Organic chemistry and youYou are already a highly skilled organic chemist. As you read these words, your eyes are using anorganic compound (retinal) to convert visible light into nerve impulses. When you picked up thisbook, your muscles were doing chemical reactions on sugars to give you the energy you needed. Asyou understand, gaps between your brain cells are being bridged by simple organic molecules (neuro-transmitter amines) so that nerve impulses can be passed around your brain. And you did all thatwithout consciously thinking about it. You do not yet understand these processes in your mind aswell as you can carry them out in your brain and body. You are not alone there. No organic chemist,however brilliant, understands the detailed chemical working of the human mind or body very well.

We, the authors, include ourselves in this generalization, but we are going to show you in thisbook what enormous strides have been taken in the understanding of organic chemistry since thescience came into being in the early years of the nineteenth century. Organic chemistry began as atentative attempt to understand the chemistry of life. It has grown into the confident basis of vastmultinational industries that feed, clothe, and cure millions of people without their even beingaware of the role of chemistry in their lives. Chemists cooperate with physicists and mathemati-cians to understand how molecules behave and with biologists to understand how moleculesdetermine life processes. The development of these ideas is already a revelation at the beginning ofthe twenty-first century, but is far from complete. We aim not to give you the measurements of theskeleton of a dead science but to equip you to understand the conflicting demands of anadolescent one.

Like all sciences, chemistry has a unique place in our pattern of understanding of the universe. Itis the science of molecules. But organic chemistry is something more. It literally creates itself as itgrows. Of course we need to study the molecules of nature both because they are interesting in theirown right and because their functions are important to our lives. Organic chemistry often studies lifeby making new molecules that give information not available from the molecules actually present inliving things.

This creation of new molecules has given us new materials such as plastics, new dyes to colour ourclothes, new perfumes to wear, new drugs to cure diseases. Some people think that these activities areunnatural and their products dangerous or unwholesome. But these new molecules are built byhumans from other molecules found on earth using the skills inherent in our natural brains. Birdsbuild nests; man makes houses. Which is unnatural? To the organic chemist this is a meaningless dis-tinction. There are toxic compounds and nutritious ones, stable compounds and reactive onesbutthere is only one type of chemistry: it goes on both inside our brains and bodies and also in our flasksand reactors, born from the ideas in our minds and the skill in our hands. We are not going to setourselves up as moral judges in any way. We believe it is right to try and understand the world aboutus as best we can and to use that understanding creatively. This is what we want to share withyou.

Organic compoundsOrganic chemistry started as the chemistry of life, when that was thought to be different from thechemistry in the laboratory. Then it became the chemistry of carbon compounds, especially thosefound in coal. Now it is both. It is the chemistry of the compounds of carbon along with other ele-ments such as are found in living things and elsewhere.

1What is organic chemistry?

P

We are going to give youstructures of organic compoundsin this chapterotherwise itwould be rather dull. If you do notunderstand the diagrams, do notworry. Explanation is on its way.

OH

11-cis-retinalabsorbs light when we see

NH

HONH2

serotoninhuman neurotransmitter

The organic compounds available to us today are those present in living things and those formedover millions of years from dead things. In earlier times, the organic compounds known from naturewere those in the essential oils that could be distilled from plants and the alkaloids that could beextracted from crushed plants with acid. Menthol is a famous example of a flavouring compoundfrom the essential oil of spearmint and cis-jasmone an example of a perfume distilled from jasmineflowers.

Even in the sixteenth century one alkaloid was famousquinine was extracted from the bark ofthe South American cinchona tree and used to treat fevers, especially malaria. The Jesuits who didthis work (the remedy was known as Jesuits bark) did not of course know what the structure ofquinine was, but now we do.

The main reservoir of chemicals available to the nineteenth century chemists was coal. Distil-lation of coal to give gas for lighting and heating (mainly hydrogen and carbon monoxide) alsogave a brown tar rich in aromatic compounds such as benzene, pyridine, phenol, aniline, andthiophene.

Phenol was used by Lister as an antiseptic in surgery and aniline became the basis for the dyestuffsindustry. It was this that really started the search for new organic compounds made by chemistsrather than by nature. A dyestuff of this kindstill availableis Bismarck Brown, which should tellyou that much of this early work was done in Germany.

In the twentieth century oil overtook coal as the main source of bulk organic compounds so thatsimple hydrocarbons like methane (CH4, natural gas) and propane (CH3CH2CH3, calor gas)became available for fuel. At the same time chemists began the search for new molecules from newsources such as fungi, corals, and bacteria and two organic chemical industries developed in paral-lelbulk and fine chemicals. Bulk chemicals like paints and plastics are usually based on simplemolecules produced in multitonne quantities while fine chemicals such as drugs, perfumes, andflavouring materials are produced in smaller quantities but much more profitably.

At the time of writing there were about 16 million organic compounds known. How many moreare possible? There is no limit (except the number of atoms in the universe). Imagine youve justmade the longest hydrocarbon ever madeyou just have to add another carbon atom and youvemade another. This process can go on with any type of compound ad infinitum.

But these millions of compounds are not just a long list of linear hydrocarbons; they embrace allkinds of molecules with amazingly varied properties. In this chapter we offer a selection.

2 1 . What is organic chemistry?

LYou will be able to read towards theend of the book (Chapters 4951)about the extraordinary chemistry thatallows life to exist but this is knownonly from a modern cooperationbetween chemists and biologists.

LYou can read about polymers andplastics in Chapter 52 and about finechemicals throughout the book.

OH

menthol

O

cis-jasmone

N

N

MeO

HO

quinine

benzene

N

pyridine

OH

phenol

NH2

aniline

S

thiophene

NN

NN

NH2H2N H2N NH2

Bismarck Brown Y

CH3 (CH2)n CH2 CH3n = an enormous numberlength of molecule is n + 3 carbon atoms

CH3 (CH2)n CH3

n = an enormous numberlength of molecule is n + 2 carbon atoms

What do they look like? They may be crystalline solids, oils,waxes, plastics, elastics, mobile or volatile liquids, or gases.Familiar ones include white crystalline sugar, a cheap naturalcompound isolated from plants as hard white crystals when pure,and petrol, a mixture of colourless, volatile, flammable hydrocar-bons. Isooctane is a typical example and gives its name to theoctane rating of petrol.

The compounds need not lack colour. Indeed we can soondream up a rainbow of organic compounds covering the wholespectrum, not to mention black and brown. In this table we haveavoided dyestuffs and have chosen compounds as varied in struc-ture as possible.

Colour is not the only characteristic by which we recognize compounds. All too often it is theirodour that lets us know they are around. There are some quite foul organic compounds too; thesmell of the skunk is a mixture of two thiolssulfur compounds containing SH groups.

Organic compounds 3

Colour Description Compound Structure

red dark red hexagonal plates 3-methoxybenzocycloheptatriene-2-one

orange amber needles dichloro dicyano quinone (DDQ)

yellow toxic yellow explosive gas diazomethane

green green prisms with a 9-nitroso julolidinesteel-blue lustre

blue deep blue liquid with a azulenepeppery smell

purple deep blue gas condensing nitroso trifluoromethaneto a purple solid

O

MeO

CH2 N N

N

NO

O

O

CN

CNCl

Cl

CN

O

F

F

F

s

p

e

c

t

r

u

m

SH SH+

skunk spray contains:

volatile inflammable liquidwhite crystalline solid

O

O

HOHO

HOHO

O

OH

HO

HO

OHCH3

CCH2

CHCH3

CH3CH3

CH3

sucrose ordinary sugarisolated from sugar cane

or sugar beet

isooctane (2,3,5-trimethylpentane)a major constiuent of petrol

But perhaps the worst aroma was that which caused the evacuation of the city of Freiburg in 1889.Attempts to make thioacetone by the cracking of trithioacetone gave rise to an offensive smell whichspread rapidly over a great area of the town causing fainting, vomiting and a panic evacuationthelaboratory work was abandoned.

It was perhaps foolhardy for workers at an Esso research station to repeat the experiment of crack-ing trithioacetone south of Oxford in 1967. Let them take up the story. Recentlywe found ourselveswith an odour problem beyond our worst expectations. During early experiments, a stopper jumpedfrom a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nau-sea and sickness from colleagues working in a building two hundred yards away. Two of ourchemists who had done no more than investigate the cracking of minute amounts of trithioace-tonefound themselves the object of hostile stares in a restaurant and suffered the humiliation ofhaving a waitress spray the area around them with a deodorant. The odours defied the expectedeffects of dilution since workers in the laboratory did not find the odours intolerable . . . and genu-inely denied responsibility since they were working in closed systems. To convince them otherwise,they were dispersed with other observers around the laboratory, at distances up to a quarter of amile, and one drop of either acetone gem-dithiol or the mother liquors from crude trithioacetonecrystallisations were placed on a watch glass in a fume cupboard. The odour was detected downwindin seconds.

There are two candidates for this dreadful smellpropane dithiol (called acetone gem-dithiolabove) or 4-methyl-4-sulfanylpentan-2-one. It is unlikely that anyone else will be brave enough toresolve the controversy.

Nasty smells have their uses. The natural gas piped to our homes contains small amounts of delib-erately added sulfur compounds such as tert-butyl thiol (CH3)3CSH. When we say small, we meanvery smallhumans can detect one part in 50 000 000 000 parts of natural gas.

Other compounds have delightful odours. To redeem the honour of sulfur compounds we mustcite the truffle which pigs can smell through a metre of soil and whose taste and smell is so delightfulthat truffles cost more than their weight in gold. Damascenones are responsible for the smell of roses.If you smell one drop you will be disappointed, as it smells rather like turpentine or camphor, butnext morning you and the clothes you were wearing will smell powerfully of roses. Just like the com-pounds from trithioacetone, this smell develops on dilution.

Humans are not the only creatures with a sense of smell. We can find mates using our eyes alone(though smell does play a part) but insects cannot do this. They are small in a crowded world andthey find others of their own species and the opposite sex by smell. Most insects produce volatilecompounds that can be picked up by a potential mate in incredibly weak concentrations. Only 1.5mg of serricornin, the sex pheromone of the cigarette beetle, could be isolated from 65 000 femalebeetlesso there isnt much in each beetle. Nevertheless, the slightest whiff of it causes the males togather and attempt frenzied copulation.

The sex pheromone of the Japanese beetle, also given off by the females, has been made bychemists. As little as 5 g (micrograms, note!) was more effective than four virgin females in attract-ing the males.

The pheromone of the gypsy moth, disparlure, was identified from a few g isolated from themoths and only 10 g of synthetic material. As little as 2 1012 g is active as a lure for the males infield tests. The three pheromones we have mentioned are available commercially for the specifictrapping of these destructive insect pests.

4 1 . What is organic chemistry?

S

S S

S

thioacetone

trithioacetone;Freiburg was evacuatedbecause of a smell fromthe distillation this compound

?

HS SH HSO

propane dithiol

4-methyl-4-sulfanylpentan-

2-one

two candidates forthe worst smell in the world

no-one wants to find the winner!

CH3S S

CH3

O

damascenone - the smell of roses

the divine smellof the black truffle

comes from this compound

OH OO

O

Hserricornin

the sex pheromone of the cigarette beetleLasioderma serricorne

japonilure

the sex pheromone of the Japanese beetlePopilia japonica

Dont suppose that the females always do all the work; bothmale and female olive flies produce pheromones that attract theother sex. The remarkable thing is that one mirror image ofthe molecule attracts the males while the other attracts thefemales!

What about taste? Take the grapefruit. The main flavour comes from another sulfur compoundand human beings can detect 2 105 parts per billion of this compound. This is an almost unimag-inably small amount equal to 104 mg per tonne or a drop, not in a bucket, but in a good-sized lake.Why evolution should have left us abnormally sensitive to grapefruit, we leave you to imagine.

For a nasty taste, we should mention bittering agents, put into dangerous household substanceslike toilet cleaner to stop children eating them by accident. Notice that this complex organic com-pound is actually a saltit has positively charged nitrogen and negatively charged oxygen atomsand this makes it soluble in water.

Other organic compounds have strange effects on humans. Various drugs suchas alcohol and cocaine are taken in various ways to make people temporarily happy.They have their dangers. Too much alcohol leads to a lot of misery and any cocaineat all may make you a slave for life.

Again, lets not forget other creatures. Cats seem to be able to go to sleep at anytime and recently a compound was isolated from the cerebrospinal fluid of cats that makes them, orrats, or humans go off to sleep quickly. It is a surprisingly simple compound.

This compound and disparlure are both derivatives of fattyacids, molecules that feature in many of the food problems peopleare so interested in now (and rightly so). Fatty acids in the diet area popular preoccupation and the good and bad qualities of satu-rates, monounsaturates, and polyunsaturates are continually inthe news. This too is organic chemistry. One of the latest mole-cules to be recognized as an anticancer agent in our diet is CLA(conjugated linoleic acid) in dairy products.

Organic compounds 5

Odisparlure

th h f th G th

disparlure

the sex pheromone of the Gypsy mothPortheria dispar

O

O

olean

sex pheromone of the olive flyBacrocera oleae

O

O

O

O

this mirror image isomerattracts the males

this mirror image isomerattracts the females

HS

flavouring principle of grapefruit

HN

N

O

O

O

benzyldiethyl[(2,6-xylylcarbamoyl)methyl]ammonium benzoate

bitrexdenatonium benzoate

CH3 OHalcohol

(ethanol)

NCH3

CO2Me

O

O

cocaine- an addictive alkaloid

a sleep-inducing fatty acid derivative

O

NH2

cis-9,10-octadecenoamide

cis-9-trans-11 conjugated linoleic acidCLA (Conjugated Linoleic Acid)

O

OH

18

10

9

111

12

dietary anticancer agent

Another fashionable molecule is resveratrole, which maybe responsible for the beneficial effects of red wine in pre-venting heart disease. It is a quite different organic com-pound with two benzene rings and you can read about it inChapter 51.

For our third edible molecule we choose vitamin C. This isan essential factor in our dietsindeed, that is why it is calleda vitamin. The disease scurvy, a degeneration of soft tissues,particularly in the mouth, from which sailors on long voyageslike those of Columbus suffered, results if we dont have vitamin C. It also is a universal antioxidant,scavenging for rogue free radicals and so protecting us against cancer. Some people think an extralarge intake protects us against the common cold, but this is not yet proved.

Organic chemistry and industryVitamin C is manufactured on a huge scale by Roche, a Swiss company. All over the world there arechemistry-based companies making organic molecules on scales varying from a few kilograms tothousands of tonnes per year. This is good news for students of organic chemistry; there are lots ofjobs around and it is an international job market. The scale of some of these operations of organicchemistry is almost incredible. The petrochemicals industry processes (and we use the products!)over 10 million litres of crude oil every day. Much of this is just burnt in vehicles as petrol or diesel,but some of it is purified or converted into organic compounds for use in the rest of the chemicalindustry. Multinational companies with thousands of employees such as Esso (Exxon) and Shelldominate this sector.

Some simple compounds are made both from oil and from plants. The ethanol used as a startingmaterial to make other compounds in industry is largely made by the catalytic hydration of ethylenefrom oil. But ethanol is also used as a fuel, particularly in Brazil where it is made by fermentation ofsugar cane wastes. This fuel uses a waste product, saves on oil imports, and has improved the qualityof the air in the very large Brazilian cities, Rio de Janeiro and So Paulo.

Plastics and polymers take much of the production of the petro-chemical industry in the form of monomers such as styrene, acry-lates, and vinyl chloride. The products of this enormous industry areeverything made of plastic including solid plastics for householdgoods and furniture, fibres for clothes (24 million tonnes perannum), elastic polymers for car tyres, light bubble-filled polymersfor packing, and so on. Companies such as BASF, Dupont, Amoco,Monsanto, Laporte, Hoechst, and ICI are leaders here. Worldwidepolymer production approaches 100 million tonnes per annum andPVC manufacture alone employs over 50 000 people to make over 20million tonnes per annum.

The washing-up bowl is plastic too but the detergent you put in it belongs to another branch ofthe chemical industrycompanies like Unilever (Britain) or Procter and Gamble (USA) whichproduce soap, detergent, cleaners, bleaches,polishes, and all the many essentials for themodern home. These products may be lemonand lavender scented but they too mostly comefrom the oil industry. Nowadays, most pro-ducts of this kind tell us, after a fashion, what is inthem. Try this examplea well known brand ofshaving gel along with the list of contents on thecontainer:

Does any of this make any sense?

6 1 . What is organic chemistry?

P

Vitamin C (ascorbic acid) is avitamin for primates, guinea-pigs,and fruit bats, but other mammalscan make it for themselves.

is this the compound in red winewhich helps to prevent heart disease?

OH

HO

OH

resveratrole from the skins of grapes

OHO

HO OH

O

OHH

vitamin C (ascorbic acid)

X

OCl

monomers for polymer manufacture

styrene

acrylates vinyl chloride

Ingredientsaqua, palmitic acid,

triethanolamine,glycereth-26, isopentane,oleamide-DEA, oleth-2,stearic acid, isobutane,

PEG-14M, parfum,allantoin,

hydroxyethyl-cellulose,hydroxypropyl-cellulose,

PEG-150 distearate, CI 42053, CI 47005

It doesnt all make sense to us, but here is a possible interpretation. We certainly hope the bookwill set you on the path of understanding the sense (and the nonsense!) of this sort of thing.

The particular acids, bases, surfactants, and so on are chosen to blend together in a smooth emul-sion when propelled from the can. The result should feel, smell, and look attractive and a greenishcolour is considered clean and antiseptic by the customer. What the can actually says is this:Superior lubricants within the gel prepare the skin for an exceptionally close, comfortable and effec-tive shave. It contains added moisturisers to help protect the skin from razor burn. Lightlyfragranced.

Organic chemistry and industry 7

Ingredient Chemical meaning Purposeaqua water solvent

palmitic acid CH3(CH2)14CO2H acid, emulsifier

triethanolamine N(CH2CH2OH)3 base

glycereth-26 glyceryl(OCH2CH2)26OH surfactant

isopentane (CH3)2CHCH2CH3 propellant

oleamide-DEA CH3(CH2)7CH=CH(CH2)7CONEt2

oleth-2 Oleyl(OCH2CH2)2OH surfactant

stearic acid CH3(CH2)16CO2H acid, emulsifier

isobutane (CH3)2CHCH3 propellant

PEG-14M polyoxyethylene glycol ester surfactant

parfum perfume

allantoin promotes healing incase you cutyourself while shaving

hydroxyethyl-cellulose cellulose fibre from wood pulp gives bodywith OCH2CH2OH groups added

hydroxypropyl-cellulose cellulose fibre from wood pulp gives bodywith OCH2CH(OH)CH3 groups added

PEG-150 distearate polyoxyethylene glycol diester surfactant

CI 42053 Fast Green FCF (see box) green dye

CI 47005 Quinoline Yellow (see box) yellow dye

NH

NH

HNH2N

O O

allantoin

The structures of two dyes

Fast Green FCF and Quinoline Yellow are colours permitted to be used in foods and cosmetics and have the structuresshown here. Quinoline Yellow is a mixture of isomeric sulfonic acids in the two rings shown.

N

OH

O

SO2OHHOO2S

Quinoline Yellow

N N

Et Et

OO2S

SO2O

OH

SO2O

2Na

Fast Green FCF

Another oil-derived class of organic chemical business includes adhesives, sealants, coatings, andso on, with companies like CibaGeigy, Dow, Monsanto, and Laporte in the lead. Nowadays aircraftare glued together with epoxy-resins and you can glue almost anything with Superglue a polymer ofmethyl cyanoacrylate.

There is a big market for intense colours for dyeing cloth, colouring plastic and paper, paintingwalls, and so on. This is the dyestuffs and pigments industry and leaders here are companies like ICIand Akzo Nobel. ICI have a large stake in this aspect of the business, their paints turnover alonebeing 2 003 000 000 in 1995.

The most famous dyestuff is probably indigo, an ancient dye that used to be isolated from plantsbut is now made chemically. It is the colour of blue jeans. More modern dyestuffs can be representedby ICIs benzodifuranones, which give fashionable red colours to synthetic fabrics like polyesters.

We see one type of pigment around us all the time in the form of the colours on plastic bags.Among the best compounds for these are the metal complexes called phthalocyanines. Changing themetal (Cu and Fe are popular) at the centre and the halogens round the edge of these moleculeschanges the colour but blues and green predominate. The metal atom is not necessary for intensepigment coloursone new class of intense high performance pigments in the orangered range arethe DPP (1,4-diketopyrrolo[3,4-c]pyrroles) series developed by CibaGeigy. Pigment Red 254 isused in paints and plastics.

Colour photography starts with inorganic silver halides but they are carried on organic gelatin.Light acts on silver halides to give silver atoms that form the photographic image, but only in blackand white. The colour in films like Kodachrome then comes from the coupling of two colourlessorganic compounds. One, usually an aromatic amine, is oxidized and couples with the other to give acoloured compound.

8 1 . What is organic chemistry?

OCH3

CN

OSuperglue bonds things together

when this small molecule joins up with hundreds of its fellows

in a polymerization reaction

LThe formation of polymers is discussedin Chapter 52.

the colour of blue jeans

NH

HN

O

O

indigo

OO

O

O

OR

OR

ICIs Dispersolbenzodifuranonered dyes for polyester

N

N

N

N

N

N

NN Cu

Cl

ClCl

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

ICIs Monastral Green GNAa good green for plastic objects

NHHN

O

O

Cl

Cl

Ciba Geigys Pigment Red 254an intense DPP pigment

LYou can read in Chapter 7 why somecompounds are coloured and othersnot.

HN

N

HN

O

R

OPh

SO2ON

N

O

R

OPh

SO2ONEt2

NH

NEt2colourless cyclic amide

Na

Na

magenta pigment from two colourless compounds

NEt2

NH2

colourlessaromatic amine

light, silver

photographic developer

That brings us to flavours and fragrances. Companies like International Flavours and Fragrances(USA) or GivaudanRoure (Swiss) produce very big ranges of fine chemicals for the perfume, cos-metic, and food industries. Many of these will come from oil but others come from plant sources. Atypical perfume will contain 510% fragrances in an ethanol/water (about 90:10) mixture. So theperfumery industry needs a very large amount of ethanol and, you might think, not much perfumerymaterial. In fact, important fragrances like jasmine are produced on a >10 000 tonnes per annumscale. The cost of a pure perfume ingredient like cis-jasmone, the main ingredient of jasmine, may beseveral hundred pounds, dollars, or euros per gram.

Chemists produce synthetic flavourings such as smoky bacon and even chocolate. Meatyflavours come from simple heterocycles such as alkyl pyrazines (present in coffee as well as roastmeat) and furonol, originally found in pineapples. Compounds such as corylone and maltol givecaramel and meaty flavours. Mixtures of these and other synthetic compounds can be tuned to tastelike many roasted foods from fresh bread to coffee and barbecued meat.

Some flavouring compounds are also perfumes and may also be used as an intermediate inmaking other compounds. Two such large-scale flavouring compounds are vanillin (vanilla flavouras in ice cream) and menthol (mint flavour) both manufactured on a large scale and with manyuses.

Food chemistry includes much larger-scale items than flavours. Sweeteners such as sugar itself areisolated from plants on an enormous scale. Sugars structure appeared a few pages back. Othersweeteners such as saccharin (discovered in 1879!) and aspartame (1965) are made on a sizeablescale. Aspartame is a compound of two of the natural amino acids present in all living things and ismade by Monsanto on a large scale (over 10 000 tonnes per annum).

Organic chemistry and industry 9

O

The world of perfumery

Perfume chemists use extraordinary language to describetheir achievements: Paco Rabanne pour homme wascreated to reproduce the effect of a summer walk in theopen air among the hills of Provence: the smell of herbs,rosemary and thyme, and sparkling freshness with coolsea breezes mingling with warm soft Alpine air. To

achieve the required effect, the perfumer blendedherbaceous oils with woody accords and the syntheticaroma chemical dimethylheptanol which has apenetrating but indefinable freshness associated withopen air or freshly washed linen. (J. Ayres, Chemistry andIndustry, 1988, 579)

cis-jasmonethe main compoundin jasmine perfume

roast meat

N

N

an alkyl pyrazinefrom coffee and

and biscuits

O

O

HO

maltolE-636 for cakes

roasted taste

OHO

corylonecaramelfuronol

O

OHO

roast meat

on a large scale

H

O

HO

CH3OOH

mentholextracted from mint;25% of the worlds supplymanufactured

vanillinfound in vanilla pods;

manufactured

H2N

HN

OCH3

O

OCO2H

H2N

HN

OCH3

O

OCO2H

asparticacid

methyl ester ofphenylalanine

aspartame (NutraSweet)200 sweeter than sugar

is made fromtwo amino acids

The pharmaceutical businesses produce drugs and medicinal products of many kinds. One of thegreat revolutions of modern life has been the expectation that humans will survive diseases becauseof a treatment designed to deal specifically with that disease. The most successful drug ever is raniti-dine (Zantac), the GlaxoWellcome ulcer treatment, and one of the fastest-growing is Pfizers silde-nafil (Viagra). Success refers both to human health and to profit!

You will know people (probably older men) who are on -blockers. These are com-pounds designed to block the effects of adrenaline (epinephrine) on the heart and hence toprevent heart disease. One of the best is Zenecas tenormin. Preventing high blood pressure also pre-vents heart disease and certain specific enzyme inhibitors (called ACE-inhibitors) such asSquibbs captopril work in this way. These are drugs that imitate substances naturally present in thebody.

The treatment of infectious diseases relies on antibiotics such as the penicillins to prevent bacteriafrom multiplying. One of the most successful of these is Smith Kline Beechams amoxycillin. Thefour-membered ring at the heart of the molecule is the -lactam.

We cannot maintain our present high density of population in the developed world, nor deal withmalnutrition in the developing world unless we preserve our food supply from attacks by insects andfungi and from competition by weeds. The world market for agrochemicals is over 10 000 000 000per annum divided roughly equally between herbicides, fungicides, and insecticides.

At the moment we hold our own by the use of agrochemicals: companies such as Rhne-Poulenc, Zeneca, BASF, ScheringPlough, and Dow produce compounds of remarkable and specificactivity. The most famous modern insecticides are modelled on the natural pyrethrins, stabilizedagainst degradation by sunlight by chemical modification (see coloured portions of decamethrin)and targeted to specific insects on specific crops in cooperation with biologists. Decamethrin has asafety factor of >10#000 for mustard beetles over mammals, can be applied at only 10 grams perhectare (about one level tablespoon per football pitch), and leaves no significant environmentalresidue.

10 1 . What is organic chemistry?

Glaxo-Wellcomes ranitidinethe most successful drug to date

world wide sales peaked >1,000,000,000 per annum

OMe2N S

NH

NHMe

NO2

three million satisfied customers in 1998Pfizers sildenafil (Viagra)

SN

O O

NMeEtO

N

NHN

NMe

Othree million satisfied customers in 1998

Pfizers sildenafil (Viagra)O

of heart disease

OHN

OH

Zenecas tenormincardioselective -blocker

for treatment and preventionprevention of hypertension

HS N

O CO2H

Squibbs captoprilspecific enzyme inhibitor

for treatment andfor treatment of bacterial infections

HO

HN

N

SH H

CO2HO

NH2

O

SmithKline Beechams amoxycillin-lactam antibiotic

O

O O

O

Br

Br

O

O

O

CN

decamethrina modified pyrethrin - more active and stable in sunlight

a natural pyrethinfrom pyrethrum - daisy-like flowers from East Africa

As you learn more chemistry, you will appreciate how remarkable it is that Nature should pro-duce three-membered rings and that chemists should use them in bulk compounds to be sprayed oncrops in fields. Even more remarkable in some ways is the new generation of fungicides based on afive-membered ring containing three nitrogen atomsthe triazole ring. These compounds inhibitan enzyme present in fungi but not in plants or animals.

One fungus (potato blight) caused the Irish potato famine of the nineteenth century and the vari-ous blights, blotches, rots, rusts, smuts, and mildews can overwhelm any crop in a short time.Especially now that so much is grown in Western Europe in winter, fungal diseases are a realthreat.

You will have noticed that some of these companies have fingers in many pies. These companies,or groups as they should be called, are the real giants of organic chemistry. RhnePoulenc, theFrench group which includes pharmaceuticals (RhnePoulencRorer), animal health, agrochemi-cals, chemicals, fibres, and polymers, had sales of about 90 billion French Francs in 1996. Dow, theUS group which includes chemicals, plastics, hydrocarbons, and other bulk chemicals, had sales ofabout 20 billion US dollars in 1996.

Organic chemistry and the periodic tableAll the compounds we have shown you are built up on hydrocarbon (carbon and hydrogen) skele-tons. Most have oxygen and/or nitrogen as well; some have sulfur and some phosphorus. These arethe main elements of organic chemistry but another way the science has developed is an explorationof (some would say take-over bid for) the rest of the periodic table. Some of our compounds also hadfluorine, sodium, copper, chlorine, and bromine. The organic chemistry of silicon, boron, lithium,the halogens (F, Cl, Br, and I), tin, copper, and palladium has been particularly well studied andthese elements commonly form part of organic reagents used in the laboratory. They will crop upthroughout this book. These lesser elements appear in many important reagents, which are used inorganic chemical laboratories all over the world. Butyllithium, trimethylsilyl chloride, tributyltinhydride, and dimethylcopper lithium are good examples.

The halogens also appear in many life-saving drugs. The recently discovered antiviral com-pounds, such as fialuridine (which contains both F and I, as well as N and O), are essential for thefight against HIV and AIDS. They are modelled on natural compounds from nucleic acids. Thenaturally occurring cytotoxic (antitumour) agent halomon, extracted from red algae, contains Brand Cl.

Another definition of organic chemistry would use the periodic table. The key elements inorganic chemistry are of course C, H, N, and O, but also important are the halogens (F, Cl. Br, I),

Organic chemistry and the periodic table 11

N

N

NHO

N

CO2Me

H NN

NOO

Cl Cl

propiconazolea triazole fungicidemany plant diseases

benomyla fungicide which controls

Li

BuLi

butyllithium

Si ClCH3

CH3

CH3

trimethylsilyl chloride

Me3SiCl

Sn HC4H9

C4H9

C4H9

tributyltin hydride

Bu3SnH

CH3Cu

CH3

Li

dimethylcopper lithium

Me2CuLi

N

NH

OHO

FHO

I

O

O

antitumour agent

Cl

Cl

Cl

Br

Br

halomonnaturally occurring antiviral compound

fialuridine

p-block elements such as Si, S, and P, metals such as Li, Pd, Cu, and Hg, and many more. We canconstruct an organic chemists periodic table with the most important elements emphasized:

So where does inorganic chemistry end and organic chemistry begin? Would you say thatthe antiviral compound foscarnet was organic? It is a compound of carbon with the formulaCPO5Na3 but is has no CH bonds. And what about the important reagent tetrakis triphenyl phos-phine palladium? It has lots of hydrocarbontwelve benzene rings in factbut the benzene rings areall joined to phosphorus atoms that are arranged in a square around the central palladium atom, sothe molecule is held together by CP and PPd bonds, not by a hydrocarbon skeleton. Although it hasthe very organic-looking formula C72H60P4Pd, many people would say it is inorganic. But is it?

The answer is that we dont know and we dont care. It is important these days to realize thatstrict boundaries between traditional disciplines are undesirable and meaningless. Chemistrycontinues across the old boundaries between organic chemistry and inorganic chemistry on the oneside and organic chemistry and biochemistry on the other. Be glad that the boundaries are indistinctas that means the chemistry is all the richer. This lovely molecule (Ph3P)4Pd belongs to chemistry.

12 1 . What is organic chemistry?

P

You will certainly know somethingabout the periodic table from yourprevious studies of inorganicchemistry. A basic knowledge ofthe groups, which elements aremetals, and roughly where theelements in our table appear willbe helpful to you.

Li CB N O F

Si P S Cl

Br

I

Mg Al

Se

Na

K Ti Cr Cu Zn

Pd Sn

Os Hg

Hthe organic chemist's

periodic table

1

2

3 4 5 6 7 8 9 10 11 12

13 14 15 16 17

P O

O

OO

O Na3

foscarnet antiviral agent

P

P P

PPd

[(C6H5)3P]4Pd(Ph3P)4Pd

tetrakistriphenylphosphinepalladium

We have told you about organic chemistrys history, the types of compounds it concerns itself with, thethings it makes, and the elements it uses. Organic chemistry today is the study of the structure and reac-tions of compounds in nature of compounds, in the fossil reserves such as coal and oil, and of thosecompounds that can be made from them. These compounds will usually be constructed with a hydro-carbon framework but will also often have atoms such as O, N, S, P, Si, B, halogens, and metals attachedto them. Organic chemistry is used in the making of plastics, paints, dyestuffs, clothes, foodstuffs,human and veterinary medicines, agrochemicals, and many other things. Now we can summarize all ofthese in a different way.

This book is about all these things. It tells you about the structures of organic molecules and thereasons behind them. It tells you about the shapes of those molecules and how the shape relates totheir function, especially in the context of biology. It tells you how those structures and shapes arediscovered. It tells you about the reactions the molecules undergo and, more importantly, how andwhy they behave in the way they do. It tells you about nature and about industry. It tells you howmolecules are made and how you too can think about making molecules.

We said it tells in that last paragraph. Maybe we should have said we tell because we want tospeak to you through our words so that you can see how we think about organic chemistry and toencourage you to develop your own ideas. We expect you to notice that four people have written thisbook and that they dont all think or write in the same way. That is as it should be. Organic chemistryis too big and important a subject to be restricted by dogmatic rules. Different chemists think in dif-ferent ways about many aspects of organic chemistry and in many cases it is not yet possible to besure who is right.

We may refer to the history of chemistry from time to time but we are usually going to tell you aboutorganic chemistry as it is now. We will develop the ideas slowly, from simple and fundamental onesusing small molecules to complex ideas and large molecules. We promise one thing. We are not goingto pull the wool over your eyes by making things artificially simple and avoiding the awkward ques-tions. We aim to be honest and share both our delight in good complete explanations and our puzzle-ment at inadequate ones. So how are we going to do this? The book starts with a series of chapters onthe structures and reactions of simple molecules. You will meet the way structures are determined andthe theory that explains those structures. It is vital that you realize that theory is used to explain what isknown by experiment and only then to predict what is unknown. You will meet mechanismsthedynamic language used by chemists to talk about reactionsand of course some reactions.

Organic chemistry and this book

The main components of organic chemistry as a discipline are these Structure determinationhow to find out the structures of new compounds

even if they are available only in invisibly small amounts

Theoretical organic chemistryhow to understand those structures in termsof atoms and the electrons that bind them together

Reaction mechanismshow to find out how these molecules react with eachother and how to predict their reactions

Synthesishow to design new moleculesand then make them Biological chemistryhow to find out what Nature does and how the

structures of biologically active molecules are related to what they do

The book starts with an introductory section of four chapters:

1 What is organic chemistry?

2 Organic structures

3 Determining organic structures

4 Structure of molecules

In Chapter 2 you will look at the way in which we are going to present diagrams of moleculeson the printed page. Organic chemistry is a visual, three-dimensional subject and the way youdraw molecules shows how you think about them. We want you too to draw molecules in the best wayavailable now. It is just as easy to draw them well as to draw them in an old-fashioned inaccurate way.

Then in Chapter 3, before we come to the theory of molecular structure, we shall introduce you tothe experimental techniques of finding out about molecular structure. This means studying theinteractions between molecules and radiation by spectroscopyusing the whole electromagneticspectrum from X-rays to radio waves. Only then, in Chapter 4, will we go behind the scenes and lookat the theories of why atoms combine in the ways they do. Experiment comes before theory. Thespectroscopic methods of Chapter 3 will still be telling the truth in a hundred years time, but the the-ories of Chapter 4 will look quite dated by then.

We could have titled those three chapters:

2 What shapes do organic molecules have?

3 How do we know they have those shapes?

4 Why do they have those shapes?

You need to have a grasp of the answers to these three questions before you start the study oforganic reactions. That is exactly what happens next. We introduce organic reaction mechanisms inChapter 5. Any kind of chemistry studies reactionsthe transformations of molecules into othermolecules. The dynamic process by which this happens is called mechanism and is the language oforganic chemistry. We want you to start learning and using this language straight away so in Chapter6 we apply it to one important class of reaction. This section is:

5 Organic reactions

6 Nucleophilic addition to the carbonyl group

Chapter 6 reveals how we are going to subdivide organic chemistry. We shall use a mechanisticclassification rather than a structural classification and explain one type of reaction rather than onetype of compound in each chapter. In the rest of the book most of the chapters describe types of reac-tion in a mechanistic way. Here is a selection.

9 Using organometallic reagents to make CC bonds

17 Nucleophilic substitution at saturated carbon

20 Electrophilic addition to alkenes

22 Electrophilic aromatic substitution

29 Conjugate Michael addition of enolates

39 Radicals

Interspersed with these chapters are others on physical aspects, organic synthesis, stereochem-istry, structural determination, and biological chemistry as all these topics are important parts oforganic chemistry.

Connections sectionChemistry is not a linear subject! It is impossible simply to start at the beginning and work throughto the end, introducing one new topic at a time, because chemistry is a network of interconnectingideas. But, unfortunately, a book is, by nature, a beginning-to-end sort of thing. We have arrangedthe chapters in a progression of difficulty as far as is possible, but to help you find your way around

14 1 . Organic chemistry and this book

we have included at the beginning of each chapter a Connections section. This tells you three thingsdivided among three columns:

(a) what you should be familiar with before reading the chapterin other words, which previouschapters relate directly to the material within the chapter (Building on column)

(b) a guide to what you will find within the chapter (Arriving at column)

(c) which chapters later in the book fill out and expand the material in the chapter (Lookingforward to column)

The first time you read a chapter, you should really make sure you have read any chapter mentionedunder (a). When you become more familiar with the book you will find that the links highlighted in(a) and (c) will help you see how chemistry interconnects with itself.

Boxes and margin notesThe other things you should look out for are the margin notes and boxes. There are four sorts, andthey have all appeared at least once in this chapter.

End-of-chapter problemsYou cant learn organic chemistrytheres just too much of it. You can learn trivial thingslike the names of compounds but that doesnt help you understand the principles behind thesubject. You have to understand the principles because the only way to tackle organic chemistryis to learn to work it out. That is why we have provided end-of-chapter problems. They areto help you discover if you have understood the material presented in each chapter. In general,the 1015 problems at the end of each chapter start easy and get more difficult. They comein two sorts. The first, generally shorter and easier, allow you to revise the material in that chap-ter. The second asks you to extend your understanding of the material into areas not coveredby the chapter. In the later chapters this second sort will probably revise material from previouschapters.

If a chapter is about a certain type of organic reaction, say elimination reactions (Chapter 19), thechapter itself will describe the various ways (mechanisms) by which the reaction can occur and itwill give definitive examples of each mechanism. In Chapter 19 there are three mechanisms andabout 65 examples altogether. You might think that this is rather a lot but there are in fact millions ofexamples known of these three mechanisms and Chapter 19 only scrapes the surface. Even if youtotally comprehended the chapter at a first reading, you could not be confident of your understand-ing about elimination reactions. There are 13 end-of-chapter problems for Chapter 19. The firstthree ask you to interpret reactions given but not explained in the chapter. This checks that you canuse the ideas in familiar situations. The next few problems develop specific ideas from the chapterconcerned with why one compound does one reaction while a similar one behaves quite differently.

Boxes and margin notes 15

HeadingThe most important looks like this. Anything in this sort of box is veryimportanta key concept or a summary. Its the sort of thing you would do well tohold in your mind as you read or to note down as you learn.

P

Sometimes the main text of thebook needs clarification orexpansion, and this sort of marginnote will contain such little extrasto help you understand difficultpoints. It will also remind you ofthings from elsewhere in the bookthat illuminate what is beingdiscussed. You would do well toread these notes the first timeyou read the chapter, thoughlater, as the ideas become morefamiliar, you might choose to skipthem.

Heading

Boxes like this will contain additional examples, amusingbackground information, and similar interesting, butinessential, material. The first time you read a chapter,

you might want to miss out this sort of box, and only readthem later on to flesh out some of the main themes of thechapter.

L

This sort of margin note will mainlycontain cross-references to otherparts of the book as a further aid tonavigation. You will find an exampleon p. 000.

Finally there are some more challenging problems asking you to extend the ideas to unfamiliarmolecules.

The end-of-chapter problems should set you on your way but they are not the end of the journeyto understanding. You are probably reading this text as part of a university course and you shouldfind out what kind of examination problems your university uses and practise them too. Your tutorwill be able to advise you on suitable problems for each stage of your development.

The solutions manualThe problems would be of little use to you if you could not check your answers. For themaximum benefit, you need to tackle some or all of the problems as soon as you have finishedeach chapter without looking at the answers. Then you need to compare your suggestions withours. You can do this with the solutions manual (Organic Chemistry: Solutions Manual, OxfordUniversity Press, 2000). Each problem is discussed in some detail. The purpose of the problemis first stated or explained. Then, if the problem is a simple one, the answer is given. If the prob-lem is more complex, a discussion of possible answers follows with some comments on the valueof each. There may be a reference to the source of the problem so that you can read further if youwish.

ColourYou will already have noticed something unusual about this book: almost all of the chemical struc-tures are shown in red. This is quite intentional: emphatic red underlines the message that structuresare more important than words in organic chemistry. But sometimes small parts of structures are inother colours: here are two examples from p. 000, where we were talking about organic compoundscontaining elements other than C and H.

Why are the atom labels black? Because we wanted them to stand out from the rest of themolecule. In general you will see black used to highlight important details of a moleculethey maybe the groups taking part in a reaction, or something that has changed as a result of the reaction, as inthese examples from Chapters 9 and 12.

We shall often use black to emphasize curly arrows, devices that show the movement of elec-trons, and whose use you will learn about in Chapter 5. Here is an example from Chapter 10: noticeblack also helps the + and charges to stand out.

16 1 . Organic chemistry and this book

N

NH

OHO

FHO

I

O

O

Cl

Cl

Cl

Br

Br

fialuridineantiviral compound

Halomonnaturally occurring antitumour agent

O

MgBrHO

1.

new CC bond2. H+, H2O

O HO

1. EtMgBr

2. H3O+

Me

O

Me Me

H

CN

O

CN CN

O

Occasionally, we shall use other colours such as green, or even orange, yellow, or brown, to high-light points of secondary importance. This example is part of a reaction taken from Chapter 19: wewant to show that a molecule of water (H2O) is formed. The green atoms show where the watercomes from. Notice black curly arrows and a new black bond.

Other colours come in when things get more complicatedin this Chapter 24 example, we wantto show a reaction happening at the black group in the presence of the yellow H (which, as you willsee in Chapter 9, also reacts) and also in the presence of the green protecting groups, one of thetopics of Chapter 24.

And, in Chapter 16, colour helps us highlight the difference between carbon atoms carrying fourdifferent groups and those with only three different groups. The message is: if you see something in acolour other than red, take special notethe colour is there for a reason.

That is all we shall say in the way of introduction. On the next page the real chemistry starts, andour intention is to help you to learn real chemistry, and to enjoy it.

Colour 17

NN

O

N

H

N

OHHH H

HH

H2O+

new C=Cdouble bond

MeO2C

BnO

OH

N

Ph

BnO

OH

N

Ph

HO

(excess)

MeMgBr

CO2HR

H NH2

CO2HH

HNH21

2

4amino acids

are chiral3

1

23

3 except glycine plane of paper is aplane of symmetrythrough C, N, and CO2H

There are over 100 elements in the periodic table. Many molecules contain well over 100 atomspalytoxin, for example (a naturally occurring compound with potential anticancer activity) contains129 carbon atoms, 221 hydrogen atoms, 54 oxygen atoms, and 3 nitrogen atoms. Its easy to see howchemical structures can display enormous variety, providing enough molecules to build even themost complicated living creatures. But how can we understand what seems like a recipe for confu-sion? Faced with the collection of atoms we call a molecule, how can we make sense of what we see?This chapter will teach you how to interpret organic structures. It will also teach you how to draworganic molecules in a way that conveys all the necessary information and none of the superfluous.

2Organic structures

LPalytoxin was isolated in 1971 inHawaii from Limu make o Hane (deadlyseaweed of Hana) which had beenused to poison spear points. It is one ofthe most toxic compounds knownrequiring only about 0.15 microgramper kilogram for death by injection. Thecomplicated structure was determineda few years later.

OHHN

HNO

HO

OO

OH

OH

OH

OHOHHO

OH

H

OHHO

HO

OHO

O

O

OHOH

OH

HO

OH

OHOH

O

HO

HO

OH

HO

O

OH

HO

HO

OH

OH

HO

OH

OH

HO OH

HO

OH

O

OH

OHHO

OO

O

HO

NH2

HO

HO

H

H

H

H

H

H

H H

H

H

H

H

H

palytoxin

Connections

Building on:

This chapter does not depend onChapter 1

Leading to:

The diagrams used in the rest of the book Why we use these particular diagrams How organic chemists name

molecules in writing and in speech

What is the skeleton of an organicmolecule

What is a functional group Some abbreviations used by all organic

chemists

Drawing organic molecules realisticallyin an easily understood style

Looking forward to:

Ascertaining molecular structurespectroscopically ch3

What determines a moleculesstructure ch4

Hydrocarbon frameworks and functional groupsAs we explained in Chapter 1, organic chemistry is the study of compounds that contain carbon. Nearlyall organic compounds also contain hydrogen; most also contain oxygen, nitrogen, or other elements.Organic chemistry concerns itself with the way in which these atoms are bonded together into stablemolecular structures, and the way in which these structures change in the course of chemical reactions.

Some molecular structures are shown below. These molecules are all amino acids, the con-stituents of proteins. Look at the number of carbon atoms in each molecule and the way they arebonded together. Even within this small class of molecules theres great varietyglycine and alaninehave only two or three carbon atoms; phenylalanine has nine.

Lysine has a chain of atoms; tryptophan has rings.

In methionine the atoms are arranged in a single chain; in leucine the chain is branched. In proline,the chain bends back on itself to form a ring.

Yet all of these molecules have similar propertiesthey are all soluble in water, they are all bothacidic and basic (amphoteric), they can all be joined with other amino acids to form proteins. This isbecause the chemistry of organic molecules depends much less on the number or the arrangement ofcarbon or hydrogen atoms than on the other types of atoms (O, N, S, P, Si) in the molecule. Wecall parts of molecules containing small collections of these other atoms functional groups, simplybecause they are groups of atoms that determine the way the molecule works. All amino acids con-tain two functional groups: an amino (NH2 or NH) group and a carboxylic acid (CO2H) group(some contain other functional groups as well).

20 2 . Organic structures

CC

NH2H

H

O

OH CC

NH2H

CH3

O

OHC

C

NH2H

C

O

OH

CC

C

CC

C

H

H

H

H HH

H

CC

NH2H

C

O

OHC

C

NH2H

C

O

OHC

CC

H2N

HH

HH

H H

H H

CC

CN

C

CC

CC

H

H

HH

H

H

H H

CC

NH2H

C

O

OHC

CH3

H3C

H H

HCC

NH2H

C

O

OHCS

H3C

HH

HHC

CC

C

N

C

O

OH

HH

H H

H

H

H

HLWe shall return to amino acids asexamples several times in this chapter,but we shall leave detailed discussionsabout their chemistry till Chapters 24and 49, when we look at the way inwhich they polymerize to form peptidesand proteins.

The functional groups determine the way the molecule works both chemicallyand biologically.

functional groupamino groupfunctional groups

CC

NH2H

H3C

O

OH CC

NH2H

C

O

OHCC

CH2N

HH

HH

H H

H H

CC

NH2H

C

O

OHCS

H3C

HH

HH

alaninecontains just the amino

and carboxylic acid

lysinehas an additional

methioninealso has a sulfide

That isnt to say the carbon atoms arent important; they just play quite a different role from thoseof the oxygen, nitrogen, and other atoms they are attached to. We can consider the chains and ringsof carbon atoms we find in molecules as their skeletons, which support the functional groups andallow them to take part in chemical interactions, much as your skeleton supports your internalorgans so they can interact with one another and work properly.

We will see later how the interpretation of organic structures as hydrocarbon frameworks sup-porting functional groups helps us to understand and rationalize the reactions of organic molecules.It also helps us to devise simple, clear ways of representing molecules on paper. You saw in Chapter 1how we represented molecules on paper, and in the next section we shall teach you ways to draw(and ways not to draw) moleculesthe handwriting of chemistry. This section is extremely impor-tant, because it will teach you how to communicate chemistry, clearly and simply, throughout yourlife as a chemist.

Drawing moleculesBe realisticBelow is another organic structureagain, you may be familiar with the molecule it represents; it isa fatty acid commonly called linoleic acid.

We could also depict linoleic acid as

or as

You may well have seen diagrams like these last two in older booksthey used to be easy to print (inthe days before computers) because all the atoms were in a line and all the angles were 90. But arethey realistic? We will consider ways of determining the shapes and structures of molecules in moredetail in Chapter 3, but the picture below shows the structure of linoleic acid determined by X-raycrystallography.

Drawing molecules 21

The hydrocarbon framework is made up of chains and rings of carbon atoms, andit acts as a support for the functional groups.

C

H

CC

CC

H

HH

HH

H H

H H H

H

C

CC

C

CC

H

H

H HH

H

H

HHH

H

HC

H

CC

CC

H

CH

HH

C H

H H H

H

H

H

H H

H

H

Organic molecules left todecompose for millions of years inthe absence of light and oxygenbecome literally carbonskeletonscrude oil, for example,is a mixture of moleculesconsisting of nothing but carbonand hydrogen, while coal consistsof little else but carbon. Althoughthe molecules in coal and oil differwidely in chemical structure, theyhave one thing in common: nofunctional groups! Many are veryunreactive: about the onlychemical reaction they can takepart in is combustion, which, incomparison to most reactions thattake place in chemical laboratoriesor in living systems, is anextremely violent process. InChapter 5 we will start to look atthe way that functional groupsdirect the chemical reactions of amolecule.

Organic skeletons

H3CC

CC

CC C

CC C

CC

CC

CC

CC

OH

OH H

H H

H H

H H

H H

HH

H H

H H

H H

H H

H H

H H

H H

H H

linoleic acid

carboxylic acidfunctional group

LThree fatty acid molecules and oneglycerol molecule combine to form thefats that store energy in our bodies andare used to construct the membranesaround our cells. This particular fattyacid, linoleic acid, cannot bemanufactured in the human body, andis an essential part of a healthy dietfound, for example, in sunflower oil.

Fatty acids differ in the length of theirchains of carbon atoms, yet they havevery similar chemical propertiesbecause they all contain the carboxylicacid functional group. We shall comeback to fatty acids in Chapter 49.

HOC

CC

OH

H H H H

H OH

glycerol

H C C C C C C C C C C C C C C C C C CO2H

H

H

H

H

H

H

H

H

H

H H H

H

H H H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

linoleic acid

linoleic acid

CH3CH2CH2CH2CH=CHCH2CH=CHCH2CH2CH2CH2CH2CH2CH2CO2H

P

X-ray crystallography discoversthe structures of molecules byobserving the way X-rays bounceoff atoms in crystalline solids. Itgives clear diagrams with theatoms marked a circles and thebonds as rods joining themtogether.

a ring a branched chaina chain

You can see that the chain of carbon atoms is not linear, but a zig-zag. Although our diagram is just atwo-dimensional representation of this three-dimensional structure, it seems reasonable to draw itas a zig-zag too.

This gives us our first guideline for drawing organic structures.

Realism of course has its limitsthe X-ray structure shows that the linoleic acid molecule is in factslightly bent in the vicinity of the double bonds; we have taken the liberty of drawing it as a straightzig-zag. Similarly, close inspection of crystal structures like this reveals that the angle of the zig-zag isabout 109 when the carbon atom is not part of a double bond and 120 when it is. The 109 angle isthe tetrahedral angle, the angle between two vertices of a tetrahedron when viewed from its centre.In Chapter 4 we shall look at why carbon atoms take up this particular arrangement of bonds. Ourrealistic drawing is a projection of a three-dimensional structure onto flat paper so we have to com-promise.

Be economicalWhen we draw organic structures we try to be as realistic as we can be without putting in superfluousdetail. Look at these three pictures.

(1) is immediately recognizable as Leonardo da Vincis Mona Lisa. You may not recognize (2)itsalso Leonardo da Vincis Mona Lisathis time viewed from above. The frame is very ornate, but thepicture tells us as much about the painting as our rejected linear and 90 angle diagrams did about

22 2 . Organic structures

H3CC

CC

CC C

CC C

CC

CC

CC

CC

OH

OH H

H H

H H

H H

H H

HH

H H

H H

H H

H H

H H

H H

H H

H H

linoleic acid

Guideline 1Draw chains of atoms as zig-zags

1 2 3

our fatty acid. Theyre both correctin their waybut sadly useless. What we need when we drawmolecules is the equivalent of (3). It gets across the idea of the original, and includes all the detailnecessary for us to recognize what its a picture of, and leaves out the rest. And it was quick to drawthis picture was drawn in less than 10 minutes: we havent got time to produce great works ofart!

Because functional groups are the key to the chemistry of molecules, clear diagrams must empha-size the functional groups, and let the hydrocarbon framework fade into the background. Comparethe diagrams below:

The second structure is the way that most organic chemists would draw linoleic acid. Notice how theimportant carboxylic acid functional group stands out clearly and is no longer cluttered by all thoseCs and Hs. The zig-zag pattern of the chain is much clearer too. And this structure is much quickerto draw than any of the previous ones!

To get this diagram from the one above weve done two things. Firstly, weve got rid of all thehydrogen atoms attached to carbon atoms, along with the bonds joining them to the carbon atoms.Even without drawing the hydrogen atoms we know theyre therewe assume that any carbon atomthat doesnt appear to have its potential for four bonds satisfied is also attached to the appropriatenumber of hydrogen atoms. Secondly, weve rubbed out all the Cs representing carbon atoms. Wereleft with a zig-zag line, and we assume that every kink in the line represents a carbon atom, as doesthe end of the line.

We can turn these two simplifications into two more guidelines for drawing organic structures.

Be clearTry drawing some of the amino acids represented on p. 000 in a similar way, using the three guide-lines. The bond angles at tetrahedral carbon atoms are about 109. Make them look about 109 pro-jected on to a plane! (120 is a good compromise, and it makes the drawings look neat.)

Start with leucine earlier we drew it as the structure to the right. Get a piece of paper and do itnow; then see how your drawing compares with our suggestions.

Drawing molecules 23

H3CC

CC

CC C

CC C

CC

CC

CC

CC

OH

OH H

H H

H H

H H

H H

HH

H H

H H

H H

H H

H H

H H

H H

H H

linoleic acid

OH

Olinoleic acid

OH

O

this H is shownbecause it isattached to anatom other than C

the end of the linerepresents a C atom

every kink inthe chain representsa C atom

this C atom mustalso carry 3 H atomsbecause only 1 bondis shown

these C atoms mustalso carry 1 H atom

because only 3 bondsare shown for each atom

these C atoms mustalso carry 2 H atomsbecause only 2 bonds

are shown for each atom

all four bondsare shown to thisC atom, so noH atoms areimplied

Guideline 2Miss out the Hs attached to carbon atoms, along with the CH bonds(unless there is a good reason not to)

Guideline 3Miss out the capital Cs representing carbon atoms(unless there is a good reason not to)

CC

NH2H

C

O

OHC

CH3

H3C

H H

H

leucine

P

What is a good reason not to?One is if the C or H is part of afunctional group. Another is if theC or H needs to be highlighted insome way, for example, becauseits taking part in a reaction. Dontbe too rigid about theseguidelines: theyre not rules.Better is just to learn by example(youll find plenty in this book): if ithelps clarify, put it in; if it cluttersand confuses, leave it out. Onething you must remember,though: if you write a carbon atomas a letter C then you must add allthe H atoms too. If you dont wantto draw all the Hs, dont write Cfor carbon.

It doesnt matter which way up youve drawn it, but your diagram should look somethinglike one of these structures below.

The guidelines we gave were only guidelines, not rules, and it certainly does not matter which wayround you draw the molecule. The aim is to keep the functional groups clear, and let the skeletonfade into the background. Thats why the last two structures are all rightthe carbon atom shown asC is part of a functional group (the carboxyl group) so it can stand out.

Now turn back to p. 000 and try redrawing the some of the other eight structures there using theguidelines. Dont look at our suggestions below until youve done them! Then compare your draw-ings with our suggestions.

Remember that these are only suggestions, but we hope youll agree that this style of diagram looksmuch less cluttered and makes the functional groups much clearer than the diagrams on p. 000.Moreover, they still bear significant resemblance to the real thingcompare these crystal structuresof lysine and tryptophan with the structures shown above, for example.

Structural diagrams can be modified to suit the occasionYoull probably find that you want to draw the same molecule in different ways on different occa-sions to emphasize different points. Lets carry on using leucine as an example. We mentioned beforethat an amino acid can act as an acid or as a base. When it acts as an acid, a base (for example,hydroxide, OH) removes H+ from the carboxylic acid group in a reaction we can represent as

The product of this reaction has a negative charge on an oxygen atom. We have put it in a circle tomake it clearer, and we suggest you do the same when you draw charges: +s and s are easilymislaid. We shall discuss this type of reaction, the way in which reactions are drawn, and what thecurly arrows in the diagram mean in Chapter 5. But for now, notice that we drew out the CO2H asthe fragment left because we wanted to show how the OH bond was broken when the base attacked.We modified our diagram to suit our own purposes.

24 2 . Organic structures

O

OH

NH2

leucine

O

OH

NH H

leucine

NH2

HO2C

leucineNH2

HOOC

leucine

O

OH

O

OH

O

OH

OH

O

OHH2N

O

OHS

NH

O

OHH2N

NH2 NH2

O

NH2NH2

NH2

HN

glycine alanine phenylalanine

lysinetryptophan methionine

proline

O

O

NH2

H

O

O

NH2

OH H2O+

LNot all chemists put circles round theirplus and minus chargesits a matterof personal choice.

LThe wiggly line is a graphical way ofindicating an incomplete structure: itshows where we havementally snappedoff the CO2H groupfrom the rest of themolecule. O

OH

When leucine acts as a base, the amino (NH2) group is involved. The nitrogen atom attaches itselfto a proton, forming a new bond using its lone pair.

We can represent this reaction as

Notice how we drew the lone pair at this time because we wanted to show how it was involved inthe reaction. The oxygen atoms of the carboxylic acid groups also have lone pairs but we didnt drawthem in because they werent relevant to what we were talking about. Neither did we feel it was nec-essary to draw CO2H in full this time because none of the atoms or bonds in the carboxylic acidfunctional group was involved in the reaction.

Structural diagrams can show three-dimensional information on atwo-dimensional pageOf course, all the structures we have been drawing only give an idea of the real structure of themolecules. For example, the carbon atom between the NH2 group and the CO2H group ofleucine has a tetrahedral arrangement of atoms around it, a fact which we have so far completelyignored.

We might want to emphasize this fact by drawing in the hydrogen atom we missed out at thispoint as in structure 1 (in the right-hand margin).

We can then show that one of the groups attached to this carbon atom comes towards us, out ofthe plane of the paper, and the other one goes away from us, into the paper. There are several ways ofdoing this. In structure 2, the bold, wedged bond suggests a perspective view of a bond comingtowards you, while the hashed bond suggests a bond fading away from you. The other two normalbonds are in the plane of the paper.

Alternatively we could miss out the hydrogen atom and draw something a bit neater thoughslightly less realistic as structure 3.

We can assume the missing hydrogen atom is behind the plane of the paper, because that is wherethe missing vertex of the tetrahedron of atoms attached to the carbon atom lies. These conventionsallow us to give an idea of the three-dimensional shape (stereochemistry) of any organic moleculeyou have already seen them in use in the diagram of the structure of palytoxin at the beginning of thischapter.

The guidelines we have given and conventions we have illustrated in this section have grown upover decades. They are used by organic chemists because they work! We guarantee to follow them forthe rest of the booktry to follow them yourself whenever you draw an organic structure. Beforeyou ever draw a capital C or a capital H again, ask yourself whether its really necessary!

Now that we have considered how to draw structures, we can return to some of the structuraltypes that we find in organic molecules. Firstly, well talk about hydrocarbon frameworks, thenabout functional groups.

Drawing molecules 25

LA lone pair is a pair of electrons that isnot involved in a chemical bond Weshall discuss lone pairs in detail inChapter 4. Again, dont worry aboutwhat the curly arrows in this diagrammeanwe will cover them in detail inChapter 5.

CO2H

NH

HH

O

H

H

CO2H

NH

HH

H2O+

CO2H

NH2H

CO2H

NH2H

CO2H

NH2

P

When you draw diagrams likethese to indicate the three-dimensional shape of themolecule, try to keep thehydrocarbon framework in theplane of the paper and allowfunctional groups and otherbranches to project forwards outof the paper or backwards into it.

LWe shall look in more detail at theshapes of moleculestheirstereochemistryin Chapter 16.

ReminderOrganic structures should be drawn to be realistic, economical, clear.

We gave three guidelines to help you achieve this when you draw structures:

Guideline 1: Draw chains of atoms as zig-zags Guideline 2: Miss out the Hs attached to carbon atoms, along with the CH

bonds

Guideline 3: Miss out the capital Cs representing carbon atoms

1

2

3

Hydrocarbon frameworksCarbon as an element is unique in the variety of structures it can form. It is unusual because it formsstrong, stable bonds to the majority of elements in the periodic table, including itself. It is this abilityto form bonds to itself that leads to the variety of organic structures that exist, and indeed to the pos-sibility of life existing at all. Carbon may make up only 0.2% of the earths crust, but it certainlydeserves a whole branch of chemistry all to itself.

ChainsThe simplest class of hydrocarbon frameworks contains just chains of atoms. The fatty acids we metearlier have hydrocarbon frameworks made of zig-zag chains of atoms, for example. Polythene is apolymer whose hydrocarbon framework consists entirely of chains of carbon atoms.

At the other end of the spectrum of complexity is this antibiotic, extracted from a fungus in 1995and aptly named linearmycin as it has a long linear chain. The chain of this antibiotic is so long thatwe have to wrap it round two corners just to get it on the page.

We havent drawnwhether the CH3groups and OH groupsare in front of orbehind the plane of thepaper, because (at thetime of writing thisbook) no one yetknows. The stereo-chemistry of linear-mycin is unknown.

Names for carbon chainsIt is often convenient to refer to a chain of carbon atoms by a name indicating its length. You haveprobably met some of these names before in the names of the simplest organic molecules, thealkanes. There are also commonly used abbreviations for these names: these can be very useful inboth writing about chemistry and in drawing chemical structures, as we shall see shortly.

Names and abbreviations for carbon chains

Number of carbon Name of Formula Abbreviation Name of alkaneatoms in chain group (= chain + H)

1 methyl CH3 Me methane2 ethyl CH2CH3 Et ethane3 propyl CH2CH2CH3 Pr propane4 butyl (CH2)3CH3 Bu butane5 pentyl (CH2)4CH3

pentane6 hexyl (CH2)5CH3

hexane7 heptyl (CH2)6CH3

heptane8 octyl (CH2)7CH3

octane9 nonyl (CH2)8CH3

nonane10 decyl (CH2)9CH3

decane

This representation is not recommended. Names for longer chains are not commonly abbreviated.

26 2 . Organic structures

a section of the structure of polythene

H2N

OHOH OH OH OH

OH

OHOHOHO

CH3OH

OH

CH3 CH3

OH

CO2H

CH3

P

Notice weve drawn in four groupsas CH3we did this because wedidnt want them to getoverlooked in such a largestructure. They are the only tinybranches off this long windingtrunk.

P

The names for shorter chains(which you must learn) exist forhistorical reasons; for chains of 5or more carbon atoms, thesystematic names are based onGreek number names.

27 Hydrocarbon frameworks

Organic elements NH2 You may notice that the abbreviations for the names of carbon chains look very much like the OH symbols for chemical elements: this is deliberate, and these symbols are sometimes called organic S

elements. They can be used in chemical structures just like element symbols. It is often convenient O to use the organic element symbols for short carbon chains for tidiness. Here are some examples. 1 methionine

Structure 1 to the right shows how we drew the structure of the amino acid methionine on p. 24. The NH2stick representing the methyl group attached to the sulfur atom does, however, look a little odd.

OHMost chemists would draw methionine as structure 2, with Me representing the CH3 (methyl) MeS group. Tetraethyllead used to be added to petrol to prevent engines knocking, until it was shown to

Obe a health hazard. Its structure (as you might easily guess from the name) is shown as item 3. But its 2 methioninemuch easier to write as PbEt4 or Et4Pb

Remember that these symbols (and names) can only be used for terminal chains of atoms. We couldnt abbreviate the structure of lysine from

NH2 NH2Pb

OHOH H2N to BuH2N

O O3 tetraethyllead

lysine NOT CORRECT NH2

for example, because Bu represents OH

H H H H H H H H R

H 4 Oand not

H H H H H H H H

Before leaving carbon chains, we must mention one other very useful organic element symbol, R. R in a structure can mean anythingits a sort of wild card. For example, structure 4 would indicate any amino acid, where R = H is glycine, R = Me is alanine As weve mentioned before, and you will see later, the reactivity of organic molecules is so dependent on their functional groups that the rest of the molecule can be irrelevant. In these cases, we can choose just to call it R.

Carbon rings Rings of atoms are also common in organic structures. You may have heard the famous story of Auguste Kekul first realizing that benzene has a ring structure when he dreamed of snakes biting their own tails. You have met benzene rings in phenylalanine and aspirin.

benzeneParacetamol also has a structure based on a benzene ring. O

H N

O

OH

O Benzene has a ring structure

OH

NH2

HOO In 1865, August Kekul presented a paper at the Academie desphenylalanine paracetamol aspirin O Sciences in Paris suggesting a cyclic structure for benzene, the

When a benzene ring is attached to a molecule by only one of its carbon inspiration for which he ascribed to a dream. However, was Kekul the first to suggest that benzene was cyclic? Some

atoms (as in phenylalanine, but not paracetamol or aspirin), we can call it a believe not, and credit an Austrian schoolteacher, Josef phenyl group and give it the organic element symbol Ph. Loschmidt with the first depiction of cyclic benzene structures.

In 1861, 4 years before Kekuls NH2 NH2 dream, Loschmidt published a book in

which he represented benzene as a set OH is OH of rings. It is not certain whether

equivalent Ph Loschmidt or Kekulor even a Scot named Archibald Coupergot it right

O O first. to

the phenyl group, Ph

Any compound containing a benzene ring, or a related (Chapter 7) ring system is known as aro-matic, and another useful organic element symbol related to Ph is Ar (for aryl). While Ph alwaysmeans C6H5, Ar can mean any substituted phenyl ring, in other words, phenyl with any number ofthe hydrogen atoms replaced by other groups.

For example, while PhOH always means phenol, ArOH could mean phenol, 2,4,6-trichlorophe-nol (the antiseptic TCP), paracetamol or aspirin (among many other substituted phenols). Like R,the wild card alkyl group, Ar is a wild card arylgroup.

The compound known as muscone has only rel-atively recently been made in the lab. It is the pun-gent aroma that makes up the base-note of muskfragrances. Before chemists had determined itsstructure and devised a laboratory synthesis theonly source of musk was the musk deer, now rarefor this very reason. Muscones skeleton is a 13-membered ring of carbon atoms.

The steroid hormones have several (usually four) rings fused together. These are testosterone andoestradiol, the important human male and female sex hormones.

Some ring structures are much more complicated. The potent poison strychnine is a tangle ofinterconnecting rings.

One of the most elegant ring structures is shown above and is known as Buckminsterfullerene. Itconsists solely of 60 carbon atoms in rings that curve back on themselves to form a football-shapedcage.

Count the number of bonds at any junction and you will see they add up to four so no hydrogensneed be added. This compound is C60. Note that you cant see all the atoms as some are behind thesphere.

Rings of carbon atoms are given names starting with cyclo, followed by the name for the carbonchain with the same number of carbon atoms.

28 2 . Organic structures

OH

phenolPhOH = OH OH OH

Cl Cl

Cl HN

O

phenol 2,4,6-trichlorophenol paracetamol

P

Of course, Ar = argon too, but sofew argon compounds exist thatthere is never any confusion.

O

muscone

Me

OHMe

O

OHMe

HO

H

H H H

H

H

testosterone oestradiol

Buckminsterfullerene

N

N

O

OH

H

H

H

strychnine

Buckminsterfullerene is namedafter the American inventor andarchitect Richard BuckminsterFuller, who designed the structuresknown as geodesic domes.

Buckminsterfullerene

To the right, structure 1 shows chrysanthemic acid, part of the naturally occurring pesticidescalled pyrethrins (an example appears in Chapter 1), which contains a cyclopropane ring. Propanehas three carbon atoms. Cyclopropane is a three-membered ring. Grandisol (structure 2), an insectpheromone used by male boll weevils to attract females, has a structure based on a cyclobutane ring.Butane has four carbon atoms. Cyclobutane is a four-membered ring. Cyclamate (structure 3), for-merly used as an artificial sweetener, contains a cyclohexane ring. Hexane has six carbon atoms.Cyclohexane is a six-membered ring.

BranchesHydrocarbon frameworks rarely consist of single rings or chains, but are often branched. Rings,chains, and branches are all combined in structures like that of the marine toxin palytoxin that wemet at the beginning of the chapter, polystyrene, a polymer made of six-membered rings danglingfrom linear carbon chains, or of -carotene, the compound that makes carrots orange.

Just like some short straight carbon chains, some short branched carbon chains are given names andorganic element symbols. The most common is the isopropyl group. Lithium diisopropylamide(also called LDA) is a strong base commonly used in organic synthesis.

Iproniazid is an antidepressant drug with i-Pr in both structure and name.Notice how the propyl part of isopropyl still indicates three

carbon atoms; they are just joined together in a different wayinother words, as an isomer of the straight chain propyl group.Sometimes, to avoid confusion, the straight chain alkyl groups arecalled n-alkyl (for example, n-Pr, n-Bu)n for normaltodistinguish them from their branched counterparts.

Hydrocarbon frameworks 29

O

HO

chrysanthemic acid

OH

grandisol

HN

SO3H

cyclamate

1

2

3

-carotene

i -Pr the isopropyl group

Li

Nis equivalent to LiNi -Pr2

lithium diisopropylamide (LDA)

part of the structure of polystyrene

N

NH

OHN

iproniazid

LIsopropyl may be abbreviated to i-Pr,iPr, or Pri. We will use the first in thisbook, but you may see the others usedelsewhere.

Isomers are molecules with the same kinds and numbers of atoms joined up indifferent ways n-propanol, n-PrOH, and isopropanol, i-PrOH, are isomericalcohols. Isomers need not have the same functional groups, these compounds areall isomers of C4H8O.

O

OHCHO

O

is equivalent toN

NH

O

i -PrHN

The isobutyl (i-Bu) group is a CH2 group joined to an i-Pr group. It is i-PrCH2Two isobutyl groups are present in the reducing agent diisobutyl aluminium hydride (DIBAL).

The painkiller ibuprofen (marketed as Nurofen) contains an isobutyl group.

There are two more isomers of the butyl group, both of which have common names and abbrevi-ations. The sec-butyl group (s-butyl or s-Bu) has a methyl and an ethyl group joined to the same car-bon atom. It appears in an organolithium compound, sec-butyl lithium, used to introduce lithiumatoms into organic molecules.

The tert-butyl group (t-butyl or t-Bu) group has three methyl groups joined to the same carbonatom. Two t-Bu groups are found in BHT (butylated hydroxy toluene), an antioxidant added tosome processed foods.

30 2 . Organic structures

i -Buthe isobutyl group Al

H

diisobutyl aluminium hydride (DIBAL)is equivalent to HAli-Bu2

CO2H

Ibuprofen

s -Buthe sec-butyl group

Li

t -Buthe tert-butyl group OH

BHT

Me

OH

t-But-Bu

BHT

is equivalent

to

is equivalent to s -BuLi

LNotice how the invented nameibuprofen is a medley of ibu (from i-Bufor isobutyl) + pro (for propyl, thethree-carbon unit shown in gold) + fen(for the phenyl ring). We will talk aboutthe way in which compounds arenamed later in this chapter.

Primary, secondary, and tertiaryThe prefixes sec and tert are really short for secondary and tertiary, terms that referto the carbon atom that attaches these groups to the rest of the molecularstructure.

A primary carbon atom is attached to only one other C atom, a secondary to twoother C atoms, and so on. This means there are five types of carbon atom.

These names for bits of hydrocarbon framework are more than just useful ways ofwriting or talking about chemistry. They tell us something fundamental about themolecule and we shall use them when we describe reactions.

OH OH OHOH

Me OH

butan-1-ol

n-butanol

butan-2-ol

sec-butanol

2-methypropan-2-ol

tert-butanol

2,2,-dimethylpropan-1-ol

methyl(no attached C)

primary(1 attached C)

methanol

secondary (2 attached C)

tertiary(3 attached C)

quaternary(4 attached C)

This quick architectural tour of some of the molecular edifices built by nature and by man servesjust as an introduction to some of the hydrocarbon frameworks you will meet in the re