The science of chemistry chemistry, the whole thing is analysed in terms of systems thinking over three pages of this web book. This third page deals with non-linear (unpredictable, complex, chaotic) chemistry systems.
Consider the first 36 main
group elements, hydrogen to barium, not as gas-phase monoatomic species,
but as chemicals in bottles: as reagent chemicals in their standard (thermodynamically most stable) state at 298 Kelvin and 100 kPa (25°C & 1.0 atm) pressure:
The bulk properties: structure, melting/boiling
points, electrical & thermal conductivity conductivity, reactivity, etc., of the main group elements
as materials are not predictable from first principles, and neither are
they periodically related in a general way.
Consider the elements N,
P, O & S in the standard state. All exist as molecules, but:
Nitrogen exists as N2
Phosphorus exists as P4
Oxygen exists as O2
Sulfur exists as S8
Indeed, where is the regular change?, in:
Ar (single atom molecular)
While it is relatively
easy to explain after the fact "why" a particular
allotropic form is stable under a particular set of conditions using
the phase diagram, valence and molecular orbital theory... these
arguments are invariably based on empirical (experimental) evidence
and always end up being circular:
Sulfur exists in S8
rings because sulfur exists in S8
sports fans! Have you noticed how much easier to explain why
the team won the game, than it is to predict which team
is going to win? Hindsight
is a wonderful thing; it gives 20:20 vision in sport, and also
with chemical science.
Should it have been the
case that sulfur existed in S10 rings... well,
we would have been able to explain that as well...
Remove the standard state (298 Kelvin and 100 kPa) constraint, and things get far more involved as different
can be found which are stable (or meta-stable) under various conditions:
Until 1991, only two carbon
allotropes were known: graphite and diamond. Since then many more have
been discovered, including: literally dozens of spherical and football
(rugby ball) shaped "buckyballs"
like C36, C60, C128,
etc., as well as various types of single & multi wall carbon nanotubes
For many years it has been
predicted that hydrogen will form a metallic
phase at high pressure, however, this form of the element has not
yet been observed in the lab (writing in July 2005 and still in September 2010),
although there is plenty of indirect evidence that it exists deep inside
the gas giant planets Jupiter and Saturn. Hydrogen is the simplest element,
and if the phase diagram of any element is going to be predicted from
first principles it will be hydrogen (or helium).
Oxygen has two allotropes
dioxygen, O2, and trioxygen or ozone, O3.
However, O2, is a diradical
that can exist in several electronic spin states, each of which is a
distinct chemical species. Ground state triplet oxygen is paramagnetic
and is attracted to magnets, here.
Ozone is able to undergo 1,3-dipolar cycloaddition, a class of pericyclic
In 1999 a new pentanitrogen
cation was announced, [N5]+, but unfortunately
not named (Christe
et al, AngChem IntEd, 38, 2004-2009, 1999). I have
always wondered just how (un)stable the azide salt of this pentanitrogen
cation will be: "N-five azide", [N5]+
[N3]. This material would be
a unique ionic allotrope.
Napoleon's army had uniform
buttons made from metallic tin, Sn, but during the long march to Moscow
in 1812, the intense cold of the Russian winter transformed tin metal
into the mechanically weak network covalent allotrope, and the buttons
turned to powder.
Etc., etc., etc... and we
are just talking about elements.
Generally, it is not
possible to deduce an element's equation of state or phase diagram from
first principles; they must be experimentally determined.
As expected, chemical compounds
are far more involved than the chemical elements.
[At least they are usually are: the main group hydrides and congeneric
series used in the chemogenesis analysis
are notable exceptions.]
Oxides are particularly
difficult. Consider, for example, the oxides of the period 2 elements:
Li, Be, B, C, N, O, F & Ne. According to webelements,
the set of period 2 oxides consists of:
This set of chemical compounds
clearly presents as an unpredictable "broken terrain". It is
not possible to predict which period 2 oxides will exist from first
principles. Indeed, it is not an impossible scenario that a new
Period 2 oxide will be discovered. Should this is be the case, theory
will be used to explain why the new compound is stable and how it is able
I predict that
the carbon oxide C2O2,
O=C=C=O, should exist from my knowledge of carbon dioxide, CO2 (O=C=O), and carbon suboxide, C3O2 (O=C=C=C=O), both of which are known.
I can generate all three homologs in Spartan,
a molecular modelling package employing high level (QM/HF/DF) theory.
However, I know that chemists will take little or no notice of
my prediction until it is verified by experiment, the new carbon
oxide is made and its melting point determined.
Kroto predicted the existence of fullerene, C60 (Wikipedia),
in 1985 after he observed an ion at m/e 720 by mass spectrometry,
in a molecular beam experiment which created carbon clusters. This
cluster had to contain 60 carbon atoms and he assigned the "football" structure, but scientists only took note
and awarded the Nobel prize after the substance had been
prepared in relative bulk in 1991.
Thinking further... I suspect C2O2 will
be susceptible to fragmentation, yielding two molecules of carbon
monoxide, CO. Bother...
The set of all possible
compounds is a huge, complex, broken terrain. It has been estimated
that there are more that 1060 possible organic molecules
with a molecular mass of 500 or less. Bohacek
et. al., Med. Res. Rev.16, 3-50, 1996
just one molecule of each compound were to be produced, the total
mass would nearly equal that of a million suns. Do the math:
There will be more
heavier isomers that lighter isomers, so assume the average molecular weight is close to
Total mass is
(500 x 1060)/(6 x 1023) = 8 x 1035Kg
x 1035) /
(2 x 1030) ~ 400,000 ~ half a million...
The set of known
compounds is strongly biased towards issues of biological, medical,
military, commercial and/or academic interest. The three largest online
chemical databases are:
(the Chemical Abstracting Service) has a database of close to 50
million substances (as of Aug 2009), and about 5000 more are added
per day, that is more than a million a year.
Beilstein: 9 million organic substances Gmelin:
2 million inorganic compounds
The chemical industry
produces vast numbers of compounds for testing, particularly in the
areas of drug discovery and flavouring/fragrance. Industry probably
has proprietary (secret) information on [intelligent guess here]
half a billion chemical substances/compounds.
The set of commercially
available chemicals is represented by online databases.
The CAS developed
a database of chemicals and suppliers. The database lists 8 million
commercially available chemicals, 750 suppliers of commercial chemicals
and 900 chemical catalogs
Gases discrete atomic or molecular particles
particles are well separated and have no regular arrangement
particles are able to move freely at high speeds, colliding with
container walls and each other
samples are fluids able assume the shape and volume of the container
free flowing fluid: Navier-Stokes
atomic or molecular particles
are packed closely together, but with no regular arrangement
particles vibrate, and they are able to move about by "sliding
past" each other
samples are fluids able assume the shape of the part of the container
which it occupies
not easily compressed
free flowing fluid: Navier-Stokes
ionic, molecular particles bonded together in a lattice
particles are tightly
packed, usually in a regular pattern
vibrate jiggle about but generally do not move from place
retain a fixed volume and shape
free flowing (unless granular, which is a special case)
Later we learn to understand
the physics and chemistry of gas, liquid and solid phases in terms of
kinetic theory, thermodynamics and solution theory, as discussed in the
section on linear chemistry here, and solid
structure in terms of bonding theory, here
So it is surprising to find
out just how quickly complexity emerges in the gas-liquid-solid system
when phases are mixed together.
Consider the Phase Interaction
Matrix ('interaction table', a type of Karnaugh
At first sight, there appear
to be just six possibilities:
mixture of two gases Gas/Liquid Mixture
of a gas and a liquid Liquid/Liquid Mixture
of two liquids Gas/Solid Mixture
of a gas & a solid Liquid/Solid Mixture
of a liquid & a solid Solid/Solid Mixture
of two solids
But this is an illusion because
phase interactions usually but not always lead to
the formation of phase boundaries, heterogeneous systems and emergent
complexity that is critically dependent upon the nature of the phase boundary
Some points before we begin:
phases (gases and liquids) are very efficiently kneaded together by
turbulence. Efficient intermingling makes a system homogeneous and simple.
In other words, all parts are chemically identical.
turbulent mixing to produce homogeneity is somewhat ironic because
turbulence is itself a complex non-linear process that is here
being used to smooth out the chaos and complexity associated with
unstirred mixtures. One type of chaos destroying another.
the opposite of turbulence and complexity. If there is a density difference
between two phases and there usually is AND one
or both phases are fluid, then gravity will act over time to separate
the phases. Mechanical agitation will speed this process.
systems can either consist of:
The same substance
in different phases: ice and steam. In this situation the phase change
processes are: melting, evaporation, sublimation, etc.
Two (or more different) substances: oil and water.
of both types appear below.
consist of small particles of one phase dispersed in another
phase. Colloidal size is typically 0.001 micron to 1 micron.
Milk and smoke
are both colloids.
interaction processes discussed below are illustrated by phase separation
methods and by technologies that exploit the mixed phase system under
discussion, such as chromatography.
Gas/Gas: A mixture
of two or more gases such as air.
Mixtures of gases are
always homogeneous if they are at thermal equilibrium.
The mixing time can be determined by Graham's
law of diffusion/effusion which is mass dependent: low mass
gases like hydrogen and helium diffuse into each and mix with
other more quickly than heavy gases like xenon and krypton. Turbulent
mixing efficiently scrambles gaseous samples to a distance scale
where Graham's law can take over and render a system homogeneous.
of gases is seldom an issue in the lab where containers are
small. However, the Earth's atmosphere very large and it is
not at thermal equilibrium due to differential heating by the
Sun. The is atmosphere is decidedly heterogeneous gaseous system,
as we experience with the changing weather.
Mixtures of gases
such as air or natural gas (methane + ethane + propane)
can be separated by low temperature fractional distillation.
separates by mass rather than boiling point. The method has been
used to separate uranium 235U and 238U isotopes by diffusing gaseous
uranium hexafluoride, UF6, through porous
hexafluoride is used for two reasons. Firstly, UF6 is a molecular solid that sublimes to gas at 56°C. More
importantly, fluorine only has one isotope, 19F, so there is
no blurring the uranium's isotopic mass by the six attached
of a gas and a liquid: clouds, foams, aerosols, sprays
Mixtures of gases and
liquids are always heterogeneous. Clouds, aerosols and sprays
consist liquid droplets dispersed in a gas. Foams consist of surfactant
stabilised bubbles of liquid filled with gas. Clouds, aerosols,
sprays and foams are unstable states, and the gas and liquid components
are usually separated by gravity within a short time. Clouds may
be charge stabilised with individual droplets having a net charge,
the result is that droplets repel each other and the rate of condensation
It is likely that the
gas will have some solubility in the liquid, and that the liquid
will exert a vapour pressure "into" the gas phase.
fluids are materials in a state above their critical temperature,
Tc, and critical pressure, Pc,
a regime where gases and liquids "coexist" in a state
of matter outside our usual everyday experience. Decaf coffee
by removing the caffeine using a solvent of supercritical CO2.
liquid chromatography, GLC, involves vapour phase analyte
species differentially partitioning between the vapour phase and
a liquid phase bound to a solid carrier phase support. As the
carrier gas moves with respect to the stationery phase, analyte
species are separated and assayed by some sort of detector.
of two liquids, which may be miscible or immiscible
Mixtures of immiscible
liquids are always heterogeneous, with a phase boundary, although
the two liquids will always be partially soluble in each other.
The two phases will
separate by differential density and gravity. In the laboratory
the separation of immiscible liquids is conveniently carried out
using a separating funnel:
Solute molecules can
partition between the two immiscible phases. In pharmaceutical
science the partitioning of medicinal agents between immiscible
octan-1-ol and water is a common measure of overall polarity.
(There is a JAVA partition calculator here.)
Turbulent mixing by "shaking the sep' funnel" will maximise
the phase boundary surface area and will speed up partition equilibrium.
Mixtures of miscible
liquids are homogeneous if completely stirred. Turbulent
mixing is particularly efficient at thoroughly mixing miscible
However, at high concentrations
close to 1:1 molar ratios classic homogeneous systems
like methanol and water are actually considerably more involved than may be assumed. A recent paper says:
a simple alcohol such as methanol or ethanol is mixed with water,
the entropy of the system increases far less than expected for
an ideal solution of randomly mixed molecules. Our data indicate
that most of the water molecules exist as small hydrogen bonded
strings and clusters in a 'fluid' of close packed methyl groups,
with water clusters bridging to neighbouring methanol -OH functions
through hydrogen bonding. "Molecular Segregation Observed in Concentrated Alcohol-Water Solution by Dixit et. al., Nature, 416, 829-832 (2002), abstract.
In other words, the
concentrated methanol/water mixture only appears to be homogeneous and on
a molecular scale the mixing is incomplete. It follows that the methanol/water
phase diagram is more complex than expected.
As a rule of thumb, linear behaviour should only at less than < 0.1 molar... water in methanol or methanol in water.
It should be said
that water is a particularly complex material due to its polar,
hydrogen bonding nature. Mixtures of for example
dichloromethane, CH2Cl2, and trichloromethane (chloroform), CHCl3,
are far more predictable than concentrated aqueous solutions.
Miscible liquids can
be separated by fractional distillation or by 'freezing out' one
of the components. For example, the ethanol concentration an ethanol-water
mixture can be increased by cooling the mixture to about -10°C
and removing the crystals of pure water ice. (This method was/is used to produce vodka during the cold Russian winter.)
several types of liquid phase solvent:
immiscible with water
van der Waals interactions
cyclohexane to ethylacetate, MIBK, etc.
Weakly Protic Solvents
miscible with water
van der Waals interactions not Brønsted acidic, but form
an equilibrium with hydroxide ion
acetone, acetonitrile, etc.
miscible with water
van der Waals interactions
not Brønsted acidic
pKa > 30
DMF, DMSO, HMPTA
miscible with water
pKa < 20
water, alcohols, acetic acid
van der Waals interactions
Liquid SO2, liquid NH3
A few observations:
dissolve in themselves.
a given type, solvents *tend* to be infinitely miscible with
each other (if they don't react).
a profound and useful difference between the non-polar organic
solvents and water that is exploited in solvent extraction,
dipolar aprotic solvents like DMF lie between the non-polar
organic solvents and the polar protic solvents.
isobutyl ketone is the most polar of the organic solvents that
is immiscible with water. Indeed, MIBK is an important industrial
extraction solvent used to pull polar organic molecules and
complexes into the organic phase.
and other sugar molecules are covered with hydroxy groups able
to hydrogen bond with water and so are very soluble in water.
mixture of a gas and a solid can take two forms: foam or
Gas/solid systems are
stone (a volcanic material), bread
are all solid foams in which a gas is held in solid matrix
with an open structure. Much modern technology uses gas/solid
foams because they can be engineered to be strong, energy adsorbing
and very light.
of low density solid particles suspended in a gas.
Properties of smokes
and foams are controlled by the surface area of the solid, which
may be small or very large. Activated carbon has a huge surface
area, a paper here
reports 500 square meters per gram. Aerogels can have surface
areas up to 4000 square meters per gram, here.
Solid foams can be
separated by crushing/cutting and gravity, or the gas may diffuse
out and away if the foam structure is open enough. The solid components
of smokes can be filtered out.
Fluidized beds use
moderate density, granular solids supported by high pressure flow
Gas phase reaction
systems commonly employ heterogeneous solid phase catalyst systems.
For example, hydrogenation reactions often use Ni/Pd/Pt transition
metals dispersed over the large surface area of an activated carbon
or ceramic materials.
The solid may be insoluble in the liquid, or it may be soluble,
or an emulsion may form.
The two phase
mixture is by definition heterogeneous. There may be some solubility
of the solid into the liquids phase. (The range from soluble to
insoluble is, of course, continuous.)
liquids can be separated by filtration.
chromatography and HPLC,
involves analyte species differentially partitioning between a
mobile liquid phase and a stationary solid phase. As the carrier
solvent moves with respect to the stationary phase, analyte species
are separated before being assayed by some sort of detector.
Soluble: sugar and
Solubility of a solid
in a liquid or more technically, a solute in a solvent
is temperature dependent. Generally gases become
less soluble in solvents with increasing temperature and they
are "out gassed" at the boiling point, where as solids
become more soluble, but there exceptions, ie sodium sulfate,
solubilities curves are linear, but individual curves cannot be
predicted from first principles and the set of solubility curves
a discussion about the thermodynamics of solubility, and an
insight as to why it is so difficult to predict solubility,
on the ChemGuide
Stirred solutions are
homogeneous, and the rate of dissolution is dramatically increased
by turbulent mixing.
The stirred solid-dissolved-in-liquid
system is the preferred reaction environment for practical chemistry.
Many components can exist in the solution. The system can be
controlled in terms of relative and absolute concentration,
temperature, time, etc. With turbulent stirring there is intimate
mixing of all components.
The solid and liquid
components of a solution can be separated by cooling, crystallisation
and filtering off the solid phase and moving it away from the
liquid phase. Alternatively, the solvent can be evaporated away
from the solid and condensed. The final stage this latter process
is usually referred to as drying.
cycles of dissolution followed by crystallisation represent a
very efficient way of purifying solid.
milk and butter
Solid fats can emulsify
with water in two ways: fat in water and water in fat.
Dairy products are
of biological origin and have many components present, but they
illustrate this point rather nicely: Whole milk is a colloidal
emulsion largely consisting of fat particles suspended
in water, and butter is a emulsion largely consisting of
a suspension of water droplets in fat.
mixture of two solids can result in a heterogeneous mixture
or a homogeneous alloy.
The two phases are
intimately mixed together in a melt to give a solid homogeneous
mixture on cooling. However and it should be said somewhat
confusingly there are several types of alloy, some of which
are actually heterogeneous mixtures.
heterogeneous eutectic alloys are formed from a homogeneous
melt of two or more metals, which partially phase separate
on cooling. Metallic alloys are discussed here,
with reference to their positions with respect to the Laing
tetrahedron of material type.
Polymer alloys are
formed by turbulently mixing two or more thermoplastic polymers
in the liquid state. The polymer alloy is formed on cooling.
Dye can be added to a polymer which is evenly dispersed throughout
It is very difficult
to separate the individual components from an alloy. It may
be necessary to dissolve the alloy in a solvent and chemically
separate the individual components from a liquid phase environment.
For polymer alloys, it may be necessary to crack the individual
polymer components back to the starting monomers and separate
these by distillation.
iron filings + sand or granite
There will always be
two (or more) distinct solid phases, although this may only be
apparent under microscopic examination.
Separation is by physical
means which always starts with mechanical crushing, followed by:
separation by size
separation by density
iron is a special case because magnetic separation is
In solid/solid alloys
and heterogeneous mixtures it is not possible for mixing to occur
because there is no mobile fluid phase. Therefore the only chemical
reactions that can occur are temperature and/or pressure induced
phase changes. Geologists and geochemists are particularly interested
in how rocks are metamorphosed over geological time. The ice-water-steam
system is exceedingly involved, here.
This type of analysis
is not new. Here is an old "like-dissolves-like" diagram
from 1751 using old alchemical symbols:
English edition of Gellert's Metallurgic Chymistry. First published
in German in 1751, with an intro by Fathi Habashi. ISBN:
rule of thumb is that homogeneous solutions are simple, whereas
heterogeneous systems are complicated because they are dominated by
the nature of the phase boundary. However, solutions particularly
aqueous solutions can only be expected to be ideal (linear) when
solute concentrations are below 0.1 molar. This situation is restricted
Mixtures of gases (stirred)
Mixtures of miscible liquids (stirred and where one component
is < 0.1 molar)
Solution of a solid in a solvent (stirred and where the solute
is < 0.1 molar)
Solid solutions (where one component is < 0.1 molar)
high concentrations, activity and fugacity "fiddle factors" have to be employed.
behaviour is rare. Most phase interactions are non-linear, inherently
complex and emergence abounds.
Isomers and Emergent
As molecular size increases,
so does complexity, and emergent new properties appear. Consider the linear
and branched alkane alcohols, the alkanols. Above, it was argued that
One structural isomer
of the C1 alcohol: methanol
alcohols: 1-propanol & 2-propanol
alcohols: 1-butanol, 2-butanol, 2-methyl-1-propanol & 2-methyl-2-propanol
Eight C5 alcohols...
However, some of the alkanols
the first example is 2-butanol, CH3CHOHCH2CH3
have a chiral centre with four different groups attached
about a tetrahedral carbon. The implication is that there are two ways
(configurations) that the groups can attach to the tetrahedral centre
and the molecule can exist as a pair of "handed" enantiomers
or "stereoisomers". So, actually there is:
structural and stereo of the C1 alcohol
Eleven C5 alcohols
Enantiomers can only be distinguished
in a chiral environment, but biology is very, very chiral and with
just one exception (glycine): all amino acids, all nucleic acids, all
sugars, all peptides, all proteins, all DNA strands and all organisms
are chiral and are enantiomer selective. Biologically, (2R)-2-butanol
is completely different to (2S)-2-butanol.
Molecules with more than one
chiral centre exist as diastereoisomers (diastereomers), which unlike
enantiomers are chemically distinguishable in an achiral (non-chiral)
environment. Diastereomers have different melting points, different IR
spectra, different reaction chemistry as well as different biology.
Consider the biologically
important D-aldohexose sugars, a set which includes glucose. Each D-aldohexose
has three variable chiral centres, which leads to a set of eight (2^3)
D-diastereomers, each with a unique and distinct melting point, IR and
H-NMR spectra, reaction chemistry and biochemistry:
As molecular size and complexity
increases, further degrees of freedom emerge. For example, molecular structure
cannot be fully described in terms of bond lengths, three atom [X-Y-Z]
bond angles and chiral centre configurations. As illustrated by hydrogen
peroxide, HOOH, here
and specifically, here,
the four atom dihedral angle emerges as an ever more important
Variations in dihedral angle
lead to conformational isomers, and variations in dihedral angle
with time lead to rotormers and dynamic molecular structures.
For example, at room temperature, cyclohexane, C6H12,
exists as dynamic mixture of interchanging chair, boat and in-between
twisted boat conformations, with attached groups adopting axial or equatorial
Most pharmaceutical agents
are smallish molecules (GFW = 50 - 300) that are able to enter enzyme
active sites or hormone receptor sites where they "mimic"
more technically, agonise (positive effect) or antagonise
(negative effect) the local biosystem in some way.
These days much drug
discovery research involves modelling how substrate molecules and
synthetic agonists & antagonists interact with and effect the active
site, a process that involves understanding
the conformation(s) and dynamic conformational changes adopted by
molecules while in or bound to the active site.
An example of the software
available to pharma industry scientists is Omega
by OpenEye Scientific Software.
Omega is able to "generate multi-conformer structure databases
so that conformational expansion of drug-like molecules can be performed".
Below are two [of thousands of possible] overlaid conformers of the
cholesterol-lowering medication Lipitor:
molecular structures grow in size and complexity, emergent properties
like diastereoisomerism and dynamic conformation become ever more important.
All reaction mechanisms can
be deconstructed into sequences of STAD (substitution-transfer-abstraction-displacement)
steps, as discussed here, although
it is usually more useful to consider reaction mechanisms in terms of
unit mechanistic steps and sequences of unit steps, as discussed here:
Many factors determine when
an particular mechanism is able to come into play, and mechanisms can
compete with each other. This is nicely illustrated by the common undergraduate
laboratory preparation of tertiary butyl chloride (2-chloro-2-methylpropane),
Tertiary butanol (2-methylpropan-2-ol), (CH3)3COH,
is carefully mixed with concentrated hydrochloric acid in a separating
funnel. After a few minutes an upper organic layer appears. After 30
minutes the lower aqueous layer is discarded, and the upper organic
layer is washed with aq. base/water, dried and distilled to give tertiary
butyl chloride, (2-chloro-2-methylpropane), (CH3)3CCl.
The yield of tertiary butyl
chloride is always low. One reason is because the reaction proceeds
via a first order nucleophilic substitution, SN1,
mechanism, a pathway that has a tertiary carbenium ion (3° carbocation,
R3C+) species as an intermediate. The 3° carbenium
ion can react in two ways: either it can complex with chloride ion nucleophile,
Cl, to give (CH3)3CCl,
or it can lose a proton, H+, to form methylpropene.
The ratio of alkyl chloride
to alkene is dependent on everything: temperature, solvent polarity,
mode of addition, relative and absolute concentrations, rate of stirring,
Reactions can give fast forming
kinetic products, or the more stable thermodynamic products. This effect
is illustrated with the sulfonation of naphthalene giving 1-naphthalene
sulfonic acid and/or 2-naphthalene sulfonic acid:
Under moderate temperature
conditions (~80°C) and short reaction times the 1-naphthalene sulfonic
acid is formed. This is the kinetic or "fastest forming" product.
At higher temperatures (~160°C),
the less sterically hindered and more stable the 2-naphthalene sulfonic
acid is formed.
Molecular conformation can
influence chemical reactivity.
Alkyl chlorides can undergo
base catalysed E2 elimination to give an alkene and HCl. The
base commonly used is ethoxide ion in a solvent of ethanol.
There is a rule explainable
in terms of frontier molecular orbital (FMO) theory that the
H and the Cl atoms must be "diaxial" (at 180° with respect
to each other) before the E2 mechanism can occur. This constraint is
not an issue with small molecules like 2-chloropropane, CH3CHClCH3,
where bonds are free to rotate, but things are rather more involved
Consider neomenthyl chloride
(below). There is a large, bulky isopropyl group, CH(CH3)2,
that prefers to sit in an equatorial position about the cyclohexane
ring, an influence that dominates the ring conformation. One effect
of this conformation is that the H and the
Cl are forced into axial positions that are 1,2 relative
to each other. The result is fast base mediated E2 elimination to give
However, in menthyl
chloride, a diastereoisomer of neomenthyl chloride, the chlorine
is held in an equatorial position by the bulky isopropyl function. In
this situation, it is only when the ring (occasionally) flips into another
conformation that the chlorine finds itself 1,2-diaxial with respect
to a hydrogen. The result is that menthyl chloride undergoes base mediated
E2 elimination at only 1/600th of the rate of neomenthyl chloride, and
the product is a different isomer, 3-isopropyl-6-methylcyclohexene:
Ph.D. students with research
projects looking at target synthesis or synthetic methodology learn to
explore how configuration and conformation influence competing mechanistic
previous page of this web book, here,
introduced the idea of the mechanism
matrix. However, the proposed schema which looked plausible
simply cannot be mapped to the complex terrain of reaction chemistry
the chemistry presented in textbooks simply does not reflect the reality
of low yield reactions where products are often accompanied by large
quantities of ill defined black gunk.
While systems at equilibrium
and approaching equilibrium are predictable and linear, as discussed here,
non-equilibrium systems are a rich source of complexity, emergent behaviour
There are two main ways of
producing a non-equilibrium thermodynamic state in a chemical system:
use electrical or photon stimulation rather than thermal (heat) energy
to excite the system, or, heat a system locally, but do not stir.
One of the central ideas
of equilibrium thermodynamics is that of the Boltzmann distribution
of particles between two (or more) states, i and j. The
rule is that at thermal equilibrium there will always be more
species in the lower energy state i than the higher energy state
However, if species are excited
from i to j is by a light source with a wave length/energy
that exactly matches the energy difference i and j (j
i), then a population inversion will be set up
with more species in the higher energy state j. This is a non-equilibrium
system, and the Boltzmann equation does not hold.
operation requires population inversion. The laser "works"
by species in the higher energy state falling to the lower state and
emitting a photon of energy j i. This photon stimulates
adjacent species in the higher state to emit their photon as well
as predicted by Einstein producing a cascade of coherent light,
where "coherent" light is all of the same frequency and is
According to classical
equilibrium thermodynamics, it should not be possible to form ozone,
O3, from dioxygen, O2:
because the Gibbs free energy
for this process is positive and anti- spontaneous at all temperatures.
The reaction is thermodynamically "disallowed" on both enthalpy
and entropy grounds. In fact, the reverse ozone to oxygen process, 2O3
3O2, has a negative Gibbs free energy at all temperatures.
However, ozone can be formed
when O2 is exposed to short wavelength UV light, the process generates
the ozone layer
high in the atmosphere.
+ UV photon 2O
O + O2
and other methods of non-thermal excitation are widely exploited.
If a layer of fluid is heated
from below, the density at the bottom layer becomes less than at the
top layer due to thermal expansion. Experiments, carried by Bernard
in 1900, showed that hexagonal convection cells develop, here:
The appearance of
Bernard cells is an example of order out of chaos. The local
heating causes entropy to increase, but the density inversion induces
complex & non-linear behaviour: convection cells that arrange into
a regular hexagonal lattice, classic emergent behaviour. This is exactly
analogous to the one dimensional waves of slowing and speeding found
on highways at high traffic densities. As discussed in the intro to
this section here.
of Bernard convection is that local heating can cause complex emergent
behaviour. To eliminate such effects it is necessary to stir (turbulently
mix) the fluid and render the system homogeneous.
The Sun also heats
our planet with thermal radiation, but the atmosphere is large and it
has a spherical geometry, so it cannot be mixed to homogeneous. Indeed,
on Earth, the Bernard cells present as ocean currents and weather systems.
Life on Earth
Our planet is
in a non-equilibrium thermodynamic situation with respect to the
The Sun heats
us and bombards us with high energy photons (light) that are exploited
by photosynthetic systems in cyanobacteria and plants to convert
carbon dioxide into glucose and oxygen.
of non-equilibrium thermodynamic systems generating complexity are
both extraordinary and profound, as eloquently summed up by Prof.
Peter Atkins of Physical Chemistry textbook
fame on the BBC:
driving force [for complexity on Earth] is the Sun. It dissipates
its energy and drives the processes of life on Earth. An analogy.
Imagine you were sitting in front of a screen and there was a
weight on the floor, and you saw the weight rise up. You would
think it was a miracle. But if you looked behind the screen and
see there is a heavier weight that is falling down and pulling
the front weight upwards, you realise there is a rational explanation.
That is, the dispersing energy [of the falling weight] is driving
the events that give rise to complexity [the weight rising]. Overall
there is increasing disorder, but locally there is increasing
The BBC has
a listen again facility, and you can hear this fascinating discussion
about the second law of thermodynamics on the BBC
web site and clicking the "Listen Again" link. Real
Player is required as the download file is .RAM format, not
living cells consists of just a few hundred chemicals: amino acids,
sugars, metabolites, intermediates etc., as well as the molecular
biology apparatus for replication and protein synthesis. However,
the various enzyme catalysed biochemical processes are not at thermodynamic
equilibrium. The emergent complexity of the cell is due to
it being a non-equilibrium system. A dead cell that is at equilibrium.
For a technical discussion
of non-equilibrium thermodynamics go to the Wikipedia page, here.
systems are prone to develop in complex ways that exhibit emergent behaviour.
If the following reagents are
added together in a flask:
and the reaction mixture is
stirred vigorously, an oscillating Belousov-Zhabotinsky reaction
(BZR) is set up:
The BZ reaction
is an auto-catalytic reduction-oxidation (redox) process. Each step
of the multi-step reaction sequence generates a catalyst that speeds
up the counter reaction:
As the reduction
step proceeds it produces more and more catalyst to speed up the oxidation,
and vice versa.
The reduced state
reaction is red while the oxidised state is a pale brown.
But if the reaction system
is not stirred, diffusion
control takes over. This can be observed when the reaction mixture
is prepared as a thin film, 0.5 - 1 mm deep, to avoid any vertical mixing,
and waves of reaction can be seen propagating through the unstirred mixture:
For a chemical reaction
between X and Y to proceed, the chemical species first have to meet
each other in the reaction medium. In an unstirred reaction medium,
the rate at which the various chemical species move, meet and react
is limited and so controlled by the speed that the species
diffuse through the reaction medium. The effect the BZ
type auto-catalysis is to cause the rather dramatic moving waves, and
these are made visible by the colour change.
There are many resources
about the BZ reaction and other non-linear process on the web:
metals, alloys [and other materials] solidify by the growth of complex
crystals called dendrites. Unlike most inorganic crystal which
display a faceted interface, dendrites exhibit a smooth, continuously
variable interface, which displays multiple branching. This leads
to the formation highly complex growth patterns."
The left image
shows a theoretically modelled dendritic crystallisation that is is
described as "seaweed". The image to the right shows the
"as-solidified microstructure of Cu undercooled by 280 K".
may undergo a kinetically induced instability which results in repeated
multiple tip splitting, or doublon formation":
efficiency can be boosted if the active material is deposited on a solid
support with a fractal surface:
render of Ru10Pt2 catalyst
particles (shown in red) anchored on and within a disordered porous
silica support (grey). Data was obtained via tomography, an electron
microscopy technique that generates a three-dimensional volume from
a series of two-dimensional projections taken at different angles.
A fractal analysis (performed using standard box-counting algorithms)
revealed that the fractal dimension of the surface to be 2.4 +/- 0.1.
The number of catalyst particles accessible to reactant gas molecules
will therefore depend on their size according to this fractal distribution
of surface sites, strongly influencing catalytic activity and selectivity." EPW Ward, T J V Yates and P A Midgley, Department
of Materials Science, University of Cambridge.
usually like to work with turbulently mixed, homogeneous solutions so
as to avoid diffusion controlled artifacts. Materials
scientists are not so lucky, and they often have to work under diffusion
Time, Gravity, Geometry, Temperature, Chemical Potential, Physical Separation
Chemists use clever experimental
design implemented using laboratory equipment constructed from
glass, stainless steel, rubber tubing and Teflon that exploit time,
gravity, geometry, differential temperature, chemical potential, physical
separation, etc., to influence the outcome of reaction and separation
processes, usually to maximise the % yield or separation of a particular
material or compound and/or to minimise the formation of unwanted by-products
There as a number of standard
pieces of laboratory equipment: flasks, condensers, syringes, pipettes,
burettes, separating funnels, filters, Bunsen burners, Dean & Stark
traps, etc., (in different sizes). Bespoke equipment is developed as well.
This lab apparatus dramatically increases the complexity of reaction chemistry
As a first approximation,
the reaction system is the system universe, here.
But as soon as the reaction system is constrained to a physical experiment,
the reaction system is bound by the experimental design.
Some examples taken
from literally thousands of possible examples of how intelligent
design is used to optimise a reaction system space in various ways:
The Bunsen Burner
Methane burns in air, but
in the Bunsen
burner, methane is premixed with air to create a mixture that burns
with a hot, smokeless flame. The Bunsen burner is carefully designed
and constructed to maximise localised heating.
The Dean & Stark Trap
Benzaldehyde reacts with
ethylene glycol (1,2-dihydroxyethane) to form the cyclic acetal (2-phenyl-1,3-dioxolane).
The reaction is an equilibrium process, and the cyclic acetal product
can be formed in 100% yield if the water by-product is removed as it
One very convenient and elegant
method for removing the water from the reaction is to use an azeotroping
solvent, such as toluene, with a Dean
& Stark trap:
The water produced in the
reaction is co-distilled with the refluxing toluene solvent with which
it forms a vapour phase azeotrope. The toluene/water vapour phase complex
rises into the condenser where it cools and condenses. However, as liquids
toluene and water are immiscible and they separate into two phases.
The denser water (containing a blue dye in the photo above) collects
in the "trap", and the toluene - with water removed - returns
to the main reaction vessel.
With this experimental design:
gravity, temperature are geometry are exploited.
Gravity is required
to set up two density gradients:
The hot vapour
phase azeotrope rises into the condenser.
Immiscible water and toluene separate in the trap.
Dean & Stark apparatus would not work in the zero gravity of
the International Space Station.
temperature differences are required to:
Overcome the activation
energy and speed up the reaction.
Form the refluxing reaction mixture and produce the vapour
Condense the vapour phase azeotrope into the two immiscible
liquids, water and toluene.
The geometry of
the Dean & Stark trap physically separates the water generated
in the reaction and so drives the equilibrium position to the formation
of the acetal.
A experimental set up
with a simple reflux condenser would not drive the equilibrium to
the right by removing the water.
Temporal (time) considerations
usually involve exploiting differential rates of reaction, where "rate"
is measures of moles of material transformed per unit time.
Cyclopentadiene is a reagent
commonly used in the study cycloaddition chemistry (here),
and organotransition metal chemistry.
However, the cyclopentadiene
monomer is in equilibrium with the dimer. At room temperature the
dimer is stable and over just a few hours the cyclopentadiene monomer
will completely dimerise.
Therefore, before use the
cyclopentadiene dimer must be cracked to the cyclopentadiene
To use cyclopentadiene
in a reaction it is necessary to heat the dimer at reflux (170°C)
for a couple of hours to "crack" the dimer to the monomer.
The pure monomer is distilled off and used immediately, and before
it has time to re-dimerise. The rate of dimerisation can also be reduced
by dilution in a suitable solvent.
Chemical Potential (Reagent
Benzene is nitratrated to
nitrobenzene with nitrating mixture, here,
a mixture of concentrated sulfuric acid and concentrated nitric acid.
Nitrating mixture produces as equilibrium concentration of nitronium
ion, [NO2]+, the electrophilic agent which partakes
in the electrophilic aromatic substitution of benzene.
However, vary in their reactivity
towards nitration. Activated aromatics like phenol are nitrated far
more easily than benzene and the reaction can be carried out with dilute
nitric acid. Other aromatic compounds require more forcing conditions
(or are not stable in nitrating mixture) and for these situations the
highly potent nitronium tetrafluoroborate can be used. This ionic reagent
consists of the tetraborate ion, [BF4], stabilised salt or nitronium
The chemical potential of
the nitrating agents increases:
dilute nitric acid <<
nitrating mixture << NO2BF4
Another example. It is a
common procedure in synthetic chemistry carry out the nucleophilic substitution
of a nucleofugal leaving group at an acyl carbon centre. (This mechanism
is also referred to as addition-followed-by-elimination and the tetrahedral
mechanism.) It is known that leaving group ability the ease with
which X is lost correlates with the pKa
of the leaving group's conjugate Brønsted acid. With this knowledge
in mind it is possible to develop a range of substituted acyl species
which under go ever more facile substitution with a nucleophile.
Reagents with greater chemical
potential partake in more exothermic reactions. For example, a methyl
ester can be converted into an ethyl ester by adding excess ethanol
and a bit of H+ catalyst (a couple of drops of conc. H2SO4
or 0.1g of para toluene sulfonic acid). No heat will be generated as
the Keq is about 1.0. However, if ethanol
is added directly to acid chloride will be a great fizzing as the reaction
gets hot because it is very exothermic.
process environments can be designed chemically, spatially, thermally
most reaction systems, chemists are able to prepare (or buy) a reagent
of suitable power and reactivity.
The species must be
stable over a defined time scale and/or set of conditions. For example,
benzyne is an interesting
an useful chemical species that "exists", but it is only transiently
stable at room temperature and is only known as a reactive intermediate
in solution. These days many chemical reagents are available that are
long lived, but that are not stable when exposed to air and/or moisture.
Examples of such compounds would be lithium aluminium hydride, LiAlH4,
and methyl cyanoacrylate, otherwise known as "Superglue".
There must be a method
of making synthesizing the species in question. In other
words there must be a suitable reaction mechanism (atom-to-atom
mapping) available AND there must be practical reaction conditions
available to make the compound AND under these conditions there must
not be any alternative reaction mechanism available which will render
any intermediates or the final product unstable.
A pertinent paper
titled "What Is the Smallest Saturated Acyclic Alkane that Cannot
Be Made?" (de Silver & Goodman, J.
Chem. Inf. Model. 2005, 45, 81-87), examines this very question
with respect to branched alkanes, exemplified by the structures below:
The C5 (five carbon)
molecule above, neopentane, is well known but the C17 homolog (3,3-bis-(1,1-dimethylethyl)-2,2,4,4-tetramethylpentane)
is unknown. The paper's authors write: "[The C17 molecule] has
never been synthesized, and studies show that it must be extremely strained.
However, this is not a proof that it is impossible to prepare. Indeed,
molecules which include this carbon framework have been synthesized..
and their existence suggests preparation [of C17] may be possible."
It was argued above that the
set of compounds is a complex, broken terrain. That being the case,
the synthetic route to a specific compound must involve a complex path
through the broken terrain exploiting intermediate compounds to act
as way points up the mountain.
Synthesis is analogous with
the well known children's game of Snakes
& Ladders or Chutes
& Ladders where ability to produce a material or compound
is a synthetic ladder, and lack of stability is an anti-synthetic
snake. In reaction chemistry space there are few ladders but many,
Consider a couple of related
examples from industrial inorganic chemistry: the extraction of the metals
iron, Fe, and titanium, Ti, from their oxide ores, Fe2O3
and TiO2. Both oxide ores are common and both can
be reduced by carbon at high temperature.
Extraction of Iron
The overall iron(III)
oxide plus carbon reduction reaction is:
This reaction process represents
a "synthetic ladder": at high temperature (1200°C) the
reducing ability of the carbon and the entropy driven loss of gaseous
CO2 is able to drive a redox reaction to give
liquid iron metal. (The pig iron produced by a blast
furnace must be further purified to steel and wrought iron, but this
is not the issue here.)
Extraction of Titanium
can also be reduced by carbon to titanium metal and carbon dioxide,
however, the hot titanium reacts with carbon to form titanium carbide,
Even small amounts of TiC
impurity make titanium metal very brittle and unusable. The titanium
carbide cannot be removed, and its formation is an "anti-synthetic
snake". As a result, the simple, direct carbon reduction
reaction pathway cannot be used.
An alternative pathway is
employed by industry, the Kroll
process. The carbon reduction reaction is carried out in the presence
of chlorine, Cl2, to form titanium(IV) chloride,
TiCl4, and carbon dioxide. A great advantage of
this method is that titanium tetrachloride is a low boiling point molecular
liquid, bp 136°C, which can be distilled to very high purity. In
the second synthetic step, titanium tetrachloride is reduced with sodium
or magnesium metal to give high purity titanium metal and sodium (or
That is not quite the end
of the story because there are other anti-synthetic snakes: titanium
tetrachloride is readily hydrolysed by water, at elevated temperature
the titanium metal is rapidly oxidised by air back to titanium(IV) oxide
and hot titanium even reacts with nitrogen, N2,
to form titanium(III) nitride, TiN. As a result, air and moisture have
to be rigorously excluded, and the second-step processes are carried
out under an atmosphere of inert argon.
The major downside of the
two-step synthetic route to titanium is that it is expensive, not because
of the use of argon which can be recycled, but because two moles of
chlorine and four moles of sodium are consumed for each mole of metal
produced; the process is said to have a poor atom
economy. However, titanium is so useful as a material that the expense
of the extraction process can be adsorbed.
The thirteen-step synthesis
of vitamin A, by O. Isler et al (1947), shows a long and complex
O. Isler et al, Helv. Chima.
Acta, 30, 1911(1947)
R. O. C. Norman, Principles
of Organic Synthesis, Chapman and Hall, 1978, pp 711
The reason why the total synthesis
of natural products is so tantalising to the cognoscenti is that Nature
throws up some extraordinary structures, and the biosynthetic route
if known is usually little guide to developing a successful laboratory
And, of course, the beauty of
the natural product is that there can be no doubt that the species really
does exist, so lack of stability arguments cannot be used!
the greatest synthetic chemist of the 20th century, was heard to say
while his research group was attempting a particularly difficult synthesis "If we can't make strychnine,
we'll take strychnine."
Or, as more put
generally by the scientific philosopher, and advocate of Darwin, T.H.
Huxley (1825-1895): "The great tragedy of science - the slaying
of a beautiful hypothesis by an ugly fact"
set of possible compounds is a broken terrain, and the individual species
that occupy this space can act as stepping stones or way points, from
which multi-step synthetic routes are constructed.
the broken terrain there will be compounds which in principle exist
but which in practice cannot be made, however, this can never be proved.
brings in some philosophy. Karl Popper introduced the idea of falsifiability in science, the notion that a scientific idea can only proved to be
false, not true: "All crows are black because [insert your theory
here]". Find one white crow, and the black crow theory is false.
of unnatural target compounds turns this idea round because there
are many ways not to make something. It follows that it is
impossible to prove that a compound cannot be synthesized, only that
a synthetic route a series of synthetic ladders in reaction
chemistry space that avoids all of the anti-synthetic snakes is very
difficult, and in the 20th century target synthesis represented the
pinnacle of chemical science. Will this continue in the 21st century?
& Complexity: Summing Up
is and will remain an experimental science because predictions
can seldom be made from first principles due to the inherent complexity.
predictions are made from theory they always need to be verified
in the laboratory.
There is an excellent & recent RSC paper (2008) that discusses these matters:
R. Frederick Ludlow & Sijbren Otto Systems Chemistry
Chem. Soc. Rev., 2008, 37, 101-108