If you decide to focus your pharmaceutical career in the creation of new drugs, you would spend a lot of time studying and recording different chemical reactions and processes. This if these reactions are carbon-based this specialization is known as organic chemistry. Carbon is extremely important, animals are often called a carbon based life forms as it is what we are all essentially made of. Carbon has this incredible ability to be able to form multiple bonds with many different elements and therefore, it is very well suited to making exotic compounds with remarkable properties, which could be used in the treatment of disease.
Importance of organic chemistry to the pharmaceutical sciences
The vast majority of medications are organic, studying and absorbing the principles of organic chemistry will be very important to any future pharmacist. As a foundation, organic chemistry leads to biochemistry and biochemistry leads to the pharmacy sciences. Each, like the building blocks found on the periodic table, builds upon another until you are ready to work in the pharmaceutical industry and hence, your study for the PCAT. Most man made products, like plastics and oils, all originate from a common hydrocarbon source.
Types of hydrocarbons and their names
There are several types and subtypes of hydrocarbons. Hydrocarbons naturally occur in crude oil (which is a precursor of gas you put in your car), it is produced from the decomposition of organic matter over the millennia. There are four major groups of hydrocarbons, including saturated hydrocarbons, unsaturated hydrocarbons and aromatic hydrocarbons, cycloalkanes.
Quick test, what does the molecule bromochlorobutene look like? Look like another language? Well it almost is... However, with all languages there is a syntax which enables you to decipher its meaning. By the end of this section you will be able to draw this molecule. The best place to start is to remember this table:
Number of carbon atoms
Name of alkane
Name of alkyl
Figure 12-1: Alkane nomenclature.
Figure 12-1 describes alkanes, which are single bonded carbon, hydrogen molecules. A few rules to follow when naming hydrocarbons:
- When they contain a double bond they are called alkenes, i.e. butane, which has a double bond, is called butane.
- When they contain a triple bond (this is not very common) they are called alkynes, i.e. butyne, which has one triple bond between two of its carbon atoms.
- When they contain an alcohol group -OH, the word will end in -ol, like methanol or ethanol.
- When the hydrocarbon is a straight line, but then has a hydrocarbon side group, this part is called an alkyl, e.g. a long 8-carbon alkane with a two carbon side chain on the third position is called octane-2-ethyl.
- When the hydrocarbon contains a -COOH carboxylic group, the word will usually end with -ic acid. The most common carboxylic acid is CH3COOH, acetic acid.
- When the hydrocarbon contains an inorganic, like Chlorine, the Chloro- will usually proceed the name of the hydrocarbon, which itself will be proceeded by Di-, Tri- denoting how many molecules are attached.
So knowing that, what does bromochlorobutene look like? It contains, bromine, chlorine and a 4-chain double bond alkene, so BrClC4H6. Easy! Try CHCl3 what would the name of this be? Well, it has three (Tri) chloride atoms (Chloro), so TriChloro-, it also has a one-carbon backbone (methane), so the name would be trichloromethane. What about CH3CHaCH2CH2CH3, well this is easy, it's just a simple five-chain alkene (you can tell it is an alkene as the second carbon only has on hydrogen attached, so it would be called pentene.
The other type of hydrocarbons have a ring structure called cycloalkanes have more than one carbon ring with hydrogen atoms attached to them. These are single chemical bonds and they are further divided into groups called small, common, medium and large cycloalkanes. Although similar to alkanes, like natural gas or oil that have single bond saturated (one carbon to every two hydrogen atoms, except at the ends of the cyclic) hydrocarbons in a chain structure, cycloalkanes have a cyclic structure. They will have more density and a higher melting and boiling point. The smaller cycloalkanes can, however, be a bit unstable, such as cyclopropane.
Explanation and structural drawings of alkanes and alkenes
Its all well and true, to talk about chemical formulas, but what do these molecules look like in real life? To visualize an atom or complex molecule for real is quite difficult, you would have a ting central nucleus to each atom covered by a cloud of electrons, like a golf ball in the middle of a soccer pitch, try draw that!
Polymers, polymerization and hydrocarbons
If you take a bunch of short-chain alkanes like methane or butane, then stick them all together so that they form a long line of carbon and hydrogen atoms, this would be a polymer, which is formed by polymerization. There are several systems of polymerization and a few forms as well. These forms and systems include step-growth polymerization, chain-growth polymerization and others.
If monomer groups contain oxygen or nitrogen, there will be a step-growth reaction between them. In chain-growth polymerization, you'll find double and triple carbon bonds and your reaction will end up with a structure that resembles a chain.
So, why should you care about polymerization? You'll find polymers in many parts of everyday life including hair care products, vegetable oil, composites for dental restoration, plastics, candles and imaging products all utilize polymers.
In the pharmaceutical industry, polymers are used for blood substitution, drug delivery and therapy systems and for aiding time-released medications, among many other applications. So, if you're in the pharmaceutical industry, you're in the polymer industry.
Nondysfunctional, Functional Groups
Within the organic chemistry world, there are groups of atoms that will carry out similar chemical reactions, known as functional groups. These a common misnomer for functional groups is a moiety, however, the difference between a moiety and a functional group is that a moiety can contain more than one functional group. Although there are many functional groups, we're going to focus on a few key functional groups.
Most important functional groups
The first group, known as hydrocarbyls, contain only carbon and hydrogen, but members of this group have differing numbers and orders in their bonds, so their reactions would be slightly different. We've already spoken about some of the members, alkane, alkene and alkyne. This group also includes a family of benzene derivatives and a family of toluene derivatives.
If the reaction from a member of this group causes a positive charge in that member, it becomes a carbocation and a negative charge is known as a carbanion and there are also members of this group that have specific names because of their branched or ringed alkane structure, including bornyl and butyl.
In pharmacology, the hydrocarbyls are often the backbone used to created medications and also finds its way back to human physiology. Cholesterol is a 30-carbon triterpene that is made with a group of reactions caused by enzymes. Steroids are also an off-shoot of hydrocarbyls, as are most hormone classes, including estrogen, androgen and progestogens.
Progesterone is a vital hormone that helps the uterus lining to prepare for the ovum. It also turns off further ovulation when a woman is pregnant. As we spoke of earlier, without this hormone, a woman could theoretically have multiple pregnancies at various stages of development at any given time and this would divide the female body's resources to a point where no ovum would successfully become a fetus.
Estrogen is also very important for women. As a woman's body develops, it is the release of estrogen that completes her development through puberty. When a woman is pregnant, estrogen is behind the development stimulation of the mammary glands, preparing the woman for breastfeeding.
Androgen, on the other hand, is more important to men. Like estrogen, androgen is the hormone responsible for a boy's development into a man through puberty.
Next is the functional group that contains halogens. This group's reactions can be heavily affected by conditions of the solvent that is used to create the reaction and by the pH of nearby protons. Included in this group are haloalkane, fluoroalkane, chloroalkane, bromoalkane and iodoalkane. Notice that all members of this functional group maintain the alkane posture.
This group may be the most important or at least most apparent of the functional groups in our everyday world. Members of this group are found in many industrial chemicals, solvents and pesticides. They are also used directly in drug manufacture and indirectly in the development of polymers that we spoke of earlier. Some antibiotics are developed from this group, including chloramphenicol.
This group is also included in the atmospheric bi-products of fungi, kelp and algae and has some responsibility for ozone layer depletion.
The oxygen-containing functional group has a few members you've probably heard of, including alcohol, ketone, carbonate and peroxide. It also includes a bunch you probably haven't heard of, such as aldehyde, acyl halide, carboxylate, ester and methoxy, to name a few. Depending on which group member you are looking at, they will have very different reactions, affected most by the geometry created during the carbon and oxygen bonding process and its location.
The alcohols have a couple of specialized sub-groups. You've certainly heard of or consumed a bit of ethyl alcohol. This member, along with enthanol, is grouped in a sub-set known as acyclic alcohols and their separation is caused by something known as aroma. In organic chemistry, aroma has nothing to do with small, but rather refers to the surprising stabilization that the aromatics display from an unsaturated, empty orbital or conjugated bond. The most notable aromatic is probably benzene.
Alphatic compounds, on the other hand, do not contain benzene or any other aromatic. When the carbon atoms in an aliphatic compound join in a non-aromatic ring, they are known as alicyclic. Most of the aliphatic compounds are flammable, such as acetylene for welding, liquefied natural gas (LNG) for heating and methane as a fuel.
The remaining alcohol functional group members are normally given a nomenclature that includes a suffix. An example of this would be wood alcohol, which you have heard called methanol or the alcohol used on your skin before an injection, known as isopropyl alcohol. There are a few outliers in this functional group, including glucose, that have hydrogen and hydroxyl functional groups, but doesn't have the suffix.
The functional group that contains nitrogen is next on our list and includes amides, amines, imines, imides, azides, azo compounds, cyanetes, nitrates, nitriles, nitrites, nitro compounds, nitroso compounds and pyridine derivatives and there is a lot of biology and chemistry going on in this group.
Amines (think amino acids) are an important member of this functional group because they are often used as an antagonist or agonist. An antagonist, in medicine, is a medication that tells the human body that something that normally happens should not continue to happen or vice versa. As an example, the human body reacts to dopamine. Sometimes, as is the case with some mental illness, the body is over-reacting to dopamine. A dopamine antagonist would help the body to stop over-reacting to dopamine or depress all dopamine reaction, depending on the dosage of the medication. As you will discover during your studies, there are dozens of medications that focus on dopamine antagonism only and which one is prescribed depends on the depth of dopamine suppression desired, interactions with other medications (commonly known as indications/contraindications) and other measures of an individual patient.
Agonists, on the other hand, are used to help the human body to meet or exceed a biological function that should be happening but is not. Superagonists, such as morphine, are used to produce the maximum pain suppression response in humans. Partial agonists are used to boost a biologic process, but may not completely meet or exceed a normal physiological reaction. Partial agonists are generally preferred as the human body can, as is the case with morphine, become heavily dependent, or addicted, to the help of a superagonist. As a pharmacist, much of your work will surround working with physicians to maximize the positive effects of a medication while minimizing the negative complications that may result. This is particularly true with pain medication. You will frequently see a physician's initial dosage of pain medication be low in the hopes that the patient will feel relief without the possibility of addiction. If the desired pain relief is not felt by the patient, the doctor will either increase the dosage or switch to another pain relief medication.
If you've ever had a dental procedure or stitches where a local anesthetic was used, you have probably been introduced to an amide. Examples include lidocaine and polocaine. Your last cup of coffee was also helped by an amide in the form of caffeine. Amides are known for their uses as a stimulant, depressant or anesthetic.
You'll also find amides at work in industrial applications where a surfactant, stabilizer or release agent is needed, but they can cause cancer, so they are usually used to produce products that won't have direct human contact such as uses as a solvent in the production of rubbers and plastics.
There are also amides found in human biology. Urea, produced during the breakdown of proteins, is an example of a naturally occurring amide. It is also a partner in amino acids.
Nitrates also have an important role in modern medicine. An example is nitroglycerin. By causing blood vessels to relax, nitroglycerin is used as an important medication when urgency is an issue. Patients who are diagnosed with diseases affecting the arteries will frequently have a standing prescription for nitroglycerin that they can use when they experience sudden chest pain. Nitroglycerin and aspirin are the first medications given to an emergency room patient who may be experiencing a heart attack because they work together to slow or stop the consequences of heart muscle death. While the nitroglycerin is relaxing and expanding the arteries, the aspirin is working to thin the blood.
Nitroglycerin is also used for patients who are diagnosed with angina. Angina is a condition where coronary arteries are blocked or the arteries are in spasm and nitroglycerin's relaxing effect allows for relief. Angina is distinct from a true heart attack in that it will be relieved by rest, oxygen therapy or medication and doesn't require any further medical intervention. The physical symptoms are very similar to a heart attack, so the diagnosis frequently requires additional testing so as to determine whether a possible arterial blockage needs to be cleared or can be controlled with medication.
The pain associated with angina or a heart attack is unique. Simply described, this pain is the heart's alarm system, or scream for additional oxygen. As the lack of oxygen continues, the pain will escalate and is frequently only eliminated when the blockage is cleared and the heart is receiving the oxygen it wants and needs. Angioplasty is frequently used to clear the blockage and patients, post angioplasty, often feel like they can immediately resume normal activities because the symptoms completed disappear. And, yes, nitroglycerin is also used to make dynamite and the plastic explosive Cordite.
Azo compound medications tend to focus on another area of the human body, but their roots helped to create the modern pharmaceutical world you are now entering. In the 1930's, researchers were struggling to find treatment for outbreaks of staphylococcal, streptococcal and pneumococcal infection. Today, we would know these as strep throat, staph infections and pneumonia. German researchers had created an azo compound in the form of a red dye.
What their research showed was that this azo compound was very effective in fighting bacterial disease and this discovery marked, in our opinion, the birth of modern antibiotic research and creation and earned the lead researcher a Nobel Prize. As a side history lesson, the lead researcher, Dr. Gerhard Domagk, was forced by the German Gestapo, to return the award and its cash reward because the Nobel committee had previously awarded a prize to a known pacifist. Ultimately, Dr. Domagk was able to re-claim his prize after the Second World War ended.
The sulfa drugs that were developed were used to treat a wide range of bacteria, including bacteria associated with sexually transmitted diseases, bacteria in burns and meningitis. During the Second World War, sulfa powder was spread across open wounds to reduce infection. Over time, however, other drugs have been developed to provide bacteria control that are more specialized, so today's azo compound drugs are primarily used to treat yeast and urinary tract infection (UTI).
Pyridine derivatives are often used in the synthesis and manufacture of a variety of medications... You'll find that drugs that fight arteriosclerosis, anti-inflammatory drugs, x-ray contrasts and antidepressants involve pyridine derivatives in their formulations.
As we return to our conversation about functional groups, we next introduce the group that contains sulfur. Thiol, sulfides, disulfides, sulfoxides, sulfones, sulfonic acids, thiocyanates, thiones and thials are all included in this group.
Skin diseases are often treated with medications containing thiols. A thiol is an oil that has been purified with ammonia. By the way, thiols tend to smell pretty bad. So, it's a thiol that's added to natural gas so we can smell it and fix a leak before it hurts anyone. Thiols are also found in the natural world, as the compounds responsible for bad breath and flatulence. Skunks use thiol compounds in their defensive spray. Garlic and onions also use thiol compounds to make sure their smell remains on surfaces long after washing.
Sulfoxides are also often used on the skin, but they are used to commute medications into the human body. As a delivery system, sulfoxides increase primary drug absorption, so they are used to help antioxidents, analgesics and anti-inflammatory medications as well as topically to treat finger and toenail fungi. It is unfortunately also included in alternative medicine drugs, known as DMSOs (dimethyl sulfoxide) and touted as "miracle” cures for multiple ailments including cancer.
Cystic fibrosis patients suffer from an absence of thiocyanate in their body. Thiocyanate is used by the human body to balance the thyroid. Cystic fibrosis is a disease where too much mucous is created in the lungs and other body systems, making the patient very susceptible to lung infections and other problems as the human body's defence systems are depressed.
The phosphorus-containing functional group only has four members and they are phosphine, phosphonic acid, phosphodiester and phosphate. Phosphates are found throughout the human body and pharmaceuticals are most frequently used to increase phosphate levels in the body. Phosphates are found in their largest quantities in the bones and teeth. Because we lose a lot of phosphate in urine and feces, the body must continually produce more. Phosphates are used in the body to regulate the acid-base balance in saliva, blood, urine and lots of other body fluids. As part of this work, phosphates create reactions in glycogen, lactic acid and other body substances. Equally important is the role that phosphates play in the body's energy storage and use as well as allowing cells to "teach” their genetic information to other cells during cell creation.
The human body can also have too much phosphate, as is common when a person drinks too many cola drinks. Typically, if the body's phosphate levels are very high, their calcium level will be very low. The opposite is also true. Too much calcium increases the odds that the person will develop kidney stones and other malodies. Medical phosphates are sometimes prescribed prior to intestinal tests because they trick the body into absorbing more fluid and pushing digestion to a higher speed to clear the intestines for testing. You can consume phosphates in meat and dairy products as well as grains or supplements.
Another functional group shares boron. This group includes boronic acid, boronic ester, borinic acid and borinic ester. You may become involved in research involving this functional group because there is an increased interest in boron and how we might use it for human health. We aren't completely sure about boron, but it is believed that boron is used by the human body to handle other minerals, including phosphorus and magnesium. Current uses for boron and boronic acid include treating stubborn vaginal yeast infections and there is a lot of research currently being done because it is thought that boron may increase testosterone, slow or stop bone loss, improve cognitive functions and be used for the treatment of osteoarthritis.
Although there are almost 60 functional groups, these are the groups that seem to have the most significant impact on pharmaceutical science.
When you mix a hydroxyl functional group with an aromatic compound, you will create a phenol. Phenols are a distant cousin of alcohols, but are different in that they have an unsaturated atom binder. If you get a sore throat and reach for Chloraseptic, you'll be using phenol as the active ingredient in treating the discomfort. This use was developed after phenol was used a local analgesic in World War 2. Phenol was also terribly used by the Nazis in injections to kill many Jewish prisoners.
Phenol is a bit two-faced, because when used in small and proper uses, it is excellent at numbing soft tissue, as in Chloraseptic, but it is highly toxic in large does. In addition to its numbing action, phenol also inhibits germs. Phenol is also used, in higher but controlled doses, to quickly and easily remove skin problems including warts, scars and precancerous growths. Face peels and skin lighteners also use phenol. It is thought that one or both of these was responsible for Michael Jackson's lighter skin color over the years,
Aldehydes and Ketones
Many of the things we smell or taste are the result of aldehydes and ketones. The pharmaceutical industry also maintains a keen focus on these two. Both have butane as their parent. To understand aldehydes and ketones, it's often easier to look at an example from the natural world.
At some point in your life, someone has claimed that carrots are good for your eyes. The primary compound in carrots, and all orange colored, non-citrus fruits and vegetables is beta-carotene. The liver metabolizes beta-carotene, produces vitamin A (start thinking about vitamin A by its other name- retinol). Retinol is oxidized and turns into an aldehyde when it is isomerized into 11-cis-retinal. This aldehyde reacts with a protein called opsin and the combined compound becomes rhodopsin, having an imine molety. Rhodopsin likes light, so an increase in rhodopsin means that the eye sees more light, and, voila, better vision!!
Aldehydes are also used in medical and scientific study. Using aldehydes has given medical professionals a way to study LDL, which you'll remember is good cholesterol.
Ketones are produced naturally in the human body, However, increased production of ketones is probably not good news, because ketones are produced when the body doesn't sense enough insulin in the blood. So, ketones would also be a reaction to too much glucose in the blood because insulin is used by the human body to balance glucose. This is a serious medical condition known as diabetic ketoacidosis and it is fatal if not rapidly and aggressively treated. Under normal circumstances, the human body will process ketones in the liver to be oxidized into the muscles and the dance between ketones and insulin is always happening.
Spectroscopy is the study of how matter and radiation interact with each other. A spectrograph is often used to measure the amount or concentration of a chemical species and this specialized study is known as spectrometry.
Spectoscopy is used to diagnose illness, including devices that diabetics use to test their blood and pulse oximetry that is used to measure the amount of blood oxygen in a patient without drawing a blood sample. Commonly known as near-infrared spectroscopy (NIRS) is also used to monitor brain function without skull invasion and is sometimes used when an MRI machine is not practicle. Using a dye medium, brain scans using NIRS can "see” how blood is flowing through the brain and to monitor heart and arterial blood flow after heart or other surgeries.
Properties of Organic Compounds
Organic compounds can be studied in a variety of ways. We can look at the structure or other physical characteristics of a compound. Or, we can look at the chemical properties of an organic compound. Since all life is formed by organic compounds and any non-natural object we create is still based on organic compounds, the study of all of the properties of organic compounds is essential to understanding our world. In the pharmaceutical industry, great resources are expended as the industry seeks deeper understanding of all of the characteristics of a compound and this requires qualitative (somewhat subjective) and quantitative (data based) study. As an example, we might all agree that a bag of garbage left in the sun will probably smell badly. How bad each of us defines the smell is a qualitative result, because each one of us will have a different starting point and ending point for our analysis. If one of us has a badly stuffed nose, their description for the bad smell will be defined differently.
Quantitative study is based on measurements and calculations. There is no wiggle room with quantitative study. Something either happens or it doesn't. When it happens, at what temperature it happens, where it happens and how long it took to happen would all involve quantitative study.
Melting and boiling points
All organic compounds will eventually boil and/or melt. If we are attempting to qualify how pure a compound is, we will compare the points at which the compound boils and melts and compare them to known results of pure compounds. Normally, you can draw an inference about melting and boiling points based on molecule polarity and weight.
Occasionally, we find compounds that evaporate without heat or melting. Two simple examples of this are dry ice and moth balls. Dry ice will evaporate without the heat energy that normal ice would need. Moth balls evaporate over time at room temperature. If you put iodine crystals in a bowl, they will turn to a gas without ever passing through a liquid state.
Compounds can also be "afraid” of water or not. What we really mean is that some compounds are more likely to mix with water than others. You've probably heard that oil and water don't mix. It's true.
You can also measure solubility using a wide range of solvents, including ethyl alcohol, a pure substance or solvents with paraffinic properties such as turpentine or paint thinner. As a pharmacist, you will have chronic awareness of the solubility of a compound or medication because solubility is largely what determines how much, or the dose of the medication to be administered. If a drug doesn't have good solubility, the drug maker will create experiments to enhance how quickly the human body will absorb the medication and adjust their manufacturing of the drug accordingly.
Solid state properties
The physical shape and particle size of a compound is critical knowledge and is reported as the solid state properties of the compound and this is of particular interest if you are studying polymers.
Reactions of Organic Compounds
Each organic functional group such as the alcohols, the alkenes, the ketones, etc. will have differing reactions. As a simple definition, organic chemistry is fundamentally the study of different reactions. Let's look at a few key reactions.
In an addition reaction, molecules combine to form a new, larger molecule. This can happen with two molecules or a whole group of molecules. There are two key types of addition reactions. First, there are addition reactions that lead to a regioisomer. A regioisomer is a constitutional isomer is a structural isomer. The three categories here are functional, positional and skeletal isomers. Skeletal isomers are also known as chain isomers and these addition reactions will see a structural difference in the combined molecule. Positional isomers will group themselves in different ways across the parent and functional isomers maintain their molecular formula, but the change in the atoms will make the groups dissimilar.
Stereoisomers, on the other hand, don't differ in their atom sequence, but rather in the way the atoms are oriented. They can be cis-trans, or geometrical isomers or they can beoptical isomers (enantiomers) that are a mirror image of each other.
In each of these cases, the focus is on what bonds break and what bonds are created when the molecules combine.
Elimination reactions, as their name implies, lose one hydrogen atom when the molecules combine. You'll remember that the unsaturation of the combined molecule increases because of the hydrogen.
When the functional group of a chemical compound is completely replaced by another group, it is known as a substitution reaction. By closely monitoring the reaction as we alter variables, we can begin to predict what future reactions might be and we will be particularly interested in the electrophilic and nucleophilic substitution reactions.
Pericyclic reactions involve a combined molecule that demonstrates a ring and we will see an orchestrated or non-chaotic continuation of the reaction. Pericyclic reactions are a version of a rearrangement reaction and there are several types, including electrocyclic, cycloadditions, dyotropic, cheletropic, group transfer and sigmatropic reactions.
In rearrangement reactions, the carbon skeleton will change and a new structural isomer of the molecule is formed.
When an atom or compound is oxidized, it gains electrons and when it is reduced it loses them. Often, you will know the oxidation state of most of the elements in the compound and finding the oxidation number for carbon is the goal. To calculate the carbon's oxidation state, you'll need to accept that there will never be an absolute value for the oxidation state and that only the changes in oxidation state should be your focus. Functional groups will have a similar oxidation state and are typically arranged from lowest to highest.
A Chain Reaction
Also known as free-radical reactions, chain reactions will frequently have an initiation step or steps, a propagation step and a termination step in their reactions. You may also find an antagonist to the reaction in a chain reaction inhibitor.