Intravenous Anaesthetics

In the eighteenth century surgery was limited to essential operations, such as the amputation of gangrenous limbs, performed on conscious patients who were strapped in and held down by assistants.

By the mid-nineteenth century gases like ether and chloroform were being used to reduce pain during dentistry and childbirth. Then the hypodermic syringe was developed, allowing drugs to be injected directly into the blood stream resulting in drugs that acted quickly and predictably.

But it wasn't until the early twentieth century that intravenous anaesthetics, compounds that cause loss of consciousness, became available and revolutionized surgery. 

Discover some chemistry of intravenous anaesthetics in this issue of AUS-e-NEWS

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Cholera Vaccine

The holiday season is here, and some friends have decided to visit Panama (where else would an Engineer want to go for a holiday but to the Panama Canal?). One of the diseases they want protection against before traveling there is cholera which is caused by a water-born bacteria. The product they are taking is called DUKORAL® which comes in two parts. The first part part is a glass vial containing a whitish fluid which is the oral vaccine made up of inactivated cholera bacteria, which is probably of interest to the biology students reading this. Chemistry students, however, will be much more excited by the second part; a sachet containing a dry granular powder which is labelled as buffer.
The ingredients listed on the buffer sachet are:

• sodium bicarbonate
• citric acid, anhydrous
• raspberry flavour
• sodium carbonate, anhydrous
• sodium citrate
• saccharin sodium

The instructions for use by adults are:

1. Dissolve the effervescent granules from the buffer sachet in a glass of cool water (approximately 150 mL)
2.  Shake the vaccine vial
3. Add the vaccine to the effervescent (bubbly) solution. Mix well and drink mixture.

And, you have to take two of these doses 1 to 6 weeks apart, and 2 weeks before arrival at your destination.
The good news is that most people should be protected cholera for up to two years, so I guess my friends will make their way back to the tropics next year.

Suggested Reading
 http://www.ausetute.com.au/namiform.html
 http://www.ausetute.com.au/wriiform.html
http://www.ausetute.com.au/acidbase.html
 http://www.ausetute.com.au/buffers.html
http://www.ausetute.com.au/esters.html

Suggested Study Questions

1.  What is another, systematic name for sodium bicarbonate?
2. Give the molecular formula for each of the following:
   • sodium bicarbonate
   • citric acid, anhydrous
   • sodium carbonate, anhydrous
   • sodium citrate
3. Draw a structural formula for each of the following:
   • sodium bicarbonate
   • citric acid, anhydrous
   • sodium carbonate, anhydrous
   • sodium citrate
4. Use chemical terms to explain the relationship between:
   • sodium bicarbonate and sodium carbonate
   • citric acid and sodium citrate
5. Explain what a buffer is.
6. Explain why the dry, granular powder in the sachet was labelled "buffer".
7. Why do you think a buffer is needed for this vaccine to be effective?
8. What type of chemical compound is the "raspberry flavour" likely to be?
9. One molecule responsible for raspberry flavour is shown below:
   
   What 2 reactants would you need to produce to this molecule in the school laboratory?
10. What does the term effervescent mean?
11. Write a balanced chemical equation to show why effervescence is observed when the buffer in the sachet is added to water. 
12. What does the term "anhydrous" mean?
13. Why are some of the buffer sachet's ingredients listed as "anhydrous"?
14. What is the purpose of the saccharin in the buffer sachet?

Aspro, Aspirin, and World War I

2015, a very significant year for all Australians and New Zealanders, marks the centenary of the "Landing at Gallipoli" on 25^th April 1914 and the birth of the ANZAC legend. It also marks the centenary of "Aspro" and the birth of a giant international pharmaceutical company that began in Australia as a direct result of World War I.

Felix Hoffman, a German Chemist, first synthesized aspirin, acetylsalicylic acid (2-Ethanoyloxybenzene carboxylic acid), in 1897 while working for the German pharmaceutical company Bayer AG. This was the first major product released by Bayer AG and the trademark Aspirin was registered worldwide. Prior to 1914 Germany exported Aspirin all over the world.

German supplies of Aspirin to Australia (and other countries) were cut off with the outbreak of World War I in 1914, prompting the then Attorney-General W. M. Hughes (and the 7^th Australian Prime Minister from 1915 to 1923) to suspend German patents and trademarks and grant them to any Australian-based manufacturer who could meet the requirements for purity and safety.

George Richard Rich Nicholas, a pharmacist who had opened a pharmacy in Punt Road, Windsor in Victoria in 1912, set out to make acetylsalicylic acid. Using kitchen utensils, he measured out quantities of the white salicylic acid powder and the acrid smelling acetic anhydride liquid and reacted them in kerosene tins. Needless to say, although he succeeded in producing acetylsalicylic acid it was impure! With the help of Henry Woolf Shmith, an entrepreneur, the experiments continued until they had pure samples of acetylsalicylic acid. In 1915 their product was tested by the government analyst and found to comply with the requirements of the British Pharmacopoeia so Shmith, Nicholas & Co. were granted a licence to make and sell aspirin in Australia.

Their acetylsalicylic acid product was originally marketed as Nicholas-Aspirin, but George was concerned that the name Aspirin could be reclaimed by Bayer after the war, so, in 1917 the name Aspro was registered.

After the war, in 1921, the name of the company  making Aspro was changed to Nicholas Pty Ltd and moved from Windsor to South Melbourne. In 1923, New Zealand began production of Aspro. Between 1925 and 1927 sales of Aspro were expanding in Europe and Asia. In 1927,  George's brother Alfred set up the company Aspro Ltd in England, which became a public company in 1935. In 1969 Nicholas Australia Ltd bought out the English Aspro-Nicholas Ltd, which, in 1970, became Nicholas International Ltd. In 1981 Nicholas International Ltd merged with Kiwi International Ltd (makers of the famous Kiwi shoe polish) to form the Australian public company Nicholas Kiwi. In 1984 Sara Lee acquired Nicholas Kiwi, and in 1988 Piramal India acquired Nicholas Laboratories from Sara Lee.

Ready to learn about the chemistry of aspirin and aspro?
Go to the Free Chemistry Tutorial on Aspirin at AUS-e-TUTE to read about the reactions that produced aspirin as well as the physical and chemical properties of aspirin.
(AUS-e-TUTE Members should log-in to the Test Centre and use the "Members ONLY" Aspirin Tutorial).
AUS-e-TUTE members also have access to other learning resources, such as games, tests and exams on the chemistry of aspirin.
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Molecule with Anti-Cancer Kick

In 2013, medical researchers found a molecule that fights cancer in animals by boosting the cell's production of a powerful natural antitumor protein known as TRAIL. The Researchers referred to this anti-cancer molecule as TIC10, short for TRAIL Inducing Compound number 10.
The structure of this molecule, as confirmed by mass spectroscopy, was published at this time as is shown below:

Chemists at The Scripps Research Institute (TSRI) found a way to synthesize this molecule in the laboratory. However, when the Chemists gave their molecule to Biologists to test on cancer cells, this molecule failed to show any anti-cancer activity!
So, the Chemists asked the Biologists to supply some of the TIC10 that had shown anti-cancer activity. The Chemists spent months analyzing both TIC10 molecules to determine their exact molecular structure. And they discovered that the molecule the biologists had shown to fight cancer did not have the structure that was originally published, so the molecule that the Chemists had synthesized in their laboratory would not fight cancer cells,.
However, the Chemists found that the molecule that DOES fight cancer cells has a very similar structure. The structure of the active molecule is shown below:

Note that the structure originally published for TIC10 had the three nitrogen containing rings in a straight line. This new, correct, structure for TIC10 has two of the nitrogen containing rings in a straight line, but the third ring sticks out at an angle from the other two. Only this "angular" isomer (the molecule with a kick) shows any anti-cancer activity.

Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI has been quoted as saying, "One lesson from this has got to be: don't leave your chemists behind".
(http://www.sciencedaily.com/releases/2014/05/140519184505.htm)

Reference:
Nicholas T. Jacob, Jonathan W. Lockner, Vladimir V. Kravchenko, Kim D. Janda. Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL. Angewandte Chemie, 2014; DOI: 10.1002/ange.201402133

Further Reading
Molecular Formula  
Condensed Structural Formula 
2-Dimensional Structural Formula
Skeletal Formula
Percent Composition
Functional Groups
Benzene
Mass Spectroscopy for Structural Determination

Suggested Study Questions:

1. Refer to the structure of TIC10 as shown above. In one molecule, how many
   • carbon atoms are present?
   • hydrogen atoms are present?
   • oxygen atoms are present?
   • nitrogen atoms are present?
2.  Write the molecular formula for a molecule of TIC10.
3. For the TIC10 molecule, calculate the percent by mass of
   • carbon
   • hydrogen
   • oxygen
   • nitrogen
4. Convert the skeletal structure for the active anti-cancer molecule into a 2-dimensional structural formula.
5. Circle one benzene ring in the structure of the active anti-cancer molecule.
6. Circle and name the functional group containing an oxygen atom on the active anti-cancer molecule.
7. What value do you expect for the mass-to-charge (M/Z) peak on a mass spectrum of the anti-cancer TIC10 compound ?
8. Do you think mass spectroscopy alone could be used to distinguish between the two structures proposed for TIC10 above? Explain your answer.

Ibuprofen

Before you take that nurofen, advil, motrin,brufen, or one of the many other trade-names for ibuprofen, why not learn something about its chemistry first?

AUS-e-TUTE has just added a new tutorial, game, test and exam exploring the chemistry of ibuprofen.
Members should log-in to use these new resources.

Not an AUS-e-TUTE Member?
There is a free tutorial available at http://www.ausetute.com.au/ibuprofen.html

Paracetamol

AUS-e-TUTE has just added new resources for the paracetamol (acetaminophen) topic.

AUS-e-TUTE Members should log-in to view the new tutorial, play the new game or answer the new test questions.

Not a member? The free tutorial is located at http://www.ausetute.com.au/paracetamol.html

Relenza Synthesis

Relenza, a pharmaceutical drug used to fight influenza (flu), went into production in 1999.

The synthesis of Relenza is a multi-step process involving a number of chemical reactions that should be familiar to High School Chemistry students.

The June 2012 issue of AUS-e-NEWS outlines the steps used to sythesise Relenza from commercially available N-acetyl-neuraminic acid.

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Trifluoromethyl Groups in Pharmaceuticals

The trifluoromethyl group is a component of several commonly used drugs including the antidepressant Prozac, arthritis medication Celebrex, and Januvia which is used to treat the symptoms of diabetes. Trifluoromethyl groups are also a common component of agricultural chemicals such as pesticides.

Chemists often use hydrogen fluoride to attach a trifluoromethyl group to an organic compound, but under the conditions of the reaction this might produce unwanted reaction products. MIT chemists have designed a new way to attach a trifluoromethyl group to certain compounds using a palladium catalyst. The key to the success of this catalyst has been the use of a ligand called BrettPhos. During the reaction, a trifluoromethyl group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. The trifluoromethyl containing molecule is then released and the catalytic cycle begins again. The chemists have tried the synthesis with a variety of aryl compounds and have achieved yields between 70% and 94%.

Reference:
Eun Jin Cho, Todd D. Senecal, Tom Kinzel, Yong Zhang, Donald A. Watson, Stephen L. Buchwald. The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides. Science, 2010; 328 (5986): 1679-1681 DOI: 10.1126/science.1190524

Study Questions

1. Write the chemical formula for the trifluoromethyl group and for hydrogen fluoride.
2. Write a chemical equation to show the possible reaction between hydrogen fluoride and cyclohexane.
3. Write a chemical reaction to show the possible reaction between hydrogen fluoride and cyclohexene.
4. For each reaction above, assuming you start with 100g of each reactant, what mass of fluorinated product would be produced if the yield was 70%?
5. For each reaction above, assuming you begin with 25 moles of each reactant, what mass of fluorinated product would be produced if the yield were 94%?
6. For the catalytic reaction discussed in the above article, why do you think the reaction does not produce a 100% yield?