Paracetamol Synthesis Experiment

Posted at 01.10.2018

N-(4-hydroxyphenyl)ethanamide, often known as Paracetamol or acetaminophen depending on where you reside in the entire world, is one of the very most widely used over-the-counter drugs. It has the molecular solution C8H9NO2. It is an analgesic (pain reliever) and also an antipyretic (fever reliever). For these reasons it is utilized to relieve a person of gentle to average pain, for example; toothache, head aches or symptoms of a frigid and also to control fever (temperature, also called pyrexia). For treatment it works by interfering with certain chemicals in the torso called prostaglandins. Prostaglandins were first found out in the 1930's from individual semen, thinking the chemicals had come from the prostate gland he known as them prostaglandins, but it's since been founded they are simply synthesised atlanta divorce attorneys cell in the body. They become chemical substance messengers like hormones but do not move to other sites, they stay static in the cell that these were synthesised in. Prostaglandins have a variety of physiological results, one because they are released in response to pain or injury, paracetamol functions by inhibiting the creation of prostaglandins making your body less aware of the pain or accident. Paracetamol reduces temperatures by acting on a location of the mind called the hypothalamus, responsible for regulating body temperature.

The record of paracetamol is an interesting one, at the methodology of the 20th century, the discovery and synthesis of drugs was alternatively arbitrary, with scientists generally just testing new substances on humans immediately and then observing if it experienced positive (or negative) results. The storyplot of paracetamol begins with the first aniline (also known as phenylamine or aminobenzene) derivative to be found to possess analgesic and antipyretic properties, acetanilide. Aniline is an organic substance with the molecular formula

Aniline (1)

C6H5NH2, shown above, contains a phenyl group attached to an amino group. The new potential treatments acetanilide have been synthesised by just the aniline getting a secondary amide group, by reacting the aniline with ethanoic anhydride, ethanoic acid would also be produced. The reaction is shown below.

C6H5NH2 + (CH3CO)2O † C6H5NHCOCH3 + CH3COOH

Acetanilide (2)

The finding was soon posted and acetanilide medication was soon in creation in 1886, remaining in use for several years scheduled to how cheap it was to create. But although acetanilide was proven to act as being effective in lowering fever and relieving light pain, a seek out less toxic aniline derivatives started out because of a few of the awful side effects acetanilide experienced, for illustration cyanosis (appearance of blue or crimson coloration of the skin due to cells near the skin being lower in oxygen) caused because of it deactivating haemoglobin in erythrocytes.

The search led to a new derivative that was antipyretic and analgesic and was less dangerous than acetanilide called N-(4-Ethoxyphenyl)ethanamide. Marketed in 1887 under the name phenacetin, it offers remained in use since but has dropped in its use because of its adverse affects on the liver. It has the chemical solution C10 H13NO2.

N-(4-Ethoxyphenyl)ethanamide (3)

In 1893 Joseph von Mering improved upon on phenacetin producing paracetamol, but mistakenly thought it possessed the same adverse effects as acetanilide. Within the 1940's it was realised that paracetamol was a significant metabolite of phenacetin, it was then considered to quite possibly be the part that induced phenacetin to really have the desired results and that the unwanted effects were caused by a minor metabolite released. Then in 1953 paracetamol struck the marketplaces, being marketed as more advanced than aspirin in that it was safe for children and with people with ulcers.

Structural equation demonstrating Phenacitin being turned into its metabolites in the torso, as you can see from the diagram, the main metabolite is paracetamol. (4)

Paracetamol is manufactured by many different pharmaceutical manufacturers, each providing their products different brands. In the united kingdom currently there tend to be more than ninety over-the-counter products made up of paracetamol. Different brands may contain different levels of paracetamol per medication dosage, it will be stated on the presentation, usually in milligrams. Sometimes it may be coupled with other medicines such as decongestants (a type of medicine that delivers temporary relief for a obstructed nasal area).

While it is a very effective medication, even small overdoses can be fatal, because it is metabolised into non-toxic and harmful products in the liver. The advised single dose for parents is 1000mg and up to 4000mg in a day. Paracetamol is hepatoxic, and therefore even in the healing dosages stated previously, it can still damage hepatocytes (liver skin cells) and in combo with other drugs like alcohol the harmful results are multiplied. Extended daily usage can cause upper gastrointestinal difficulties such as tummy bleeding. Untreated paracetamol overdoses (which would usually entail overtaking the therapeutic dosages for a number of days) results a lengthy and painful illness. Individuals who overdose often wrongly presume it will render them unconscious, however this doesn't happen, rather the procedure of dying takes around 3 to 5 days anticipated to serious liver failure.

Aims:

1. To synthesise paracetamol in one step, beginning with 4-aminophenol i. e. amide synthesis
2. To try synthesise paracetamol in a microwave using a similar solution to how aspirin is synthesised
3. To recrystallise about 50 % of my samples of paracetamol, leaving the other half crude
4. To compute the percentage produces of paracetamol, in both methods and compare them
5. To perform analysis of my synthesised samples of paracetamol, both recrystallised and crude using analytical techniques such as

• Melting point test
• Thin level chromatography
• Back Titration (that may provide a quantitative analysis, concentrations)
• Infra-red spectroscopy

6) To then use the results of these analytical techniques to determine which approach to synthesis produces

1. The most natural paracetamol test,
2. The greatest ratio yield

by checking the percentage yields and purities of both the crude and recrystallised samples of both methods.

1. To draw out paracetamol from commercial tablets and compare the purity to my synthesised samples
2. To then use the aims 6 and 7 to finally determine which approach to synthesis of any amide, paracetamol, is most efficient.

Chemical theory:

Amines: (5)

Amines are the organic chemistry family members of Ammonia, they can be derive by swapping one, two or all three of the hydrogen atoms with alkyl categories which determines which type of amine it is. Exchanging one of the hydrogen atoms provides primary amine, changing two a second amine and everything three a tertiary amine.

Below shows female amine being created from a halogenoalkane with bromine as the halogen, the alkyl group would range depending on specific major amine desired. It really is a substitution response, with the hydrogen on the ammonia being substituted for the alkyl group on the halogenoalkane.

NH3 + RBr †RNH2 + HBr

A primary amine (6) A secondary amine (7)

Amines with low comparative molecular public are gases or volatile fluids, similarly to ammonia there is also strong smells, amines have a "fishy" smell. The properties of amines are very very much like ammonia because of the fact both have the lone pair of electrons that open up a variety of opportunities. Their properties are only slightly customized by their alkyl categories including the status at room heat range.

4-Aminophenol, the foundation of paracetamol (reacting 4-aminophenol with ethanoic anhydride offers paracetamol) is, the burkha amine.

4-Aminophenol (8)

4-Aminophenol is made by reacting phenol with sulphuric acid and sodium nitrate gives two products, 1- nitrophenol and 2-nitrophenol. The 2-nitrophenol is then reacted with sodium borohyride, which produces 4-aminophenol.

Step one in synthesis of 4-aminophenol (4)

Step two in synthesis of 4-aminophenol (4)

-Very soluble in water

Similarly to Ammonia, amines can develop hydrogen bonds with drinking water because of the highly electronegative nitrogen being bonded to the hydrogen atom; these are attracted to normal water substances and vice versa. Amines with small alkyl teams are soluble but those with larger alkyl categories are insoluble because the alkyl communities disrupt the hydrogen bonding in the. That is significant because 4-aminophenol being truly a building block of paracetamol this is a common impurity, therefore with the recrystallisation, it will in theory be removed very effectively as it should be very soluble and not reach its limit of solubility. This will be discussed down the road.

-Act as a base

Again much like ammonia, the lone couple of electrons on the nitrogen can develop a dative covalent connection with hydrogen atoms, meaning it works as basics. In drinking water the presence of hydroxide ions causes it to carefully turn alkaline. When the ammonia/amine is positioned with acid, then your acid will donate more protons than water, so the effect will go on until completion, and therefore many ammonium ions/amine ions are developed and therefore the fishy smell is lost. This can impact on the effectiveness of a chromatogram in skinny covering chromatography.

-Acting as a nucleophile:

Ammonia as well as amines can become nucleophiles, which is why they can develop an amide when reacted with an acylating agent like ethanoic anhydride. When ammonia operates as a nucleophile it can react with a halogenoalkane or acylating agent to form an main amide, the lone couple of electrons on the nitrogen atom invasion the positively polarised carbon atom and via a substitution reaction will replace the halogen (e. g. chlorine) or practical band of the acylating agent (e. g. HCL from ethanoyl chloride). This occurs by the electrons in the connection being donated to the halogen or specific efficient group of the acylating agent. This breaks off with both electrons and for that reason leaves the carbon with a high positive demand, allowing the negative nitrogen to create a dative covalent bond with the carbon. Amines likewise have a lone couple of electrons on the nitrogen atom and so can also harm electrophiles, such as the delta positive carbon atom on the acylating agent. Much like the ammonia effect, a nucleophillic substitution reaction occurs with the electron moves referred to above and the appropriate functional group is removed and replaced by the R-N-H developing the secondary amide, with the next hydrogen atom being removed from the primary amine combined with the efficient group.

(9)

Reaction of your primary amine with ethanoyl chloride an acylating agent, as is seen the chlorine atom from the ethanoyl chloride is removed as well the hydrogen from the principal amine, producing HCL. This would've took place as result of the nitrogen lone pair attacking the central carbon. The causing secondary amide is produced when the R-N-H bonds to the carbon.

Synthesis and hydrolysis of an Amide: (10)

All amides contain the useful group CONH

All amides contain this practical group (11)

An amide can either be major or secondary, most important amides have the overall method R-CONH2, the Nitrogen atom is bonded to two hydrogen atoms and then a carbon atom, which is dual bonded to an oxygen, the fourth relationship of the carbon is to the R group which can either be an alkyl group (methyl, ethyl etc. ) or a benzene.

These can be produced by reacting Ammonia with an acylating agent such as an acyl chloride like Ethanoyl chloride. They are carboxylic acid derivatives that are reactive enough to form an amide. Hydrogen from the ammonia breaks off as well as the chlorine of the acyl chloride, developing HCL (g). The first carbon (with the double bond air) then bonds with the Nitrogen this forms the useful group.

The general formula for, the burkha amide

Secondary amides are different for the reason that the Nitrogen is merely bonded to 1 hydrogen and the third bond would go to another R group, supplying secondary amides the overall method R-CONH-R'. The R organizations will be the same, or may differ.

Paracetamol (N-(4-hydroxyphenyl)ethanamide) as explained earlier gets the molecular solution C6H9NO2, by looking at its structural formulation shown below, it could be seen that it consists of three main parts, beginning with the still left, in the box is the phenol group, one of the R sets of the amide, this points out the "hydroxyphenyl" part of paracetamols systematic name as it was actually part of the 4-aminophenol amine. Next in the oval, is the real amide functional group, finally on the very good right in the triangle is the other R group (R') which in paracetamol is simply a methyl group. From all this we can determine that paracetamol is a secondary amide.

(4)

Secondary amides are made by reacting a primary amine with an acylating agent like Ethanoic anhydride, in my own investigation, I'll use ethanoic anhydride as my acylating agent. This occurs by the response system of nucleophillic substitution, which is shown below in a curly arrow diagram, with ammonia getting used as the nucleophile, attacking the carbon atom.

Steps in Nucleophillic substitution: (12)

1. The very first thing to note is that, as explained previously, ammonia (which is operating as the nucleophile in the example above) as well as amines can act as nucleophiles, due to the fact they have got the lone couple of electrons on the nitrogen atom, they have a incomplete negative demand which is attracted to an electrophile (has a incomplete positive charge), in cases like this the polarised carbon atom (as it is bonded to the highly electronegative oxygen atom) on the ethanoic anhydride.
2. The very first thing that happens would be that the Nitrogen starts its "attack" on the partly positive, also known as delta positive, carbon. Because of the lone pair, it sorts a dative covalent relationship with the carbon
3. Because it is dative, the carbon atom has gained an electron therefore at has been reduced, so it then donates an electron within the double bond with oxygen to the air atom, this makes the already partly negatively charged oxygen to become adversely charged. There is now only a single bond between the carbon and air.
4. The carbon atom then donates an electron to the air below it that it is also singly bonded to, liberating an ethanoate ion (CH3COO), it has given the carbon atom that donated the electron a positive fee as it has now had a online loss of one electron from its original electron construction. That is now a carbocation.
5. The response then dates back to the negatively recharged oxygen that the central carbon donated its electron to early, what occurs now could be that the air donates the electron again, now that the central carbon is positively priced, this reforms the two times bond between your now partially negative air and partially positive carbon.
6. The nitrogen that has bonded to the carbon then loses the third hydrogen atom as nitrogen can only form three bonds in a neutral organic compound, this happens by the hydrogen donating its electron to the nitrogen. The hydrogen then bonds to the ethanoate ion, developing ethanoic acid (CH3COOH) and ethanamide, ethan- the prefix from the two carbon atoms present and the suffix -amide due to the CONH practical group.
7. The ethanoic acid produced then will react with any unnecessary ammonia to form ammonium ethanoate, it is because ammonia and amines can act as bases because of the reasons stated previously, the hydrogen on the ethanoic acid breaks off and bonds to the nitrogen atom.

The "curly arrow" diagram of this effect is shown below, the level number relates to the device diagram shown above it and explained above, step one 1 is omitted since it is an intro, the first rung on the ladder of the response mechanism, is step two 2 i. e. shown below step two 2 is the attacking of the nitrogen nucleophile to the