Option D: Summary ofMedicinal ChemistryMs. KielyCoral Gables Senior High SchoolIB Chemistry SL

Medicines v.s. Drugs

A drug is a chemical that affects how your body works, whether those effects are positive or negative.

A medicine is a substance that specifically improves health, therefore a medicine is a drug that intends to have only positive effects on the body and mind. Medicines, which may be natural or synthetic, therefore contain beneficial drugs. The beneficial effect of a medicine is known as its therapeutic effect.

BioavailabilityThe fraction of an administered drug that actually reaches the blood supply of an individual is known as the drug’s bioavailability.

When a drug is taken orally, for example, some of its components will be broken down during different metabolic processes before ever being able to be absorbed into the bloodstream.

The method in which a drug is administered can affect a drug’s bioavailability. For example, when a drug is administered intravenously, (through an IV), 100% of that drug will enter an individual’s bloodstream. When someone instead swallows a pill or capsule, only about 20-40% of the drug will enter the person's bloodstream.

Side EffectsRemember, a drug is any chemical that affects how the body works, whether those effects are intended or unintended.

We only refer to the unintended effects caused by a drug as side effects. Unintended effects can be beneficial, benign, or adverse.

Side EffectsExamples of beneficial, benign, and adverse side effects:

-Beneficial: for example, aspirin, which is taken for pain relief, has the beneficial side-effect of protecting against heart disease.

-Benign: some antibiotics can cause stomach cramps, nausea, constipation, etc. These are symptoms that are not desired, but they are not very harmful- they are just annoying.

-Adverse effect: extreme drowsiness (which can affect how you drive or operate machinery), damage to organs, deformities

DosageThe dosage for a drug that is prescribed to a patient depends on many factors, some being:1) the method that the drug is administered

2) the drug’s bioavailability (and whether any functional groups exist in the drug that alter the bioavailability)

3) the solubility of the drug

4) any potential side effects

5) the age, sex, weight of the person,etc.

DosageIdeally, the dosage should result in constant levels of the drug being present in the blood; however, this is almost impossible to achieve unless the person is hooked up to an IV continuously throughout their treatment.

Therefore, the most important thing is that the concentration of the drug in the bloodstream remain within a certain range: above this range medically unacceptable side effects may occur, and below this range the drug may not be effective. We call this range the therapeutic window.

DosageThe therapeutic index is the ratio of the dose that produces toxicity to the dose that produces a clinically effective response in a population.

In animal studies lethal doses are determined; however, in human trials the upper limit is the toxic dose. This means that the therapeutic index is defined differently in the two groups:

The therapeutic window can be quantified as the therapeutic

index:

DosageThe therapeutic index (TI) is a measure of a drug’s safety because a higher value indicates a wide margin between doses that are toxic. A low TI means a low margin of safety, where a slight change in the dose may produce an undesirable adverse side-effect.

Drug action depends on interactions with receptorsThe activity of most drugs is determined by their ability to bind to a specific receptor in the body. A receptor is a site in the body that responds to a particular chemical. The receptors we are discussing in relation to drugs and medicine are usually proteins, such as enzymes, chemical structures of the membranes of cells, or DNA.

A drug’s effect can only occur if there is a “chemical fit” between the drug and the receptor.

Drug action depends on interactions with receptorsVideo: 2-Minute Neuroscience

These are the most common functional groups found in drugs, and therefore the

important groups for Option D.

Functional groups that you definitely want to memorize!

Painkillers, a.k.a. Analgesics Our body’s ability to perceive pain is one of our body’s very best defense mechanisms. Depending on the severity, we almost always immediate try to eliminate our sources of pain.

From an evolutionary perspective, this makes a lot of sense since by eliminating pain we are consequently reducing further damage to ourselves!

Painkillers are, therefore, one of the largest class of drugs and medications that exist. We call this popular class of drugs the analgesics.

The sensation of Pain is all in the BrainPain is detected as a sensation by the brain when nerve

messages are sent from various pain receptors located around the body.

This is where a strong analgesic plays a role in order to be an effective painkiller.

A strong analgesic intercepts or blocks the pathway between pain receptors on the body and the brain so as to reduce our “sensation” of pain.

Painkillers, a.k.a. Analgesics Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are mild analgesics.

Mild analgesics act by preventing stimulation of the nerve endings at the site of pain, and inhibit the release of prostaglandins from the site of injury.

This gives relief to inflammation and fever as well as to pain. Because these analgesics do not interfere with the functioning of the brain, they are also known as non-narcotics.

Aspirin; a mild analgesic

-The development of the most widely used drug in the world, aspirin, began with the discovery that chewing the bark of a willow tree gave relief to pains and fever. The chemical in willow bark that allows for such pain relief is salicin, which converts into salicylic acid in our bodies.

-Salicylic acid tastes horribly however; patients would vomit immediately when trying to ingest it! Therefore, the Bayer Company made an ester derivative of salicylic acid that proved to be less disgusting than salicylic acid alone.

Synthesis of Aspirin to make it less GROSSAgain, since salicylic acid itself was gross and upsetting to the stomach, scientists found ways to make it more palatable and less irritable. They combined salicylic acid with ethanoic anhydride, producing acetylsalicylic acid (a.k.a aspirin) and ethanoic acid. This is called an esterification reaction, a.k.a. condensation reaction.

Notice that the original salicylic acid has two functional groups on it: a carboxylic acid group -COOH, and a hydroxyl group -OH

When it is converted to acetylsalicylic acid (aspirin) it maintains the carboxylic acid group, but loses the hydroxyl group and instead gains an ester group (circled in red. Refer to pg. 571 for neon greenfunctional group diagram)

Synthesis of AspirinAs seen on the last slide, salicylic acid can be converted into aspirin

(acetylsalicylic acid) by reacting salicylic acid with ethanoic anhydride.

After the reaction is complete, the aspirin is isolated in hopes of purifying it from the mixture it is in. So imagine that this reaction is happening within

aqueous solution- we want to make sure we only retrieve from the solution the pure aspirin and NOT the ethanoic acid that is also produced, and also NOT

any other impurities that might be in the mixture.

We therefore have the products go through a process called recrystallization.

Synthesis of AspirinHOW DO WE PURIFY THE SOLUTION AND GET PURE ASPIRIN?

The products are first cooled to a low temperature, the reason being that aspirin has a low solubility at low temperatures, therefore, it will NOT dissolve in low temperatures- instead, it will crystallize. Impurities do not crystallize easily in cold solution. We can then separate the crystallized aspirin from the rest of the solution via filtration. Cold temperatures therefore speed up the crystallization process of aspirin.We further ensure the purity of our aspirin by dissolving it in hot ethanol, which is a great solvent for impurities but not for aspirin! Therefore, once again, once we cool off the product, we should only see aspirin crystallizing and we should be able to filter it out from the impurities. This is called recrystallization.

A way to justify that the recrystallization process indeed increased the purity of the product is to compare the melting points of the crude aspirin (the first time you filtered it) to the recrystallized aspirin: the recrystallized melting point should be higher, it should be within a range of 138°C - 140°C! And the recrystallized melting point be closer to that of the literature value.

Synthesis of AspirinEXERCISE 5 from Pg. 577:In order to answer this stoichiometry question, you need to refer to the reaction between salicylic acid and ethanoic anhydride in producing aspirin (acetylsalicylic acid) and ethanoic acid.

This reaction can be written as:C₇H₆O₃ + C₄H₆O₃ → C₉H₈O₄ + C₂H₄O₂

If the following reaction is not supplied to you on the test, then at the very least the above image would have to be supplied to you.

Synthesis of AspirinEXERCISE 5a from Pg. 577:

C₇H₆O₃ + C₄H₆O₃ → C₉H₈O₄ + C₂H₄O₂Now use the balanced equation to solve like you would for any other stoichiometry problem:

%yield = experimental yield x 100% Theoretical yield

According to the question, the experimental yield is: 55.45g of aspirin, C₉H₈O₄

You need to use the limiting reactant (50.05g of salicylic acid,C₇H₆O₃) to determine the theoretical yield of aspirin:

50.05g C₇H₆O₃ x 1 mol C₇H₆O₃ x 1 mol C₉H₈O₄ x 180.17g C₉H₈O₄ = 65.28g C₉H₈O₄ 138.13g C₇H₆O₃ 1 mol C₇H₆O₃ 1 mol C₉H₈O₄

NOW WE NEED TO PLUG THIS INTO THE PERCENT YIELD FORMULA (NEXT SLIDE)

Synthesis of AspirinEXERCISE 5a from Pg. 577:

%yield = 55.45g x 100% = 84.94% 65.28g

EXERCISE 5b from Pg. 577:

You can check the purity of your product by comparing its melting point (the crude aspirin you just formed) to that of recrystallized aspirin, which should be within a range of 138°C - 140°C

Arenes (Topic 10 & Option D)To further understand the structure of salicylic acid and of acetylsalicylic acid (aspirin), we must first understand what an arene is, and therefore, what a benzene ring is:

Arenes are a class of organic compounds that are derived from the molecule Benzene, C₆H₆. Arenes are also referred to as aromatic compounds.

Arenes contain the phenyl functional group, C₆H₅-, which as you can see is just a benzene ring with one less hydrogen. The the original hydrogen is likely going to be replaced with a substituent or another functional group.

You might remember addition and substitution reactions from Topic 10. Benzene only likes to undergo substitution reactions, where one of its hydrogen atoms can be substituted by something else, such as a halogen.Benzene doesn’t want to undergo an addition reaction, because adding something to this structure is not energetically favored since it would involve disrupting the cloud of delocalized electrons, which is the whole reason that Benzene is even special to begin with!

THIS IS WHY SALICYLIC ACID UNDERGOES A SUBSTITUTION REACTION IN THE ESTERIFICATION REACTION THAT TURNS IT INTO ASPIRIN (ACETYLSALICYLIC ACID)Salicylic acid when reacting with ethanoic anhydride during esterification substitutes a

hydroxyl group for an ester group. Nothing was neccesarily added to the original salicylic acid; instead, something was removed (the hydroxyl group) and then something took its place (the

ester group).

Making aspirin more soluble (more bioavailable)

Aspirin is made in many ways with many different coatings, for instance. These coatings can delay the effects of aspirin by reducing their solubility in the human body. The idea is, when we

swallow aspirin, it has to travel to our small intestine before we can feel its effects.

We can, however, make a modified version of aspirin (acetylsalicylic acid) that makes it more soluble! We can do this by reacting it with a strong base, such as NaOH. Reacting it with a strong base produces an ionic salt version of aspirin that is much more soluble in water [in the human

digestive system]. This modification increases aspirins bioavailability.

Making aspirin more soluble (more bioavailable)The reason the ionic salt version of aspirin is more soluble is because the original

aspirin is non-polar.

REMEMBER, water is polar, and LIKE dissolves LIKE! Meaning, nonpolar solutes are dissolved easily in nonpolar solvents, and polar

solutes are dissolved easily in polar solutes.

By modifying aspirin to be polar, we are allowing for polar water to be able to dissolve it more easily.

IR InformationRemember from Topic 11.3 that Infrared data is used to decipher the structure of an unknown sample of matter

that either is or contains an organic compound.

These two images are of salicylic acid and

acetylsalicylic acid (aspirin), respectively.

Make sure to take a look at section 26 of your IB data

booklet to know what these peaks refer to.

Aspirin; a mild analgesic You should know:-That salicin, found in willow bark, is the active ingredient in aspirin. You should also know that once it enter the human digestive tract it becomes salicylic acid.

-Since aspirin is not only a painkiller but also a fever reducer, it is also referred to as an antipyretic: fever reducer.

-Aspirin is an anticoagulant, meaning it reduces the ability of blood to clot. This is why it is often prescribed to treat patients at risk of heart attacks and strokes. This makes aspirin a prophylactic (something that prevents diseases).

-The physiological effects of aspirin are more acute when it is taken with ethanol in alcoholic drinks. This effect is known as synergy, and means that care must be taken when consuming alcoholic drinks with medication. These synergistic effects in that case of alcohol and aspirin can cause increased bleeding of the stomach lining and increased risk of ulcers.

This is a bacteria culture. In the center is penicillin. As you can see, all around the penicillin is a clear ring, indicating its ability

to break down bacteria and cause it to stop growing.

Penicillin: an early antibioticAntibiotics are chemicals that are usually produced by microorganisms, which have action against other microorganisms.

One of the most popular antibiotics are the penicillins. Penicilln was discovered by a man named Alexander Fleming who was working with bacteria cultures. He noticed that a fungus (mold) known as Penicillium natatum had contaminated his bacteria cultures- however, the fungus had left a clear region in his bacteria sample! This indicated that the penicillium natatum fungus had caused the bacteria to be unable to grow colonies- it had essentially wiped out all the bacteria.

The actual active ingredient within the fungus that was causing this clearing is now known as penicillin, an antibacterial agent

that is produced by the penicillium fungus/mold.

Penicillin: an early antibioticIt is important to also know that the structure of penicillin was found by biochemist Dorothy

Hodgkin via the tehnique of X-ray crystallography. She specifically determined the structure of penicillin G.

The structure is a dipeptide formed from two amino acids, cysteine and valine (shown below). The molecule contains a very important five-membered ring (shown in red). It is called a beta-lactam ring. This ring consists of one nitrogen and three carbon atoms, and

is the part of the molecule responsible for its antibacterial properties.

Penicillin: an early antibioticThe beta-lactam ring experiences what is known as a “ring strain”, meaning it goes through a bit of a struggle; HOWEVER, this very struggle is what gives penicillin its awesome benefits.

You see, the beta-lactam ring of penicillin has unstable bond angles: that box, the beta-lactam ring, is forced to maintain 90 degree angles, BUT THE CARBON ATOMS THAT MAKE THE RING WANT TO FORM BONDS WITH ANGLES OF 120 AND 109.5 DEGREES! This strain on the bonds of the BL ring weaken those very bonds, consequently breaking the ring- which is the key to penicillin’s biological activity.

Penicillin: an early antibioticBacteria have a cell wall, similar to that of plant cells. Bacteria cannot exist without their cell wall. This is exactly how penicillin attacks bacteria: as discussed, the BL ring of penicillin easily falls apart due to the strain on its bonds. When this happens, it is able to trap an enzyme of bacteria called transpeptidase (pictured as the letter E below in the image). The broken BL ring of penicillin is able to do this because of its very active amide functional group.

Inactivation of the transpeptidase enzyme of bacteria blocks the process of cell wall construction within the bacterium. The cell wall is therefore unable to support the bacterium, and so it bursts and dies!

*Later in Option D, you will learn about Viruses. BE CAREFUL, DO NOT LET IB TRICK YOU. Antibiotics are not effective against viruses since viruses have no cell wall and thus no structure to attach.

Penicillin: an early antibioticIn summary: The beta-lactam ring of penicillin is under a lot of strain since it maintains 90 degree bond angles that actually want to be 120 and 109.5 degree bond angles, making them more triangular planar and tetrahedral shaped, respectively.

When the ring breaks due to this strain, the very highly reactive amide functional group binds to the bacterial enzyme, transpeptidase, causing it to inactivate. That enzyme is responsible for the bacterial cell wall. A bacteria with no cell wall = a broken bacteria!

Penicillin: an early antibioticPenicillin is effective against many range of bacteria, many of which are responsible for ear, nose, and throat infections.

However, a disadvantage of penicillin G is that it is broken down by stomach acid, and so has to be injected directly into the blood. Biochemical modifications have been made to the side chains of the original penicillin in order to make it effective in pill form. Its use, though, is limited worldwide due to the fact that a significant number of people are allergic to penicillin.

DANGERS OF THE OVERUSE OF ANTIBIOTICS-leads to bacterial resistance of antibiotics/makes antibiotics less effective

-increased side effects due to larger dosages

-antibiotic overuse can destroy useful/beneficial bacteria,

-resistant bacteria can pass on their resistance/mutation to next generation of bacteria

BACTERIA FIGHT BACK: Antibiotic ResistanceNow, even though we just discussed how awesome penicillin is as an antibiotic due to its ability to break down the cell walls of bacteria with its beta-lactam ring, some antibiotic-resistant bacteria have emerged in our environment! These antibiotic-resistant bacteria can resist penicillin and actually destroy its activity. They do so by producing a penicillin destroyer called the beta-lactamase enzyme, also known as penicillinase.

The beta-lactamase enzyme, also known as penicillinase, breaks apart the beta-lactam ring of penicillin and renders it useless since it does not allow its active amide group to bond to the transpeptidase bacterial enzyme we discussed in the last slides.

There are things we can do to try to fight bacteria that have become resistant to penicillin:

The synthesis of different forms of penicillin which are able to withstand the action of penicillinase. These include a) methicillin, which has now largely been replaced by b) oxacillin, due to the spread of methicillin-resistant bacteria.

There are things we can do to try to fight bacteria that have become resistant to penicillin: