Organic Synthesis

Tertiary alcohol

Add K2Cr2O7 (aq) and dilute H2SO4 (aq) and warm. No reaction (stays orange).

Secondary alcohol

Add K2Cr2O7 (aq) and dilute H2SO4 (aq) and warm. Orange to green.

Primary alcohol

Add K2Cr2O7 (aq) and dilute H2SO4 (aq) and warm. Orange to green.

Alcohols (all OH groups)

Add PCl5 (s). Steamy fumes of HCl

Test for acid

Add aqueous sodium hydrogencarbonate. A gas is evolved that turns limewater cloudy.

Test for alkene and observations

Add bromine water, orange bromine is decolourised.

Test for phenols

Add bromine water. The brown solution becomes colourless and a white ppt forms.

Test for alcohols

Add ethanoic acid and a few drops of concentrated sulphuric acid and warm gently. Pour into a beaker of cold water and carefully smell the product. A fruity or glue-like smell confirms an alcohol.

Recrystallisation procedure, step 3:

Allow the flask to cool. (Slow cooling produces large crystals, rapid cooling produces small crystals and you want medium size crystals).

Examiner tip

Always make sure that your diagrams of apparatus are not sealed, the water flow in a condenser is correct and that a round-bottomed (not flat) flask is used.

Purification

At the end of a synthesis, the desired product is impure because of the presence of unused reactions or the products of side reactions, so it needs to be purified.

Although the structural, displayed and skeletal formulae of an organic compound show how its atom links together, they do not show its true shape in three dimensions. SOmetimes it is importantto know and understand what the 3-D shape of a molecule is like and chemists use various models to do this. Guve some example

Ball-and-stick models, space-filling models and various types of computer models.

Why are molecular formulae usually more helpful than empirical formulae?

Because they show the actual number of atoms of each element in one molecule of a compound.

Recrystallisation example

Benzoic acid is very soluble in hot water, but almost insoluble in cold water. Therefore it can be purified by recrystallisation from hot water.

What is the other problem with measuring using boiling point determination.

Boiling points are hard to measure accurately.

Synthetic techniques

Chemists have developed a range of practical techniques and procedures for the synthesis of solid and liquid organic compounds. These methods allow for the fact that reactions involving molecules wiht covlaent bonds are often slow and that iti is difficult to avoid side reactions that produce by-products. There are five key stages in the prepraation of an organic compound.

Melting point determination

Due to the problems associated with boiling point determination it is commonplace in organic synthesis for a liquid to be converted to a solid derivative. The derivative is then purified (by recrystallisation) and its melting point determined. Impurities make the melting point range broader and lower.

Solvent extraction and purification procedure, step 1.

The aqueous layer is shaken with portions of the organic solvent and the liquids are separated using a separating funnel. The procedure is repeated and the organic portions combined.

Boiling point determination

The boiling point of an organic liquid can be determined and the value compared with literature values. The two main drawbacks with this method are: - The boiling points of similar substances are often quite loose together. - Impurities, and variation in atmospheric pressure, alter the boiling point. Impurities usually raise the boiling point.

What does the technique of combinatorial chemistry involve?

This technique involves synthesis on the surface of a resin beads a few micrometers in diameter.

What is the essential job of synthetic organic chemists

To consider to proposed structure for a target molecule and then devise a way of making it from simpler readily available starting materials.

Why do we acidify it with dilute nitric acid?

To get rid of NaOH so it doesn't react with AgNO3 to produce a ppt. Otherwise you'll get a ppt. that confuses you.

Recrystallisation procedure, step 7:

Transfer the crystals to a weighed sample vial and dry in a dessicator.

What should you do when you plan an organic synthesis?

Work backwards.

What is yield greatly affected by?

Yield is greatly affected by the number of steps in a synthetic pathway - the more steps there are the lower the yield will be.

What are the Physical Methods?

- Boiling point determination - Melting point determination

Sensitive methods of analysis are very important in monitoring organic synthesis for several reasons, what are they?

- Sensitive methods of analysis will determine the degree of purity of a synthetic product. - Sensitive methods of analysis will also identify any impurities, some of which may be toxic and in very small concentration. - If analysis reveals an impurity in the prouct, it may be possible to limit its fomration by changing the operating conditions for the reaction. CHanges in the temperature, the pressure, the solvent used or the choice of catalyst may promote the formation of a desired product while reducing the formation of impuirites - Many pharmaceutical labs that specialise in the development of new drugs product thousands of compounds every year for further testing. SOme of their products are obtained in very small concentrations and particcularly sensitive techniques are needed to analyse and identify them. The food and drugs industries operate very high stnadards of purity in their products. Impurities, depending on their toxicity, may interfere with the health and well-being of consumers. For example, traces of sodium chloride in a medcine would probably not be considered a problem, but the slighest trace of sodium cyanide would be cause for alarm.

What are the most common hazards?

- Toxicity of gases - Toxicity or corrosive nature of liquids and solids - Flammability of reactants or products - Exothermic reactions

What are the main frequencies to look out for in an IR spectrum

- a peak at around 1700/cm. This deonates the presence of a C=O group. - a peak around 3100/cm. This denotes an OH group.

There are five key stages in the preparation of an organic compound, what are they?

1. Planning. 2. Carrying out the reaction 3. Separating the product from the reaction mixture. 4. Purifying the product. 5. Measuring the yield, identifying the product and checking the purity.

Methods of separation and purification

1. Separating funnel 2. Solvent extraction of water soluble organic compounds 3. Distillation 4. Steam Distillation 5. Recrystallisation

Steam distillation advantages

1. The temperature never exceeds the boiling point of water. This permits the purification of high-boiling substances that are too heat sensitive to withstand ordinary distillation. 2. Allows the separation of volatile products from tarry material, which is often produced during the course of an organic reaction and cannot be easily removed by distillation or crystallization.

SN1 reactions always give...

A racemic mixture.

Distillation

A volatile liquid may be separated from involatile materials by simple distillation. Cooling the receiver flask minimises loss of product caused by evaporation. The boiling point range of the product (determined during distillation) indicates its degree of purity.

Stage 3: Separating the product from the reaction mixture

Chemists talk of 'working up' the reaction mixture to obtain their crud product. If the product is a solid, it can be seaparated (worked up') by filtration using a Buchner funnel with suction from a water pump. Lqiuids can often be separated by simple distillation, fractional distillation or steam distillation. Distillation with steam at 100 degrees C alllows the separation f ocmpounds that decompose if heated at their boiling temperatures. The technique works only with compounds that do not mix with water. When used to separate the products of organic preparations, steam distillation leaves behinf those reagents and products that are soluble in water.

Boiling point determination, step 3.

Clamp the thermometer in the beaker of water

Exothermic reactions

Cooling and/or slow (dropwise) addition may be needed.

The organic compounds are joined to the resin beads by what type of bonds?

Covalent bonds.

What must also be considered?

Disposal of waste products. If they are toxic or non-biodegradable they must be stored for later disposal by, for instance, incineration.

Recrystallisation procedure, step 1

Dissolve the solid in the minimum volume of hot solvent in a conical flask (or by heating under reflux). A water bath should be used - not a naked flame. Minimum volume because otherwise the crystals won't form.

Recrystallisation procedure, step 6:

Dry the crystals on filter paper.

Stage 2, carrying out the reaction

During this stage, the reactants are measured out and mixed in suitable apparatus. Most organic reactions are slow at r.t.p so it is usually necessary to heat the reactions using a flam, heating mantle or hotplate. One of the commonest techniques is to heat the reaction mixture in a flask fitted with a reflux condenser. Organic reagents do not usually mix with aqueous reagents. So another common technique is to shake the immiscible reactants in a stoppered container.

T/f: An SN2 reaction on a single enantiomer produces a racemic mixture.

False. An SN2 reaction on a single enantiomer produces a single entantiomer.

Recrystallisation procedure, step 4:

Filter off the crystals under reduced pressure, using a Buchner funnel.

Recrystallisation procedure, step 2.

Filter the solution while hot (to remove insoluble impurities, e.g. antibumping granules) into a warmed conical flask while hot so the stuff doesn't crystallise prematurely.

What is the first step towards understanding a compounds chemistry

Finding the empirical formula.

What are vapours?

Gases formed by evaporation of substances that are usually liquids or solids at room temperatures. Chemists talk about 'hydrogen gas' but 'water vapour' Vapours are easily condensed by cooling or increased pressure because of their reltaviely strong intermolecular forces.

Melting point determination how to carry out the process

Heat the solid in a test tube immersed in a water-bath until the solid begins to melt. Measure the temperature at this point. When the substance has completely melted, allow it to cool, and then measure the temperature at which it begins to solidify. The substance must be stirred all the time. Average the two temperatures. Make sure you heat slowly in both melting and boiling point determinations, or else the reading will be too low.

Heating under reflux

Heating in a flask with a reflux condenser prevents vapours escaping while the reaction is happening. Vapours from the reaction mixture condense and flow back (reflux) into the flask.

Test for halogenoalkane and observations

Hydrolyse with NaOH (aq); Acidify with dilute nitric acid and add AgNO3 (aq) Chloroalkane: White ppt Bromoalkane: Cream ppt Iodoalkane: Yellow ppt Confirm by adding dilute then conc. ammonia

WHat's so good about using a Buchner funnel?

It sppeds up filtering and facilitates recovery of the purified solid from the filter paper.

NMR spectra

Number and relative intensity of peaks and the splitting pattern can be used to distinguish between structural isomers.

Solvent extraction of water soluble organic compounds

Often an organic compound is dissolved in water and needs to be extracted into a suitable solvent for purification. The organic solvent should be immiscible with water and have a low boiling point so that it can be removed rapidly by distillation (ether (b.p. 35 degrees C) and dichloromethane (b.p. 40 degrees C) are often used.

Spectroscopic / Chromatographic Methods

Once the functional group(s) in the molecule have been identified by chemical tests, chemists use spectroscopic methods in order to identify the specific compound. - IR fingerprint - Rf values in chromatography - NMR spectra

Boiling point determination, step 1

Place a small amount of the test liquid in an ignition tube and, using a rubber band, attach it to the thermometer.

Boiling point determination, step 2.

Place an empty capillary tube in the liquid, with its open end below the surface.

Recrystallisation

The aim is to make a saturated solution of the substance which requires purification by choosing a solvent in which the substance is very soluble when the solvent is hot, but in which it is very insoluble when the solvent is cold. Soluble impurities remain in the solution on cooling because they are at low concentration.

Measuring melting temperatures and boiling temperatures

Pure solids have sharp melting temperatures, but impure solids soften and melt over a range of temperatures. SO watching a solid melt can often show whether or not it is pure. As databases now include the melting temperatures of all known compounds, it is possible to check the identity and purity of a product by checking that it melts sharply at the expected temperature. Like melting temperatures for solids, boiling temperatures can be used to check the purity and identity of liquids. if a liquid is pure, it should all distill over a narrow range at the expected boiling temperature. The boiling temperature can be measured as the liquid distils over during fractional distillation.

What are the most important economic factors in designing a synthesis?

Rate, yield, cost of reagents and energy use.

Rf values in chromatography

Rf values can be used to identify the amino acids that result from the hydrolysis of proteins

Boiling point determination, step 4.

Slowly heat the water, stirring all the time. When the stream of bubbles coming out of the capillary tube is rapid and continuous, note the temperature of the water bath and stop the heating process.

Steam distillation

Some organic compounds that are virtually immiscible with water may be separated from non-volatile impurities by steam distillation. This process is essentially a co-distillation with water and is usually accomplished by passing a current of steam through a hot mixture of the material that is to be distilled with water. The product will be carried over with the steam and, being immiscible, can be readily separated from the distillate.

What does organic synthesis mean?

Synthesis means making new chemicals from simpler ones. It is very important for chemical industry , especially in pharmaceuticals, agrochemicals and polymer science. It is also a very important area of study for chemists in universities.

So in general...?

The aim is to use the minimum number of steps.

Solvent extraction example, 1-chloropentane

The compound 1-chloropentane can be prepared by adding excess PCl5 to pentan-1-ol: CH3C9H2)3CH2OH (l) + PCL5(s) --> CH3(CH2)3CH2Cl(l) + HCL(g) + POCl3(l) Phosphorus oxychloride (POCl3) has a boiling temperature of 105 degrees C, which is similar to that of 1-chloropentane at 108 degrees C, so it would not be separated by distillation of the reaction mixture. The organic compound is separated by adding ether (ethoxyethane). This solvent dissolves the 1-chloropentane but not thePOCL3. The ether solution is purified and the ether removed by distillation.

Step 3 (combinatorial chemistry)

The diesters a mixed and split into two portions, each containing all four diesters. Hydroxyacid A is added to one portion and hydroxyacid B to the other. The addition of A to the first portion results in the production of four different triesters: R-A-A-A, R-B-A-A, R-A-B-A and R-B-B-A The addition of B to the second portion results in four other triesters: R-A-A-B, R-B-A-B, R-A-B-B and R-B-B-B. Carrying out this process n times gives you a library of 2n different polyesters.

IR fingerprint

The fingerprint region of the unknown compound is checked against a database of known compounds. The unknown sample must be extremely pure.

Combustion analysis

The first step is finding the percentage composition of the substance. This is done by burning a known mass of the substance in excess air. The water is absorbed in a suitable drying agent, such as silica gel, and the carbon dioxide is absorbed by dry calcium oxide. This measures the masses of water and carbon dioxide formed. The route is then: - mass of water --> mass of hydrogen --> % hydrogen - mass of carbon dioxide --> mass of carbon --> & carbon - 100 - (% of hydrogen + % of carbon) = % oxygen. Look at the page 46 of the revision guide.

What is organic synthesis important for?

The formation of medicines, caalysts, anticeptics, and polymers.Examples of medicines are aspirin, paracetemol to relieve pain, salbutamol to prevent astham, cloramphenical to treat typhoid and levodopa to alleviate Parkinson's Disease.

Functional group

The functional group is the atom or group of atoms that give an organic compound its characteristic properties.

n.b

The funtional group in a molecule is reponsible for most of its reactions. In contrast, the carbon-carbon single bonds and carbon-hydrogen bonds are relatively unreactive, partly because they are both strong and non-polar.

Step 2 (combinatorial chemistry)

The mix is then separated into two portions, each containing both of the products of the first step. Hydroxyacid A is added to one portion, hydroxyacid B to the second. R-A + A --> R-A-A R-B-A R-A R-B + B --> R-A-B R-B-B This gives four diesters.

Solvent extraction and purification procedure, step 2.

The organic solution is often left to stand over a drying agent such as anhydrous sodium sulphate or magnesium sulphate or calcium chloride (don't normally react with the organic molecules) to remove traces of water.

Stereospecific reactions are particularly important in what?

The pharmaceutical industry, as only one stereoisomer may be active as a medicine.

Steam distillation revision guide

This is used to extract a volatile substance that is insoluble in water from a reaction mixture that contains an immscible liquid as well as a solution, e.g. phenylamine after reduction of nitrobenzene with tin and concentrated hydrochloric acid. It can also be used to extract volatile oils from natural products such as rose petals or orange peel.

Distillation revision guide

This is used to remove a volatile substance from a mixture, e.g. a carboxylic acid from sulphuric acid and chromium compounds resulting from the oxidation of a primary alcohol.

Purification of a liquid that is insoluble in water.

The product is distilled out of the reaction mixture and the following process is carried out: - The distillate is washed with sodium carbonate solution in a separating funnel. The pressure must be released from time to time to let out the carbon dioxide. This washing is repeated until no more gas is produced. This removed an acidic impurities that may be present. - The aqueous layer is discard and the organic layer washed with water. This removes any unreacted sodium salts and any double organic substances, such as ethanol. - The aqueous layer is discarded and the organic layer dried, usually with lumps of anhydrous calcium chloride. N.b solid potassium hydroxide is used to dry amines and alcohols, as they form complex ions with calcium chloride. - The organic liquid is decanted off from the drying agent and distilled, collecting the fraction that boils at +- 2 degrees C of the data-book boiling temperatures.

What is the purpose of the combinatorial chemistry technique?

The purpose of this technique in pharmaceutical research is to produce a large range of similar compounds, which then can be tested for activity as drugs.

Solvent extraction and purification procedure, step 3.

The solution is then filtered (under gravity or suction) to remove the drying agent.

Solvent extraction and purification procedure, step 4.

The solvent is removed by distillation (often using a rotary evaporator at reduced pressure) to leave the organic compound.

Stage 1, planning

The starting point of any synthesis is to choose an appropriate reaction or series of reactions as described in the previous section. The next thing to do is to work out suitable reacting quantities from the equation and decide on the conditions for reaction. An important part of the planning stage is a risk assessment. This should ensure that hazards have been identified and that appropriate safety precautions and control measures are used in order to reduce the risk during any synthesis.

Combinatorial chemistry This can be illustrated by imagining the formation of a library of polyesters made up of two hydroxide acids of formula HOCH2CH2XCOOO, symbolised by the letters A and B. X represents a group such as H, CH3 or C2H5 and resin bead is symbolised by the letter R. What is step 1

The two hydroxyacids are mixed with resin and two products are obtained: R-A R-B.

Stereospecific reactions

These are particularly important in the pharmaceutical industry, as only one stereoisomer may be active as a medicine. SN1 reactions always give a racemic mixture, but an SN2 reaction on a single enantiomer produces a single enantiomer. The addition of bromine to an alkene proceeds via a trans-addition, where one bromine atom adds on to one side of the double bond and the other to the opposite side. Thus, the addition to CH3CH=CHC2H5 gives one optical isomer, whereas, if the addition were cis, a different optical isomer would be produced.

Both pentane-3-one and pentan-2-one have boiling poitns of 102 degrees C. The compound methyl-butan-2one has a boiling point of 95 degrees C. How can you distinguish between them?

They can be distinguished by reacting them with 2,4-DNP. The solid formed is purified by recrystallisation and its melting point determined. The derivative of pentan-3-one melts at 156 degrees C, that of pentane-2-one at 144 degrees C and that of 3-methylbutanone at 123 degrees C.

Separating funnel

This is used to separate immiscible liquids. This is often used when separating an organic liquid which has been used to extract a chemical from water.

t/f: traditionally chemical tstes were used to identify functional groups in organic molecules, together with combustion and quantitative analyssi.

True, but nowaays, modern labs rely on a range of highly snesitive, automated and instrumental techniques to identify the products of synthesis. These include chromatography, mass spectrometry and various kinds of spectroscopy.

t/f: The melting point of a solid or the boiling point of a liquid may be enough to identify it.

True, if its molecular formula and functional groups are known. The melting/boiling point is determined and its value compared with a source of data.

T/F: Steam distillation is used to extract phenylamine from the reaction mixture after the reduction of nitrobenzene with Sn/conc. HCl.

True.

The percentage composition or empirical formula of an organic compound can be found by burning it in dry excess oxygen and measuring the amounts of the products formed (H2O and CO2).

True. This technique is called combustion analysis.

t/f: The addition of bromine to an alkene proceeds via a trans-addition, where one bromine atom adds on to one side of the double bond and the other to the opposite side.

True. Thus, the addition to CH3CH=CHC2H5 gives on optical isomer, whereas, if the addition were cis, a different optical isomer would be produced.

Toxicity of gases

Use a fume cupboard

Flammability of reactants or products

Use a water (or oil) bath for heating; not a naked flame

If a reactant or product is flammable...

Use a water (or oil) bath or use an electric heater. This is essential if ether is present as the solvent of the reaction mixture, as in the reduction using lithium aluminium hydride LiAl4.

COmbustion analysis

Using careful suction, draw pure dry oxygen over a heated ample of the solid organic compound. (liquid organic compounds can be burnt forom a wick.) Oass the product gases threough anhydrous calcium chloride (or anhydrous copper (II) sulfate) to absorb any water produced, and then through anhydrous soda lie (sodium hydroxide + calcium oxide) to absorb the CO2 produced.

to distinguish between primary and secondary alcohols.

Warm with potassium dichromate (VI) and then distil the product into ammoniacal silver nitrate solution. - Primary alcohols form a silver mirror - Secondary alcohols do not react so the blue colour of the reaction mixture remains.

Recrystallisation procedure, step 5:

Wash (to remove any soluble impurities) the crystals with a small quantity (so the crystals don't dissolve) of cold solvent (so the crystals don't dissolve) and suck dry.

When is heating under reflux used?

When the reaction is slow and one of the reactants is volatile.

t/f: The larger the sclae of production, the more important it is to keep the yield high so as to avoid producing large quantites of wasteful by-products.

true.

t/f: although the structural formulae of organic compounds can often be determined by combustion analysis to find their percentage composition followed by a study of their chemical reactions, structural formulae can be obtained more definitively and more precisely by spectrometry and spectroscopy.

ture.

Toxicity or corrosive nature of liquids and solids

use gloves