Heterocycles, an introduction

Heterocycles or heterocyclic compounds are compounds composing of rings. At least one member of the ring are atoms other than carbons. These atoms are called heteroatoms. Commonly found in nature and relevant to biology and pharmacy are the heteroatoms nitrogen, oxygen, and sulfur.

Heterocycles come in various shapes and sizes. They can be five-membered rings, six-membered, or two rings joined together. They can also be non-aromatic types and aromatic types. All of these determine their physicochemical properties such as how strong a base they are and their reactivity towards nucleophiles and electrophiles.

As appetizers to our course, here are some interesting examples of heterocycles in life :

The heme molecule within our red blood cells is crucial in carrying oxygen molecules for respiration. It is made of four heterocycles called pyrroles.                                                               

Red blood cells

Quinine is the first drug used in treating the malaria disease. It is isolated from the cinchona bark. It contains within its structure a heterocycle called quinoline.

Quinine from the barks of Cinchona

In this lesson, you will learn:

-       -  How to draw, name, and identify of some common heterocycles, their aromaticity and basicity.

-       - About the reactions that heterocycles participate in

-      - How to prepare these heterocycles in classical synthesis methods

     Notes on the lesson is availble at this site: 
    http://bit.ly/18Lj32R
    

    

    

   

Elimination reactions in pharmacy: part two

Here is another example of elimination in pharmacy.

Curare is a type of drug called a muscle relaxant. It acts by blocking nerve impulses at the neuromuscular junction thus causing the muscle to relax. Such drugs are very useful during surgery when the patient needs to be immobilised. The downside to curare is that it takes a long time for the effect to wear off after surgery and can cause respiratory depression. The effect would only wear off after the drug gets metabolised – that is it gets changed in the body – to a not active form. (Metabolism is a process where a drug is changed to another form when it enters our body).

Curare is a drug used to relax the muscles during a surgery. Its effect is slow to wear off after surgery
and may cause inconvenience such as breathing suppression.

Newer muscle relaxants such as atracurium have been developed that has a built-in functional group that allows the drug to rapidly metabolised or changed into an inactive form. One such change involves an elimination reaction of the quarternary ammonium group of the drug

(Refer to notes on elimination of amines).

Elimination reactions in pharmacy: part one

Besides understanding basic principles of a reaction like the mechanisms and how to apply them to solve problems, perhaps you would appreciate an organic reaction better if I present some real-life situations especially related to pharmacy which involve elimination reactions.

The first example is elimination in the synthesis of a well known drug tamoxifen. Tamoxifen is an anti-estrogen antagonist which is used to treat breast cancer that is estrogen receptor positive. It works by binding to the estrogen receptor on the cancer cells thus stopping the uncontrolled cell growth fuelled by estrogen activity.

Tamoxifen tablet 20 mg (Nolvadex is the brand name)

A 3-D structure of tamoxifen

Here is how tamoxifen is originally made:

First, the main skeleton of tamoxifen is made by addition of a Grignard reagent, phenyl magnesium bromide (PhMgBr) which is a good nucleophile to the ketone group. This produces a tertiary alcohol. This tertiary alcohol is then treated with sulfuric acid. Here a dehydration happens. It is an E1 elimination as a carbocation is formed (favoured by it being tertiary and benzylic at the same time).

The freely rotating bond (coloured green) allows the three substituents at the carbon (blue) adjacent to the positively charged one to change positions like this:

So in an E1 elimination like this, there is no stereocontrol (stereospecificity). As the proton (coloured red) gets removed, a mixture of E- and Z-isomers are produced.

This method to make tamoxifen is apparently not satisfactory because we can’t get purely tamoxifen. There are better, improved ways to produce pure tamoxifen. Check out this website: http://www.ch.ic.ac.uk/local/projects/h_tanner/introsynth.html

Drawing reaction mechanisms with curved arrows

A reaction mechanism is a detailed step-by-step description of how reactants are converted to products. It consists of a sequence of steps showing the making of bonds and the breaking of bonds. It is a way to explain or rationalize how a reaction happens to change a reactant to a product.

When bonds are made or broken, there are movements of electrons from one molecule or a group of atoms to another.

In most reactions you meet in organic chemistry (except radical reactions), the electrons move in a pair (two). We draw the flow of this pair of electrons as a curved arrow like this:

Another important point to note is that these two electrons always move from a place of more electrons (or negatively charged) to a place with less electrons (positively charged):

Here are some common examples, which you meet in reactions you have learned:

Whichever a reaction may be, when drawing a mechanism, remember that a curved arrow means the flow of two electrons, and the electrons always flow from a place of more electrons to a place of less electrons, never the opposite direction.

Elimination reaction in a nutshell

Dear Students,

In this three-hour class, I will introduce you to another important reaction: 
Elimination.

In the previous lectures, you have seen alkyl halides undergoing nucleophilic 
substitutions (SN), for example:

The reason is that halogens are very good leaving groups. A nucleophile attacks
 the carbon to which the halogen is attached causing the halogen to leave.


An elimination reaction works quite similarly, like this: 

The halogen leaves but also a hydrogen is taken away. The hydrogen is taken away by a base. The result is the formation of an alkene, or double bond.


You will see more examples like this in my lecture. In this class, you will learn about:
-  the two mechanisms of elimination, E1, and E2
-  Stereochemistry of elimination particularly E2
-  Elimination of cyclic alkyl halides
-  Alcohols and amines can also be made to undergo eliminations


Notes for this lesson are availble for download here:
http://bit.ly/18s3joz

Tutorial questions for this topic are available here:
http://bit.ly/H1iRFH


See you in class.

Calculating UV λmax of molecules using the Woodward-Fieser Rules

Dear First Year students,

This is a short tutorial on calculating UV absorption maximum (λmax) using the Woodward-Fieser rules. I hope this would help to clear any doubts you may have, so that you will understand the topic better and do well during the coming exam.

Let's look at the questions in the previous quiz.. They are good examples for us to understand how to arrive at our λmax.

The first question:

Not so difficult,isn't it. The second question:

To sum it up, follow these general steps:

1.     First, determine the parent or base structure be it a diene, α,β -unsaturated ketone, or an aromatic ring. This would tell you which rule to use

2.     Look for any double bonds extending this diene or α,β -unsaturated ketone.

3.     Treating this conjugated system as a whole, go along the chain looking for alkyls or auxochromes directly attached to it, anything far from the chain not counted.

4.     Lastly, look for other elements such as exocyclic double bonds and homodiene element, if there are rings involved.

I hope that this tutorial will help you. Please also study the tutorials for other examples. 

I wish you all the best for exams and happy studying! 

Best wishes, Dr Lee

A tutorial on IR Spectroscopy

Dear students,

This is a tutorial on reading IR spectra to make your preparation for the exam complete. I take the opportunity to discuss the IR question from the previous quiz.

Here is the spectrum given in the quiz:

You were asked to choose between two compounds, C and D as to which the spectrum belongs to. C is an aldehyde (1-pentanal) and D is a carboxylic acid (pentanoic acid).

Let’s look closely at the spectrum. The most obvious peak is the intense and sharp carbonyl (C=O) stretch at 1727 cm^-1 signalling the presence of a carbonyl which both compounds have in common, both are carbonyl compounds. Next, look closer at a moderately intense peak at 2719 cm^-1. There are actually two peaks at ~ 2700 and ~2800 cm^-1, one of the peaks being half hidden behind the bigger saturated C-H stretch bands. This two peaks show the presence of C-H stretch of an aldehyde. So, this is clear indication that this spectrum belongs to compound C.

Some of you may have been misled by a rather medium size peak at around 3500 cm^-1. This is NOT an O-H stretch. It is probably an overtone of our intense carbonyl band at  ~1700 cm^-1. If you remember the IR spectrum of myristic acid from our Nugmeg myristicin practical, you will see that the O-H stretch band of myristic acid is distinctively different: it is broader, smooth, and spreads over a larger region (overlapping the saturated C-H bands). Have a look at it again.

An actual IR spectrum of compound D, pentanoic acid (it’s also called valeric acid) is shown below:

Hope this little discussion clears the haze regarding IR spectrum.

I include here a video on reading IR spectra (a substitute tutorial teacher ) that I find useful for your preparation. Pleasant viewing and good luck for the exams.

Source: Youtube channel Sarutahiko1 (www.youtube.com/watch?v=XIWc9eT476c)

Welcome to Good Molecules!

Dear visitors,

Welcome to Good Molecules! 

This is a place where you can find everything related to Pharmaceutical Chemistry, Medicinal Chemistry, Organic Chemistry and Pharmacognosy, useful and interesting to all Pharmacy students.

More postings will be available soon. There will be topics of interest, side-stories, fun and entertaining stuff coming soon.

Please check for postings of materials related to the current topics.

Best wishes
Dr Lee