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OPTION D: MEDICINAL CHEMISTRY HL
D7 Taxol
E.I.: Chiral auxiliaries allow the production of individual enantiomers of chiral molecules.
Nature of science Advances in technology—many of these natural substances can now be produced in
laboratories in high enough quantities to satisfy the demand. (3.7)
Risks and problems—the demand for certain drugs has exceeded the supply of natural substances
needed to synthesize these drugs. (4.8)
Understandings
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D.7 U1 Taxol is a drug that is commonly used to treat several different forms of cancer. D.7 U2 Taxol naturally occurs in yew trees but is now commonly synthetically produced. D.7 U3 A chiral auxiliary is an optically active substance that is temporarily incorporated into an
organic synthesis so that it can be carried out asymmetrically with the selective formation of a single
enantiomer. Applications and skills
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D.7 AS1 Explanation of how taxol (paclitaxel) is obtained and used as a chemotherapeutic agent. D.7 AS2 Description of the use of chiral auxiliaries to form the desired enantiomer. D.7 AS3 Explanation of the use of a polarimeter to identify enantiomers. Taxol (or paclitaxel) is a common anti-cancer drug, a chemotherapeutic drug (=a chemical that is used to
control a disease such as cancer- chemotherapy) that was first extracted from the bark of yew trees.
However, the isolation of taxol from natural sources was very wasteful as it used a lot of bark of a species
of trees that were threatened, old and took a long time to grow.
A semi-synthetic method was developed that used a natural precursor, 10-deacetylbaccatin (10-DAB)
(hence semi-synthetic) from leaves from different but more common and faster-growing yew trees.
However, this process uses many solvents and has a low yield.
Issues with chirality in drugs
Molecules of most semi-synthetic or synthetic drugs are chiral molecules (they have an asymmetrical
carbon). In nature when chirality occurs, only 1 enantiomer is produced. During the synthesis of a chiral
semi-synthetic or synthetic drug the other enantiomer is also formed usually yielding a racemate or
racemic mixture (a mixture in which both enantiomers are equimolar).
Taxol is such an enantiomer that is obtained during its synthesis from the natural precursor.
Both enantiomers of a chiral drug have the same chemical properties apart from that they react differently
with other chiral compounds such as many enzymes and can have therefore different physiological
effects; some of which will intended whilst other effects could be harmful. It is because of this reason that
the physiological effect of each enantiomer needs to be tested. Usually only one of the enantiomers has
the desired therapeutic effect and, after synthesis of the drug molecule, this enantiomer needs to be
isolated from the racemic mixture that is obtained. Occasionally both enantiomers have the desired effect
and the drug can be administered as a racemic mixture.
Using chiral auxiliaries in the asymmetric synthesis of taxol from 10-DAB
As the extraction of an enantiomer form a racemic mixture is a wasteful process (see green chemistry)
asymmetric synthesis is often used as an alternative approach. This approach synthesizes the desired
enantiomer directly by preventing the synthesis of the other enantiomer and involves the use of a chiral
auxiliary.
A chiral auxiliary is an enantiomer (optically active substance) and is used to convert a non-chiral reacting
molecule into just one enantiomer i.e. the enantiomer with the desired pharmaceutical effect. It does that
by attaching itself to the non-chiral reactant molecule to create the stereochemical conditions necessary to
force the reaction to follow a certain path i.e. the path that will yield the desired enantiomer and not the
other enantiomer.
Once the new desired molecule has been formed, the auxiliary can be taken off and recycled.
Asymmetric synthesis = the direct synthesis of a single enantiomer. To achieve this the reaction or
synthesis has to be stereospecific and the chiral auxiliary achieves this.
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Action of Taxol as a chemotherapeutic agent
Taxol is an inhibitor that is effective against solid tumour cancers as it interferes with the cell division of the
cells in the tumor and can therefore stop its growth. Taxol does this by bonding covalently with a protein
called tubulin (taxol’s target) that makes up cellular structures called microtubules. The binding with the
tubulin gives the microtubules stability preventing them from being broken down which is an essential step
in the mitosis process and stops any cell division in the tumour.
Use of a polarimeter to identify enantiomers
See notes topic 20.
D8 Nuclear medicine
E.I.: Nuclear radiation, whilst dangerous owing to its ability to damage cells and cause mutations,
can also be used to both diagnose and cure diseases.
Nature of science
Understandings
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D.8 U1 Alpha, beta, gamma, proton, neutron and positron emissions are all used for medical
treatment.
D.8 U2 Magnetic resonance imaging (MRI) is an application of NMR technology. D.8 U3 Radiotherapy can be internal and/or external. D.8 U4 Targeted Alpha Therapy (TAT) and Boron Neutron Capture Therapy (BNCT) are two methods
which are used in cancer treatment. Applications and skills
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D.8 AS1 Discussion of common side effects from radiotherapy. D.8 AS2 Explanation of why technetium-99m is the most common radioisotope used in nuclear
medicine based on its half-life, emission type and chemistry. D.8 AS3 Explanation of why lutetium-177 and yttrium-90 are common isotopes used for radiotherapy
based on the type of radiation emitted. D.8 AS4 Balancing nuclear equations involving alpha and beta particles. D.8 AS5 Calculation of the percentage and amount of radioactive material decayed and remaining
after a certain period of time using the nuclear half-life equation. D.8 AS6 Explanation of TAT and how it might be used to treat diseases that have spread throughout
the body. Radiotherapy
Radiotherapy concerns the use of ionizing radiation as emitted by radionuclides to treat diseases such as
cancer by destroying the cancer cells. It can also be used to provide detailed information in the form of
images about internal organs to diagnose any disease.
Radioisotopes have an unstable nucleus that spontaneously decay into a more stable form by emitting
radiation either in the form of subatomic particles or energy.
Radiotherapy can be:
 Internal: radionuclides are placed in the human body to target a particular cancerous tissue or groups
of receptors. Internal radionuclides are taken in orally as a solid or as a liquid or as an implant. Liquids
could also be injected.
 External: radiation source remains outside the human body and the beams of radiation (beta or
gamma rays, photons or neutrons) target specific cancerous tissues in the body. A commonly used
nuclide for this approach is Co-60.
Effect of radiation on cells
Nuclear radiation is also referred to as ionizing radiation as it removes electrons from atoms in biological
molecules converting them into ions that form reactive radicals (such H and OH) that interfere with
physiological processes causing death, mutations and cancer.
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Effect of ionizing radiation:
 Changes to the structure of the DNA within the genes of cells (genetic damage) (mutations).
 Break double-helix structure in DNA
 A reduced ability of cells to repair DNA damage.
 Limited growth and regeneration of the cells/tissue
Effect on cancerous cells
Same as above but cancerous cells are affected more by radiation than normal cells so targeted
radiotherapy (internal or external) is on obvious choice for the treatment of cancer.
Side effects
Ionizing radiation also affects normal cells but some cells more than others in particular cells that divide
rapidly such as hair follicle cells, sex cells and cells in the skin causing more damage to the DNA and
reducing growth.
Side effects:
 Hair loss
 Damage to skin and nails
 Nausea
 Fatigue
 Sterility
The different types of ionizing radiation used in radiotherapy:
 Alpha radiation involves the emission of particle equivalent to a helium nucleus as it consists of 2
protons and 2 neutrons and therefore has a charge of +2 and a relative mass of 4. As a result of this
decay the radioisotope becomes an element with a decrease of 2 atomic number as shown by the
nuclear equation below:
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Beta emissions occur when a neutron in the nucleus splits into a proton and an electron. The electron
is emitted and the proton remains in the nucleus increasing the atomic number by one unit changing
the radioisotope into a nuclide of a different element as shown below:
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Gamma is the emission of energy or photons of high frequency as part of the electromagnetic
spectrum. Often also happens during alpha and beta radiation.
Emission of protons.
Emissions of neutrons.
Positron (positively charged electrons) radiation occurs when a proton changes into a neutron and a
positron is emitted.
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Exercises on nuclear equations
Write nuclear equations for the following:
1. Alpha decay of Pb-212
2. Beta decay of Y-90
3. Beta decay of Lu-177
4. Alpha decay of Ac-255
5. Beta decay of Co-60
Some types of radiotherapy
Targeted alpha therapy (TAT)
Used for treating leukemia and other dispersed cancers; these are cancers in which the cells have spread
throughout the body from the original tumour. As alpha particles have the greatest charge and therefore
the greatest ionizing ability, they are the most destructive type of emission. Alpha particles can only
penetrate tissue, and therefore cause cellular damage, over a very short range of 0.05 mm-0.1 mm. This
also means that not too many healthy cells should be effected.
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The radioisotopes emitting the alpha radiation are directed to antibodies and bind themselves onto them.
The antibody then carries the alpha-emitted to the cancer where the alpha radiation will destroy the cells
without too much damage to the surrounding healthy cells.
Boron Neutron Capture Therapy (BNCT)
This therapy uses a beam of neutrons to produce alpha particles only at the site of the cancer. The target
of the external neutron radiation are B-10 atoms that have been taken to the site of the cancer. There the
B-10 atoms capture (absorb) the neutrons from the beam and then change into B-11 nucleii; these then
immediately decay emitting alpha particles that destroy the surrounding cancerous cells. The B-10 nucleii
are administered using intravenous injections in the form of a compound such as boronophenylalanine.
This compound tends to accumulate in brain tumours. When the compound has been absorbed by the
tumour cells the site is radiated by a neutron beam.
Diagnosis of diseases using radiation: radiodiagnostics
This often involves the use of a radioactive tracer (a radionuclide) that is attached to a biologically active
molecule to form a radiopharmaceutical that is then ingested or injected and that can be traced used
detection equipment that uses for instance gamma rays producing an image on a scan.
Commonly used tracers are Tc-99m (most common) and I-131. Different traces accumulate in different
parts of the body e.g. I-131 in the thyroid gland which is why it is used in the diagnosis and treatment
(higher dose than for diagnostic purposes) of thyroid cancer.
Common radioisotope: Tc-99m
The ‘m’ indicates that the nucleus is metastable and only exists over a short period of time.
Why is Tc-99m commonly used as a diagnostic nuclide?
 Emits gamma radiation:
o Must emit gamma radiation of sufficient energy as the source of the emission is inside the
patient body but can only be detected if the radiation can escape the body.
o Easily traced using X-ray equipment: When Tc-99m decays it emits gamma radiation that can
be detected using X-rays.
 Versatile and easily administered: Can be used to diagnose and treat cancer in different organs and
tissues as it can bind onto a number of different biological carrier. Each type of tissue has its own
biologically active molecule that accumulates there. Can easily be administered to specific areas in the
body.
 Patient is only exposed to a minimum amount of radiation:
o Emission of low energy beta radiation.
o Half life is 6 hours and most Tc-99m will have decayed after 2 days. This amount of time is just
sufficient to allow for preparation of the radiopharmaceutical, administer it and detect it.
o Low energy radiation so less hazardous to the patient: energy of photons in the gamma rays is
low so patient only affected by a low dose.
Lutetium-177 and Yttrium-90
Both types of nuclides emit both beta and gamma radiation
Rate of decay
Rate of decay is the number of nuclides that decay or emit radiation per second. The unit is Bequerel or
Bq.
Half life
Half life, t1/2 ,is the time it takes for:
 Half the initial amount or concentration of a radionuclide to decay
 The activity or rate of decay to decrease by half
Half life is independent of the concentration or starting amount of the nuclide, temperature or pressure but
is dependent on the identity of the nuclide i.e. each nuclide has own half life.
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The longer the half- life, the more slowly a radionuclide decays, the lower the activity (Inverse relationship
between half life and activity), the lower the doses of radiation emitted.
As radioactive decay only involves 1 reacting species it follows first order reaction kinetics i.e. rate = k[N].
This expression can be used to convert the half life value into a decay constant, k, that can be used for
calculations such as to determine how long a radioisotope will remain active after administration.
The expression k = 0.63/ t1/2 also indicates that, just like the half life, the decay constant is independent of
the concentration or starting amount of the nuclide or the temperature and that it remains constant
throughout the decay process.
The decay constant can then be used to calculate how much radioisotope will be left or has decayed after
a certain amount of time has elapsed. This amount can also be expressed as a percentage.
The expression to be used is �t= �0(0.5)t/k (see also IB data booklet page 2)
Nt = amount/concentration/activity after time t
N0 = initial amount/concentration/activity
t= time
k = decay constant (k = 0.693/t1/2 )
Exercises
MRI
MRI uses the same principles as NMR as the scans use very powerful magnets to detect not just H-1 but
also C-13, Na-23, He-3 and P-31 nuclei and also use low frequency radio waves that are not ionizing.
The radiowaves absorbed by the nuclei are detected and used by computers to produce 2D or 3D images
of internal organs or body parts. Protons in different tissues absorb radiowaves of different frequencies
e.g. cancerous tissue; computers identify the type of tissue a proton is in.
D9 Drug detection and analysis
E.I.: A variety of analytical techniques is used for detection, identification, isolation and analysis
of medicines and drugs.
Nature of science Advances in instrumentation—advances in technology (IR, MS and NMR) have
assisted in drug detection, isolation and purification. (3.7)
Understandings
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D.9 U1 Organic structures can be analysed and identified through the use of infrared spectroscopy,
mass spectroscopy and proton NMR. D.9 U2 The presence of alcohol in a sample of breath can be detected through the use of either a
redox reaction or a fuel cell type of breathalyser. Applications and skills
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D.9 AS1 Interpretation of a variety of analytical spectra to determine an organic structure including
infrared spectroscopy, mass spectroscopy and proton NMR. D.9 AS2 Description of the process of extraction and purification of an organic product. Consider the
use of fractional distillation, Raoult’s law, the properties on which extractions are based and explaining
the relationship between organic structure and solubility. D.9 AS3 Description of the process of steroid detection in sport utilizing chromatography and mass
spectroscopy. D.9 AS4 Explanation of how alcohol can be detected with the use of a breathalyser. Analysis of organic structures using chromatography, IR, mass spectroscopy and 1H NMR
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IR, mass spectrometry and 1H NMR can be used to detect banned or illegal chemicals such as steroids in
sport as they function as performance-enhancing drugs.
Gas chromatography
Gas chromatography can be used to separate and identify the components in a mixture such as blood and
urine. This technique relies on the different components in the mixture (blood, urine, …) having different
affinities for two different phases, a mobile phase (a gas medium) and a stationary phase (made up of a
liquid). The affinity of a component towards the mobile phase and towards the stationary phase depends
on its boiling point/volatility and its solubility in both the gas and the liquid and determines the rate at which
it passes through the stationary phase.
The mixture sample is heated (boiling point) and mixed with the gas phase (solubility) and injected in the
gas chromatography column. Each component travels though the column at a rate depending on their
volatility and solubility in both phases.
A detector measures the time that is called the retention time; this is amount of time between injection
time (t=0 on the gas chromatogram) and the time a component is eluted. The retention time is recorded as
peak on the gas chromatogram. The area underneath the peak indicates the concentration of the
component
The retention times for a variety of compounds are known and the component can therefor be identified
although identification can also be completed using the fragmentation pattern obtained using mass
spectrometry. (see 11.3)
Extraction and purification of organic products
Differences in solubility in different solvents and different boiling points are two physical properties that are
often used in the extraction of a pure drug from a mixture produced as a result of a synthesis.
Order of increasing boiling points/decreasing volatility in different classes of organic compounds
Comparison of boiling points of compounds of corresponding or very similar mass.
The main factor is the strength of the intermolecular forces BETWEEN the molecules. The weaker the
intermolecular forces, the lower the boiling point and the more volatile a compound is.
Homologous series
Lowest boiling points
ALKENES
ALKANES
HALOGENOALKANES
Least volatile/highest
boiling point
ALKANALS
KETONES
AMINES
ALCOHOLS
CARBOXYLIC ACIDS
Type of intermolecular force
Non-polar molecules
Weak Van der Waals’ forces
Polar molecules
dipole-dipole attraction)
HYDROGEN BONDING
(INCREASED POLARITY OF HYDROGEN)
As alkanes and alkenes are non-polar their intermolecular forces are weak and as a result their melting
and boiling points are low for their molar mass. Halogenoalkanes, esters and aldehydes and ketones
(less than aldehydes) have a greater degree of polarity.
In the other functional groups hydrogen bonds are responsible for a greater attraction between the
molecules; although there are differences in the number and magnitude of the hydrogen bonds.
Carboxylic acids have stronger hydrogen bonds than amines and alcohols as each acid molecule has 2
sites to make hydrogen bonds; they also tend to form dimers.
Differences in solubility between the different classes of organic compounds
Polarity of the structure of molecules determines their solubility in polar and non-poar solvents. Non-polar
molecules have very low solubility in water but higher solubility in other non-polar solvents.
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Molecules with a polar structure are very soluble in water but have low solubility in non-polar solvents.
Molecules that can hydrogen bond have the highest solubility in polar solvents.
low solubility
(non-polar molecules)
alkanes/alkenes
soluble
(dipoles)
aldehydes/ketones
halogenoalkanes
high solubility
(hydrogen bonding)
alcohols
carboxylic acids
amines
Solubility generally decreases as molecules get longer; this is because the non-polar alkane ends cancel
out the effect of dipole or hydrogen bonds.
Solvent extraction uses difference in solubility in different solvents
Examples of solvent extraction:
 Extraction of aspirin using ethanol
 Extraction of penicillin using trichloromethane.
The separation can be carried out using a separating funnel.
Fractional distillation uses differences in volatility
See information sheet on Fractional distillation and Raoult’s Law or pages 918 to 921 in your textbook.
Detection of ethanol using a breathalyzer
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Only used for detection of ethanol in breath.
Ethanol is sufficiently volatile to pass into the lungs from the bloodstream which is why it can be
detected using a breathalyzer which contains acidified potassium dichromate(VI), an oxidizing agent.
There is a direct relationship between the alcohol content in exhaled air and the alcohol content in the
blood.
In a positive result (i.e. presence of ethanol) the potassium dichromate changes form orange (Cr VI or
+6) to green (Cr III or =3) as the chromium in the potassium dichromate is reduced by the ethanol and
the ethanol (C= -2) itself oxidized to ethanal (C= -1) and ethanoic acid (C= 0). The extent of the colour
change corresponds to a particular ethanol concentration.
Equations:
oxidation: C2H5OH + H2O → CH3COOH + 4H+ + 4e−
reduction: Cr2O7 2− + 14H+ + 6e− → 2Cr3+ +7H2O
Overall: 3C2H5OH + 16H+ + 2Cr2O7 2− → 3CH3COOH + 2Cr3+ + 11H2O
Detection of ethanol using a fuel cell
A fuel cell is an electrochemical that consists of 2 platinum electrodes and an acid electrolyte and can also
be used to measure the ethanol concentration.
The breath is blown over the cell and any ethanol is oxidized to ethanoic acid and H2O at the anode
releasing electrons that produce an electrical current to the cathode where oxygen is reduced to water as
shown by the overall equation: C2H5OH + O2 → CH3COOH + H2O
The voltage of the current can be used to measure the concentration.
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