Topic 20: Organic Synthesis

Learning objectives

20.1Deduce the empirical formulae, molecular formulae and structural formulae from data drawn from combustion analysis, elementBe able to deduce the empirical formulae, molecular formulae and structural formulae from data drawn from combustion analysis, element percentage composition, characteristic reactions of functional groups, infrared spectra, mass spectra and NMR spectra (both 13C and proton)20.2Methods of increasing the length of the carbon chain in a molecule by the use of magnesium to form Grignard reagents andUnderstand methods of increasing the length of the carbon chain in a molecule by the use of magnesium to form Grignard reagents and the reactions of the latter with carbon dioxide and with carbonyl compounds in dry ether 20.3Knowledge of organic chemistry contained given in this specification to solve problems such as: i predicting the propertiesBe able to use knowledge of organic chemistry contained given in this specification to solve problems such as: i predicting the properties of unfamiliar compounds containing one or more of the functional groups included in the specification and explain these predictions ii planning reaction schemes of up to four steps, recalling familiar reactions and using unfamiliar reactions given sufficient information iii selecting suitable practical procedures for carrying out reactions involving compounds with functional groups included in this specification iv identifying appropriate control measures to reduce risk based on data of hazards 20.4CORE PRACTICAL 16 The preparation of aspirinCORE PRACTICAL 16 The preparation of aspirin.20.5The following techniques used in the preparation and purification of organic compounds: i refluxing ii purification byUnderstand the following techniques used in the preparation and purification of organic compounds: i refluxing ii purification by washing, including with water and sodium carbonate solution iii solvent extraction iv recrystallisation v drying vi distillation vii steam distillation viii melting temperature determination ix boiling temperature determination

Stage	Deduction
combustion	$n(\ce C)=n(\ce{CO2})$ and $n(\ce H)=2n(\ce{H2O})$ ; find oxygen by mass difference when appropriate
percentage composition	assume 100 g, convert each element mass to moles, then divide by the smallest
empirical to molecular	$k=M_r/M_{empirical}$ ; multiply every empirical subscript by the integer $k$
structural formula	propose connectivity only after the molecular formula and functional evidence are constrained

Evidence	Structural constraint
characteristic reactions	presence or absence of a functional group
IR	characteristic bonds; meaningful missing absorptions eliminate groups
mass spectrum	molecular-ion $m/z$ constrains $M_r$ ; fragments test plausible bond cleavages
$^{13}$ C NMR	number of signals gives distinct carbon environments; shifts indicate their surroundings
$^1$ H NMR	signals give proton environments, areas give ratios, shifts give surroundings, and splitting gives neighbouring non-equivalent H atoms

Work from independent constraints toward a small candidate set. Draw a candidate, predict its formula, functional tests and every spectral feature, then reject it if even one reliable observation conflicts. Equivalent atoms reduce the number of NMR environments, so signal count is not automatically atom count.

An empirical formula is only the simplest ratio, and one IR band or fragment cannot prove a complete structure. A final structural formula must account for all positive and negative evidence at once.

React a halogenoalkane or halogenoarene with magnesium in dry ether to form a Grignard reagent, $\ce{RMgX}$ . The C-Mg bond is strongly polarised, so the carbon bonded to Mg behaves as a carbon nucleophile and attacks electron-deficient carbon.

\ce{R-X + Mg ->[dry\ ether] R-MgX}

Electrophile	After reaction, then dilute acid/water	Carbon-chain result
$\ce{CO2}$	$\ce{RCOOH}$	adds one carbon
methanal	primary alcohol, $\ce{RCH2OH}$	joins R to one new carbon
another aldehyde, $\ce{R'CHO}$	secondary alcohol, $\ce{R'CH(OH)R}$	joins both carbon groups
ketone, $\ce{R'COR''}$	tertiary alcohol, $\ce{R'C(OH)(R)R''}$	joins three carbon groups at the alcohol carbon

For a carbonyl compound, nucleophilic addition first forms a magnesium alkoxide; acid hydrolysis then protonates oxygen to give the alcohol. Choose R by disconnecting the target C-C bond next to the future $\ce{OH}$ or $\ce{COOH}$ carbon.

Water, alcohols and acids protonate and destroy $\ce{RMgX}$ , so apparatus and ether must be dry and the acid work-up comes only after carbon-carbon bond formation.

Problem	Reliable move
unfamiliar properties	identify each functional group, then infer polarity, hydrogen bonding, acidity/basicity and characteristic reactions from structure
route of up to four steps	work backwards from the target; mark carbon-skeleton changes, then choose one compatible functional-group conversion per arrow
unfamiliar supplied reaction	extract its input-output bond change and conditions, then apply only that stated pattern
practical procedure	match volatility, solubility, phase and thermal stability to reflux, distillation, extraction, washing or recrystallisation
risk control	read the hazard data, identify the exposure route and reduce exposure with a specific control

After proposing a route, redraw every intermediate and audit each arrow: reagent, essential condition, product class, carbon count and selectivity. Check that a reagent does not also attack another group already present. If protection is not in the specification or supplied information, do not invent it.

Risk depends on both hazard and exposure. Prefer smaller scale or a less hazardous reagent when feasible; otherwise use a closed addition, condenser, cooling, fume cupboard or ignition control matched to the hazard, then appropriate eye/skin protection. State how the measure interrupts the exposure or runaway pathway.

A familiar end product does not validate an impossible intermediate. Each step must start from the structure actually produced by the preceding step, and the whole route must remain within four steps.

\ce{C7H6O3 + (CH3CO)2O ->[H+] C9H8O4 + CH3COOH}

Salicylic acid reacts with ethanoic anhydride to form aspirin (2-ethanoyloxybenzoic acid). A small amount of concentrated sulfuric or phosphoric acid catalyses acylation of the phenolic $\ce{-OH}$ group; the catalyst speeds the reaction without being consumed.

Mix measured reactants with the acid catalyst, controlling the initial exothermic mixing, then warm in a water bath. 2. Add crushed ice/water to destroy excess ethanoic anhydride and lower aspirin solubility. 3. Cool to crystallise, collect by suction filtration and wash with cold water. 4. Recrystallise from a minimum of hot solvent, collect and dry the purified crystals.

Check	Calculation / inference
percentage yield	$100\times$ actual dry mass ÷ theoretical mass from the limiting reagent
melting temperature	pure aspirin melts sharply near the reference value; residual salicylic acid or solvent usually broadens and lowers the range

Use eye protection and controlled addition for corrosive acid and ethanoic anhydride; avoid inhaling vapour and heat with a water bath rather than a naked flame. Dry before weighing or measuring melting temperature.

Cooling alone does not purify aspirin. Washing removes soluble surface contamination; recrystallisation separates impurities by solubility; complete drying is required for a meaningful yield and melting range.

Technique	Purpose and decisive detail
reflux	heat for a long reaction while vapour condenses back; vertical condenser is open, with cooling water entering at the bottom
washing	shake an organic layer with water to remove water-soluble impurities or with $\ce{Na2CO3(aq)}$ to neutralise acid; vent $\ce{CO2}$ pressure repeatedly
solvent extraction	transfer solute into a more favourable immiscible solvent in a separating funnel; several small extractions are effective
recrystallisation	dissolve in minimum hot solvent, hot-filter insoluble material, cool, suction-filter crystals, wash cold and dry
drying	remove traces of water from an organic liquid with a suitable anhydrous solid, then decant/filter; dry a solid in a warm oven or desiccator

Technique	Purpose and decisive detail
distillation	collect a volatile liquid by boiling and condensing it; thermometer bulb sits at the still-head entrance and the apparatus is not sealed
steam distillation	co-distil a steam-volatile, water-immiscible organic compound below its normal boiling temperature
melting temperature	a pure solid has a narrow range close to the reference value; impurity usually lowers and broadens it
boiling temperature	a pure liquid boils at a near-constant temperature close to the reference value at the stated pressure

Choose from physical properties: use extraction for unequal solubility between two liquid phases, distillation for volatility differences, steam distillation for a high-boiling steam-volatile material, and recrystallisation for temperature-dependent solid solubility.

The aqueous layer is not always the lower layer: identify layers from density or a water-drop test. Never heat a closed apparatus, and do not use a solid drying agent to dry a solid product because it would be difficult to separate.

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—Pearson Edexcel IAL ChemistryRead

Topic 20: Organic Synthesis

Learning objectives

Build one structure by making every data source agree

Grignard reagents make new carbon-carbon bonds

Solve organic synthesis as a constrained route, not a reaction list

Core Practical 16 prepares and verifies aspirin

Choose each organic technique for the separation job it performs

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