nucleophiles. Amines are named with the suffix amine, e.g. triethyl
amine.
●
Carboxylic acid: A compound with a -COOH substituent. Carboxylic acids and their
derivatives (below) can be transformed into each other through nucleophilic
substitution reactions. Carboxylic acids are named with the suffix -oic acid,
e.g. butanoic acid.
●
Acid anhydride: A compound with a -COOCO- component. Acid anhydrides are
derivatives of carboxylic acids, structurally resembling two carboxylic acids that have
been merged with the elimination of a water molecule. Acid anhydrides are named
with the suffix -oic anhydride, e.g. butanoic anhydride.
●
Ester: A compound with a -COOR substituent. Esters are derivatives of carboxylic
acids, structurally resembling a carboxylic acid that has been merged with an
alcohol by the elimination of a water molecule. Esters are named with -yl -oate,
e.g. butyl butanoate.
●
Amide: A compound with a -CONHR substituent. Amides are derivatives of carboxylic
acids, structurally resembling a carboxylic acid that has been merged with an amine
by the elimination of a water molecule. Amides are named with the suffix amide,
e.g. butanamide.
●
Acyl halide: A compound with a -COX substituent, where the X is a halogen. Acid
halides are derivatives of carboxylic acids, where the hydroxy substituent has been
replaced with a halogen atom. Acyl halides are named with the suffix -oyl halide,
e.g. butanoyl chloride.
Nucleophilic Addition Reaction
Nucleophilic addition reactions are an important class of reactions that allow us to convert
a carbonyl into a range of other functional groups.
In nucleophilic addition, a nucleophile reacts with an electrophile to form a single
molecular product.
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Figure 1: General reaction scheme for nucleophilic addition reaction
The Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which an organomagnesium
halide (also known as a Grignard reagent) adds to the carbonyl group of an aldehyde or
ketone to form an alcohol. The Grignard reaction is one of the most important synthetic
methods for forming carbon-carbon bonds.
Being extremely good nucleophiles, Grignard reagents are highly reactive compounds. This
means that in the lab we would prepare these freshly in situ just before we carry out our
Grignard reaction. It also means we need to keep any trace of moisture out of our reaction.
All glassware and solvents must be anhydrous (dry) and the reaction kept in a closed
system where water and air cannot get in.
Figure 2: Grignard reagent formation reaction scheme
Once the Grignard reagent has been prepared, we can add a solution of our carbonyl
compound (aldehyde or ketone) to the reagent to perform the Grignard addition reaction.
Figure 3: Grignard addition reaction scheme
The final work-up step involves pouring the reaction mixture into a mixture of sulfuric acid
and ice to break down the Grignard transition complex and produce our alcohol product.
Drug discovery
Drug discovery is the process through which new medication candidates are discovered.
Drug discovery is a combination of processes that operate at the intersection of the fields
of chemistry, pharmacology, biotechnology and medicine.
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Historically, medicines were either discovered accidentally, like penicillin, or by identifying
the active ingredients of traditional remedies (aspirin from tree bark, or morphine from
opium poppies).
These days there are multiple approaches to drug discovery:
● Chemical libraries: libraries of small synthetic chemical compounds or natural
products that can be screened quickly in cells or organisms to identify compounds
that trigger the desired biological effect. This process is known as Pharmacology.
● Medicinal chemistry: uses synthetic organic chemistry to create new compounds or
modify existing ones to increase the potency and selectivity of potential drug
candidates.
● Structure-activity studies: these studies look at the relationship between chemical
structure and its biological activity against the target. This might use existing
chemical libraries for screening or use computer-aided drug design to run algorithms
to predict the chemical and physical interactions of the compound in the target
receptor.
Once a suitable compound has been found, the process of drug development can continue,
including scale up, medicine formulation and clinical trials.
How to draw reaction mechanisms
Reaction mechanisms are drawn using curly arrows to denote the movement of the
electrons in each step of the reaction. It is very important that the arrow starts where the
electrons are and points towards where the electrons go. A curly arrow with
a whole arrowhead represents the movement of an electron pair, whereas a curly arrow
with a half arrowhead represents the movement of a single electron, typically in a radical
reaction. The two types of curly arrows are shown in figure 4.
Figure 4: The curly arrow with a whole arrowhead (left) represents the movement of an
electron pair.
The curly arrow with half an arrowhead (right) represents the movement of a single
electron.
Overall there are three different types of curly arrows:
● Arrows that break bonds. The arrow root is drawn to begin in the bond which is
broken. The arrowhead points to the atom or part of the molecule which will accept
the electron pair from the bond. In the example below, a bromine atom breaks away
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from tert-butyl bromide. The electrons that made up that bond leaves with the
bromine atom, creating a negatively charged bromine ion and a carbocation.
●
Arrows that make bonds. The arrow root is drawn to begin in the lone-pair or the
negative charge of the nucleophile which will attack. The arrowhead is drawn to
point at the electrophile where the nucleophile will attack or the new bond which
will be formed as a result of the reaction. In the example below, a lone-pair on the
oxygen atom of a water molecule attacks the electrophilic carbon atom of the
carbocation. The result is a protonated tertiary alcohol.
●
Arrows that make and break bonds at the same time. The arrows root is drawn to
begin in the bond which is being broken and the arrowhead is drawn to point at the
electrophile where the nucleophile will attack or the new bond which will be formed.
In the example below, the bond between the carbon and hydrogen is being broken,
and the electrons from that bond are used to create a new bond between that same
carbon atom and the positively charged carbon atom. The result is an alkene and a
proton.
Notice that for all the reaction mechanisms drawn, charge is conserved, just as when
writing reaction schemes. Drawing reaction mechanisms is an accounting system, so no
electrons or charges can suddenly appear or disappear.
Regioselectivity
The term regioselective can be used to describe any process that favors bond formation at
a particular atom over other possible atoms. The ‘Regio-’ prefix comes from the Latin for
‘Region’ or an area of something.
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A reaction can be said to have high regioselectivity when one major product dominates due
to the reaction being highly favored at one atomic position over another.
In the addition reaction example below the preferential formation of a stable tertiary
carbocation at the 2-position results in the reaction proceeding to give 2-Chlorobutane as
the major product.
Figure 5: Regioselectivity in the hydrochlorination of but-1-ene.
Stereochemistry
Stereochemistry relates to the three-dimensional arrangement of atoms and molecules and
the effect of this spatial arrangement on chemical reactions. Stereoselectivity is the
preference for a reaction to occur on one molecular face over another, resulting in the
preferential formation of one stereoisomer. If there’s more than one stereoisomer possible
from a reaction, and the configuration of at least one chemical bond is not known, that
bond can be represented with a wavy bond.
Figure 6: Stereoselectivity in bromide ion addition to a carbocation. Note the solid and
hashed wedged bonds.
A reaction is said to be stereoselective if the reaction mechanism selects the formation of
one stereoisomer over the other. In contrast, a stereospecific reaction is a reaction which
only allows the formation of one stereoisomer (e.g. the stereochemistry is already set by
the starting material).
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Virtual Lab Manual
Elimination Reactions: Use
cyclohexanol to create polymers
Synopsis
Eliminate the leaving group and get double-bonded! In this simulation, you will learn the ins
and outs of Elimination Reactions in Organic Chemistry. You will get hands-on experience
with some alkyl halides and discover how they go through the E1 and E2 eliminations.
Polymer production going sideways
Meet Kim: a research scientist at a polymer research and production lab. They are having
problems with optimizing their elimination reaction that converts cyclohexanol to
cyclohexene, and they need your help to understand what’s going on and how to get it right.
You will need to understand the core concepts of elimination reactions to be able to help her
out!
Eliminating the unknowns
Back in the main lab, you will brush up on your organic chemistry know-how. After
understanding Kim’s reaction a little better, you will dive into the two main types of
elimination reaction: the E1 and E2. You will be able to hands-on manipulate molecules to go
through the mechanisms of the two reactions, before being challenged to figure out Zaitsev’s
rule through an explorative and interactive exercise. You will also need to assess what
reactants are more likely to go through the two reactions. If you get this, you might get the
rockstar achievement!
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Back on track
To get to the bottom of Kim’s production puzzle, you will have to carefully work out the
mechanisms of the two reactions and what determines their reactivity and the products
they form. Will you be able to help her solve it, so her research lab can continue producing
polymers for the world?
Learning Objectives
At the end of this simulation, you will be able to…
● Explain the reaction mechanisms of the E1 and E2 reactions
● Compare the reactivity of different alkyl halides towards E1 and E2
● Predict the product of an Elimination Reaction using Zaitsev’s rule
● Predict the double-bond stereochemistry of the product in an E2 reaction
Techniques in Lab
None
Theory
Elimination reactions in organic chemistry
The main feature of an elimination reaction in organic chemistry is that two substituents
are removed from a molecule, with the formation of a double bond. Often, one of the
substituents will be hydrogen (H +).
Figure 1: Generic representation of an elimination reaction. Two substituents are removed
from the reactant, and the product contains a double bond.
E1 reaction
Basics of E1 elimination reaction
The E1 elimination is a type of elimination reaction in organic chemistry. It takes place in
two separate steps, but the rate of the reaction is only limited by one of the reactants.
Figure 2 here provides an example of an E1 elimination.
1.
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The leaving group – bromide – takes the electrons from the detaches from the main
molecule, which becomes a carbocation. Carbocations are not stable though, so some
further reaction must take place!
2.
A base abstracts a proton from the main molecule, which stabilizes the main molecule via
the formation of a double bond.
Figure 2: Example of the first and second step in an E1 elimination reaction, using
2-bromo-2-methylbutane as the main reactant.
Important factors that influence E1 reactivity
These factors generally increase reactivity towards an E1 elimination:
● A good leaving group in the main molecule
● Degree of substitution: The more substituted the (potential) carbocation is, the more
stable and therefore likely to form it is. E1 actually almost only occurs at tertiary
carbon atoms!
● Base: A strong base that can pull off that hydrogen. But E1 can actually take place
even with a weak base.
● Temperature: The rate of elimination reactions generally increases with temperature.
When in competition with substitution reactions, adding heat to the reaction will
therefore favor the elimination path.
● The solvent in which the reaction takes place can have a huge effect. How this
affect elimination reactions are beyond this simulation, but you can check out this
page for an overview of how solvents are normally categorized.
Stereochemistry of the reaction product
Because the reaction goes through a planar carbocation intermediate, there is no specific
selectivity towards cis or trans for the product, and usually the result will be a mix of the
two.
E2 reaction
Basics of E2 elimination reaction
The E2 elimination is a type of elimination reaction in organic chemistry. It takes place in
only 1 step, but the rate of the reaction is limited by two of the reactants. Figure 3 here
provides an example of an E1 elimination.
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The leaving group takes the electrons and detaches from the main molecule as a base
simultaneously abstracts a proton. Notice there is no intermediate formation of a
carbocation.
Figure 3: Example of an E2 elimination reaction, using 2-bromobutane as the main reactant.
Important factors that influence E2 reactivity
E2 eliminations are for many factors influenced in a similar way as for the E1 type.
Noteworthy differences are:
● Degree of substitution: Even though elimination reactions are generally more favored
in highly substituted molecules, E2 reactions can also take place with secondary and
even primary carbon atoms.
● It usually requires a strong base.
Stereochemistry of the reaction product
As the E2 reaction takes place in a single step, the reaction products will all have the same
configuration, and the product with trans configuration will be far more dominant. This is
due to the fact that the leaving group and the base-removed hydrogen will tend to
be antiperiplanar, that is, on opposite sides of the bond of the two carbons that the
involved groups are connected to. This is a special trait of the E2 reaction.
Zaitsev’s rule
A rule for where the double bond tends to form in elimination reactions. Zaitsev’s rule
states that a double bond will form to create the most stable alkene, that is, the one where
the carbon atoms that form the double bond hold the most substituents.
Look at the reaction below, and try to count the number of non-hydrogen side-groups on
the carbon atoms that share the double bond.
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Figure 4: Elimination reaction with 3 potential products. In this example, the product in the
middle will be the major one according the Zaitsev’s rule.
Nomenclature of simple hydrocarbons
Simple hydrocarbons are named based on a few straightforward rules. The first part of the
name – the prefix – is determined by the number of carbon atoms in the longest carbon
chain. The second part of the name – the suffix – is determined by whether double or triple
bonds are present. A visual representation of these principles can be seen in Figure 5.
Figure 5: Overview of the nomenclature principles of simple hydrocarbons.
If more than one location is possible for a double or triple bond, a number is added to
indicate its placement on the carbon chain, always counting from one end of the chain and
giving the carbon the lowest number possible.
Carbocations
A carbocation is a reactive intermediate that has a carbon atom bearing a positive charge
and three bonds to that carbon instead of four.
Since all carbocations carry a positive charge on a carbon atom – there’s an easy way to
remember this in the name. A cation is a positive ion and the carbo- indicates a carbon
atom. There are different types of carbocations and their structure determines the relative
stability and reactivity of the carbocations.
A primary carbocation is attached to only one other alkyl group. In a general structural
formula you may see the alkyl group denoted as an ‘R’ group.
Figure 6: Primary carbocation general formula and examples of primary carbocations.
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In a secondary carbocation the carbon carrying a positive charge is attached to 2 other alkyl
groups. R and R’ represent different alkyl groups which may be the same or different.
Figure 7: Secondary carbocation general formula and examples of secondary carbocations.
A tertiary carbocation is a positively charged carbon that is attached to 3 alkyl groups. R, R’
and R’’ are alkyl groups and may be the same or different.
Figure 8: Tertiary carbocation general formula and examples of tertiary carbocations.
Alkyl halides
Alkyl halides (also known as haloalkanes) are hydrocarbon compounds in which one or
more of the hydrogen atoms have been replaced by a halogen atom (iodine, bromine,
chlorine or fluorine). Incorporating halogen atoms into a hydrocarbon changes the
compounds’ physical properties – affecting size, electronegativity and bond length and
strength.
Alkyl halides are ideal substrates for reactions that require a good leaving group. The high
reactivity of alkyl halides can be explained in terms of the nature of the C-X bond. The
differences in electronegativity between the carbon and halogen atoms create a highly
polarized bond resulting in a slightly electropositive carbon and slightly electronegative
halogen. This electron-deficient carbon becomes a hotspot for nucleophilic attack, making
alkyl halides excellent substrates for nucleophilic substitution and elimination reactions.
Alkyl halides are classified according to the connectivity of the carbon atom that carries
the halogen atom:
Primary the carbon attached to the halogen is only attached to one other alkyl group
Secondary the carbon attached to the halogen is attached to two other alkyl groups
Tertiary the carbon attached to the halogen attached to three other alkyl groups
In general – due to the steric bulk of three alkyl groups surrounding the halogen in tertiary
alkyl halides – tertiary alkyl halides are far less reactive than the other classes and may
only participate in elimination reactions. The general reactivity trend across alkyl halides
classes is Primary > Secondary > Tertiary. However – this alkyl halide reactivity trend
is reversed if the rate of a specific reaction (e.g. SN1 reaction) is determined by the
formation of the most stable carbocation. In these situations, tertiary alkyl halides are
highly favored as they would form the most stable reactive intermediate.
Other factors – like which C-X bond you need to break – also contribute to the alkyl halides’
reactivity and the likelihood of a reaction occurring or not.
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In selecting the best halide starting material for a reaction – we also need to consider the
strength of the C-X bond we are trying to break. C-F bonds are so strong that fluoroalkanes
very rarely react, so don’t make great starting materials. C-X bond strength falls as we go
down the periodic table, meaning the weakly-bonded iodide is the most willing leaving
group, closely followed by bromide.
Figure 9: Trend in C-X bond strength.
Factors that contribute to nucleophilicity
There are four key factors that contribute to a species’ nucleophilicity:
● Charge A nucleophile reacts by donating electrons. This means that the higher the
electron density on a species, the more nucleophilic it is, all other things being
equal. In general, a negatively charged species will be more nucleophilic than its
neutral counterpart.
● Size A nucleophile donates electrons to an electrophile, but to do so it needs to be
in close proximity to the electrophile. This can be hard if the nucleophile is a large
and bulky molecule. In general, a smaller nucleophile is a stronger nucleophile!
● Electronegativity Highly electronegative atoms have a high electron density, but they
also have a high electron affinity, meaning that they attract the electrons strongly. A
nucleophile reacts by donating electrons, which a highly electronegative atom is less
willing to do. Therefore, a less electronegative atom is more nucleophilic, all other
things being equal.
● Solvent Solvents can be either protic or aprotic. A protic solvent can participate in
hydrogen bonding with the nucleophile, which causes the nucleophile to
be cushioned by the solvent. This makes the nucleophile less reactive, than if it was
dissolved in an aprotic solvent.
Leaving groups
A leaving group is a part of a molecule that can break away (leave the molecule) during a
reaction, and in doing so takes with it the electrons that make up the bond that is breaking.
A leaving group can be thought of like a nucleophile working backward: Accepting an
electron pair as a bond is broken – and indeed the second part of a nucleophilic
substitution reaction is the leaving group breaking away.
The key factor contributing to a species’ suitedness as a leaving group is its basicity: The
weaker the base, the better the leaving group.
Halogens are often used as the leaving group, e.g. in alkyl halides. The general order of
“ability to leave” for them is I > Br > Cl > F. But there are exceptions for specific reaction
environments!
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Virtual Lab Manual
Synthesis of Aspirin:
How to fight students’
migraines
Synopsis
Begin your learning experience in a modern pharmacy and help Marie the pharmacist, by
synthetizing some extra aspirin in the laboratory, to fight the outbreak of headaches amongst
students during the exam period.
Identify the reaction
First, let’s dive into the theory! Learn about esterification reactions and the history of
aspirin. You will be challenged to understand the correct reagents and products involved in
the synthesis of aspirin. With the basics now covered, you are ready to step into the
laboratory!
Perform crystallization and filtration
The practical part of the simulation begins. Following the canonical synthetic route, you go
through the steps of a synthesis like you would in a real laboratory, with some precious time
gained! In our virtual lab, multiple actions can happen simultaneously and you can speed up
time.
From weighing the reagent to setting the correct apparatus for the reaction, from finding the
correct ways of cooling down a solution to following the best practices to form big crystals,
you are constantly challenged and supported with the theory. A great way to learn by doing,
gain lab skills and master the equipment!
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Calculate the yield and check the quality of the product
To complete the experience, you are asked to look into which steps could have caused a loss
of product in the whole synthetic process, and calculate the yield. You are also responsible
for testing the quality of the product, and perform a qualitative analysis using the melting
point technique…
Time to check if your mission is accomplished! Did you synthetize enough aspirin to help all
those students?
Learning Objectives
At the end of this simulation, you will be able to…
● Briefly describe the reactions involved in the synthesis procedure
● Correctly assemble and use condenser apparatus
● Correctly assemble and use the suction filtration (Buchner)
● Determine the percentage yield of the final product
● Assess the purity with the melting point technique
Techniques in Lab
●
●
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Scale tare
Reflux reactions
Crystallization
Buchner filtration
Yield calculation
Melting point
Theory
Esterification reaction
Esters are chemical compounds usually characterized by a pleasant smell that often find
application in cosmetic companies that produce fragrances. No matter the dimension and
complexity of the molecule, esters are structurally formed by a carbonyl center with one or
two single bonds to alkoxy groups.
The synthetic reaction to produce them is generally called esterification and can be
performed with different reagents, depending on the needs and nature of the starting
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material. The Fisher esterification, one of the most used, involves a carboxylic acid and an
alcohol as reagents, with the formation of water as a side product. Furthermore, as the
reaction is rather slow, an acid that plays a catalytic effect is often added to speed up the
reaction.
The mechanism of how an esterification reaction occurs is complicated and involves different
stages to turn the acid into an ester:
●
●
●
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Protonation: the carboxylic acid takes a proton from the catalyst attaching it to the
double-bonded oxygen and delocalizing a positive charge.
Nucleophilic addition: the delocalized positive charge rests mainly on the central
carbon, attracting one of the lone pairs on the oxygen of the alcohol.
Proton transfer: the newly attached alcohol is positively charged and therefore
transfers one of its hydrogens to another of the hydroxyl groups thanks to an
unreacted alcohol molecule in solution.
Elimination of water: a molecule of water is lost and the remaining positive charge is
stabilized through delocalization, forming different resonance structures.
Synthesis of aspirin procedure
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The conversion of salicylic acid to acetylsalicylic acid, the main component of the drug
commonly known as aspirin, involves an esterification reaction with ethanoic anhydride and
is often used in laboratories for academic purposes.
The synthetic procedure involves a recrystallization process, which has the purpose of
separating impurities from the product. This is achieved by choosing a product that dissolves
the solid when hot, but not when cold. Different steps are involved in the process:
●
●
●
●
Weigh 1 gram of salicylic acid on a tared scale and put it into a dry pear shaped flask.
Move the flask into the fume hood and secure the flask to the support over a warm
bath, to secure the reagents. Then add 2 milliliters of ethanoic anhydride, followed by
8 drops of concentrated phosphoric acid. Insert the condenser to avoid the dispersion
of fumes. In specific synthesis, the addition of activated charcoal can adsorb the
impurities in the solution.
Add the magnetic stirrer and warm the solution in the hot water bath until the solid
has dissolved, then for another 5 minutes.
Remove the flask from the warm bath and carefully add 5 milliliters of cold water. The
solution needs to be cooled down in two steps. First, the conical flask needs to be
cooled down to room temperature, and once it is at room temperature, it can be
placed in an ice bath for further cooling. If the solution is placed straight into an ice
bath, the fast cooling and formation of crystals could trap some of the impurities
again in the crystals, making the purification less efficient.
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Suction filtration
Suction filtration (also called vacuum filtration) is a technique used to separate liquids from
solids.
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In this technique, an aspirator sucks out the air that is contained in the flask where the
Büchner funnel with a filter is placed. This causes a difference in pressure, so when the
mixture is placed in the funnel, it is forced to go through the filter. After the filtration, the
solid stays on the filter, while the liquid goes through and accumulates at the Büchner flask.
Suction filtration focuses on the recovery of the solid since the flow of air created by the
aspirator will be much drier than with a simple gravity filtration. By drying the solid much
more, we make sure that most of the weight in the filter is indeed due to the solid and not to
the solvent.
To do a suction filtration we need to:
1.
2.
3.
4.
5.
Tare a filter paper on a glass watch. By doing this before and after the filtration we
will be able to estimate the weight of the solid that was in our mixture
Assemble the suction filtration equipment and activate the pump to make the air start
flowing
Place the pre-weighed filter in the Büchner funnel and filter the solution
Once the solution is filtered, leave it a bit longer in the funnel to dry out
Weight your pre-weighed filter with the solid in the scale that you previously tared to
obtain the weight of your crystals
At the end of the process, we will be able to estimate the recovery efficiency by simply
calculating the percentage of the original solid that we have recovered.
Recovery efficiency = (Final weight – Initial weight) / Initial weight
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Fig 1. Suction filtration protocol.
Yield calculation
The calculation of the yield is referred to the measure of moles of product formed in a
reaction, in relation to the amount of reactant that has been consumed. When the subject is
the maximum amount of product that could be produced with a given reactant, it is defined
as theoretical yield, while the amount that is actually obtained is the actual yield.
The calculation of the theoretical yield starts by dividing the mass of reactant to its
molecular weight, therefore obtaining the moles. Based on the principle that in a reaction the
moles of reagent equal the moles of product, if these are multiplied by the molecular weight
of the product, the ideal mass is obtained. When the actual yield is divided by the theoretical
yield times a hundred, you obtain the percentage yield.
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Melting point technique
The melting point range is the span of temperature from the point when the solid starts
melting to the point at which the entire solid is in a liquid state.
This technique can be used to determine the purity of a solid. If the melting point range of a
pure solid is known, we can estimate the purity of our impure solid as the difference in the
melting point compared to the pure solid. An impure solid melts over a wide range of
temperatures and at a temperature lower than that of the pure solid. The closer the melting
point range of the impure solid gets to the melting point of the pure solid, the fewer
impurities it will contain.
To perform a melting point range in a solid we should follow the following steps:
1. Grind your crystals until you have a fine powder
2. Tap a capillary tube on top of your sample to load it and then tap it against the
workbench to make it go to the other end
3. Insert the melting capillary tube in the melting point apparatus and turn it on
4. Determine the temperature at which the solid starts melting
5. Determine the temperature at which the solid is completely melted
If at the end of the protocol, the melting point range of the impure solid is below the melting
point of the pure solid, it means that we still have impurities in our solid.
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Fig 1. Melting Point Range protocol.
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