thesis
Uncertainty in chemistry
It might come as a disappointment to some chemists, but just as there are uncertainties in physics
and mathematics, there are some chemistry questions we may never know the answer to either,
suggests Fredric m. menger.
In physics, the Heisenberg uncertainty
principle advises us that the momentum and
position of an electron cannot be known
both precisely and simultaneously. Similarly
in mathematics, Gödel’s incompleteness
theorem tells us that, given a formal theory
proving certain basic arithmetic truths,
there are other arithmetical statements
that are also true but not provable by that
theory. These two concepts have had an
enormous impact not only on physics and
mathematics, but on scientific philosophy in
general. For example, uncertainty in nature
has been extended to an inherent inability
to ever understand human behaviour in
detail. After all, the mind can only know
about itself by relying on what it knows
about itself. In chemistry, however, the
issue of uncertainty seldom arises. But
one cannot help wondering what aspects
of chemistry, if any, lie outside the realm
of ‘knowability’.
For two hundred years following the
late-seventeenth century, the physical
sciences dealt with ‘simple’ problems in
nature where two variables were examined
while keeping all other parameters constant.
Laws of motion and causality dominated
scientific thinking. For example, acceleration
could be determined from the mass of an
object and the force placed upon it.
Meanwhile, biology was largely engaged
in the preliminary stages of a science
involving non-quantitative collection,
description and classification.
Developments in the late 1800s,
spurred on by pioneers such as
Josiah Willard
Gibbs,
led to an entirely
different approach to the
physical sciences. The idea was not
to study two variables but to confront
‘billions’ of variables with the powerful tools
of probability theory and statistical mechanics.
Although individual variables might be erratic
— or not even known — a system collectively
possesses a certain order and analysable
average properties. Warren Weaver labelled
such systems ‘disorganized complexity,’ and
698
in a 1948 paper illustrated the concept using a
billiard table1.
Weaver pointed out that classical
dynamics can readily analyse the motion of
a ball moving about on a billiard table. In
other words, the relationship between the
positions of the ball and the times it reaches
these positions is predictable. Even two or
three balls are amenable to analysis but,
as the number of balls increases, further
analysis becomes more and more difficult.
With, say, only fifteen balls, an exact solution
becomes unmanageable. The problem
derives not from any particular theoretical
limitation (classical mechanics still applies)
but from the sheer impracticability of
dealing with so many variables. Now
imagine a huge billiard table with millions
of billiard balls moving about randomly and
colliding with each other and with the sides
of the table. As the precepts of statistical
mechanics are now applicable, the analysis
is actually simplified! Although it is not
possible to trace the motion of any one
particular billiard ball, one can calculate
how far — on average — a ball moves before
being hit by another ball.
Or one
can calculate — on average — the number of
impacts per second experienced by a ball.
Assume now that there is a city inhabited
by one million people, whose government
would like to know the number of its citizens
living in poverty. It would be possible — but
impractical — for the city government to
question each and every citizen as to their
financial situation. Now the city may decide
to survey a portion of the population, one
thousand people for example, and assume that
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the percentage of poor people in the sample
is a good approximation of the percentage
of poor people in the entire city. Note that
specific information, namely the identity of
the individuals living in poverty, would be lost
in the process.
Obviously it would be impossible for a
chemist studying a given property among
a million molecules to investigate each and
every molecule. For us chemists, however,
even the sampling method goes beyond our
capabilities. There is no way of interrogating
individually a thousand molecules in a
sample of a million molecules. The best the
scientist can do is apply statistical methods.
Consider, for example, a flask of oxygen
held at constant temperature. Although the
energy of any particular oxygen molecule
cannot be determined, one can use statistical
ideas to compute the energy distribution
of the molecules and the average energy
among them. The laws of thermodynamics,
fundamental to much of
chemistry, rest on
such statistical concepts
applied to complicated systems.
Monte Carlo and molecular dynamics
(MD) methods are among the most powerful
ways of addressing multiple molecule systems
by statistical mechanics. Such techniques
enable important thermodynamic parameters
— such as average solvation energies — to
be calculated from first principles, and this
must be considered a major intellectual
accomplishment. Experimental data
consistent with these computations would
lend a degree of confidence in the MD
method. But what if, for one of any of a

number of reasons, experimental data are not
yet available or, worse, impossible to acquire?
We must then contemplate even more
diligently the uncertainties in the MD method
that might conceivably have led us astray. For
example, does the final MD structure reside at
a global minimum rather than a local one, and
have the force field parameters been correctly
parameterized for the problem at hand?
A dilemma is thus faced when
computations are carried out on complicated
systems — either relevant experimental data
are available (or can be made available) and
computations serve primarily as a guide, or
no experimental verification seems possible
and Karl Popper’s requirement of ‘falsifiability’
rears its ugly head4. As must be clear from the
discussion thus far, computations are no doubt
valuable, but they are not, by themselves,
a source of unassailable knowledge as can
be provided by a sound experiment on a
simple system — uncertainties still remain.
Molecular dynamics is a form of modelling
and, as pointed out by Friedrich Hyek,
modelling can enable only pattern predictions,
whereas precise predictions are available from
non-complex phenomena5.
A key question, therefore, is whether
chemical systems exist that in principle
cannot ever be understood? Stated otherwise,
is there an ‘uncertainty principle’
or ‘incompleteness
theorem’ in
chemistry? I
will answer these questions
affirmatively. This response has nothing to
do with those pessimistic scientists who over
the decades have foolishly asserted that ‘an
end to science is near’. I am saying no such
thing. I am, however, claiming that elements
of chemistry will always remain unknown and
unknowable, and I now give an example taken
from our own laboratory 6.
Poly(allylamine) (Mw = 50–65 kD) is a
polymer whose long chain bears roughly
a thousand amine groups (see below).
1,000
NH2
The polymer was derivatized with a mixture
of three or four carboxylic acids selected
from a library of acids. For example, one
particular polymer possessed 7.5% octanoic
acid, 10% p-hydroxybenzoic acid, and 15%
4-imidazoleacetic acid (where ‘%’ refers to the
percentage of amine groups on the polymer
chains that had been joined to an acid through
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amide linkages), plus 5% Fe3+. Owing to the
free ammonium groups remaining on the
polymer, the polymers were always water-
soluble. Hundreds of different polymeric
systems were prepared rapidly, each differing
in the structure and/or percentage of acids
used in their synthesis. These polymeric
systems were then screened, combinatorial-
style, for their ability to catalyse the hydrolysis
of a phosphodiester. It was immediately
clear that certain polymer combinations are
far more effective catalysts than others. For
example, the ‘recipe’ given above enhances the
hydrolysis by a factor of 1.5 × 105 at a polymer
concentration of 5 × 10–5 M. In contrast,
derivatization of poly(allylamine) with only
a single functional group never produced a
catalytic polymer.
Unfortunately, it was not possible, and will
never be possible, to probe and understand
the polymer catalysis at the molecular level.
Because each sample contained >1016 polymer
molecules, and it would be an unlikely
statistical coincidence if any two polymer
chains happened to be identical, there
exists a completely intractable
mixture. Thus, it is
not possible,
and will never
be possible, to determine
which of the >1016 sequences are
the ones possessing catalytic activity. If, for
example, only 1% of the polymer chains are
catalytic (the rest being inert), then the actual
rate enhancement associated with them would
be 1.5 × 107. But detailed information of this
sort is not accessible because no conceivable
experiment, present or future, can unravel the
enormous complexity of the heterogeneous
polymer system. Thus we have on hand a
potentially useful chemical system that is as
doomed to uncertainty as is the position or
momentum of an electron.
One might, of course, claim that
uncertainty is indeed associated with
the polymer system, but it is of a rather
specialized nature — that is, it is not a
fundamental property. True though this
might be, it misses the point. Whether
complexity is a fundamental property or not,
it creates a need to separate >1016 different
molecules, determine the structure of every
single molecule (each with its characteristic
number and position of substituents), and
synthesize them for catalytic screening.
Although chemists, of course, do know
how to separate, determine structure, and
synthesize, they obviously cannot do this on
a scale of 1016 different molecules. In fact,
it is not at all obvious how one could even
begin to sequence and then synthesize a
single poly(allylamine) derivative with, for
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thesis
example, imidazole on residues 22 and 32,
a p-hydroxylphenyl on residues 13, 78 and
139, and an octyl group on residues 3, 19,
25 and 201 as might exist (who knows?) as
one permutation among the mixture of >1016
distinct molecules.
Although our polymer system defies any
possibility of analysis at the molecular level,
interesting information can nonetheless
be extracted from it. For example, the
polymer catalyst can be tested with a
variety of phosphodiester substrates to see
if it exhibits any structural selectivity. If the
rate enhancement declines with increasing
temperature, this would (tentatively)
suggest that catalysis depends upon a
heat-sensitive folding of the chains.
And if catalysis requires
a certain percent of
imidazole residues (as
it does), then
this would
(tentatively)
suggest that imidazole
is involved in the catalytic
mechanism. Of course,
to some extent our view of such a
complex system will depend on the selection
of the particular experiments applied to it
(reminiscent of the proverbial blind men
touching different parts of an elephant and
reporting back their disparate views of what
an elephant looks like).
Such uncertainty, however, need
not preclude utility. Suppose that a
poly(allylamine) system is found that rapidly
cleaves cellulose into glucose with a high
turnover number. Production of glucose from
cellulose by this means would allow a cheap
and renewable source of a fuel — ethanol —
by subsequent fermentation of the glucose.
Developing such a polymer catalyst by
random screening is a dream, but it is a dream
with a finite chance of succeeding. Success
would mean having in hand a highly useful
catalyst that, as already proven, will never
be understood.
Apart from Heisenberg and Gödel, there
are innumerable aspects of the universe
that will never be known and predicted
precisely: the number of stars; what it is
like to be an armadillo; the IQ of humans
50,000 years ago; the volume of ash from
a volcanic explosion. But among the list of
‘unknowables’, the poly(allylamine) catalyst
has salient properties worth summarizing:
(1) it is an organic chemical system; (2) it
was prepared in a single step by routine
procedures; its origins are neither esoteric nor
particularly complex; (3) any given system,
with its own unique set of >1016 molecules,
can be made reproducibly as indicated by a
constant catalytic activity from preparation
to preparation; (4) the catalyst serves a useful
699
 thesis
function with as yet unrealized potential for
commercial importance; (5) its molecular
details are unknowable; if ‘intrinsic’ is defined
as ‘belonging to the essential nature or
constitution of a thing’, then uncertainty is
intrinsic to the observed catalysis.
Although our polymer system does not
exhibit mobility, mobility greatly exacerbates
uncertainties in a disordered molecular array.
For example, consider a binary mixture of
ethanol and water at ambient temperature.
Although only two species are involved
here, the system defies a detailed molecular
description owing in part to mobility of
the components and the lack of a single
© ISTOCKPHOTO / GlObalP / lIfe On WHITe
equilibrium configuration. Thermodynamics
can provide useful information (such as
the heat of mixing) but obviously not at the
molecular level. Computations in MD are
also useful but have limitations, especially
with regard to an inability to test
experimentally (‘falsify’) the
MD model. Thus, neither
X-rays, NMR, IR, MS,
EM, DLS nor any other
experimental acronym is
700
capable of establishing the identity, geometric
disposition, and dynamic properties of,
for example, the molecules transiently
surrounding ethanol’s methyl group in an
aqueous solution. Our polymeric catalysts are
recalcitrant despite their static nature.
There is an important difference between
uncertainty in chemistry and uncertainty
in physics and mathematics. Uncertainty in
physics and mathematics is universal — one
will never be able, for example, to determine
precisely and simultaneously both the
momentum and position of an electron no
matter what the particular environment of
the electron. In chemistry (and, by extension,
biology) the problem is that, as we have just
seen, uncertainty in potentially useful systems
arises from our own physical limitations.
Systems may simply lie beyond present and
imaginable future experimental capabilities.
Now if some systems can be too
complicated to ever understand,
whereas other systems can
obviously fall within scientific
reach, then the question
arises as to where one draws
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© 2010 Macmillan Publishers Limited. All rights reserved
the line between the two. This question is
unanswerable in part because the demarcation
line changes with time (chemists’ arsenal of
investigative tools is constantly expanding).
In conclusion, we are left with a lesson
in humility (which will disappoint those
reductionist chemists accustomed to
predicting and controlling): Just as physics
and mathematics possess an inherent
uncertainty, so does chemistry — and it
may prevent chemists from ever being
able to explain and predict all aspects of
their discipline. ❐
Fredric M. Menger is in the Department of
Chemistry at Emory University, Atlanta,
Georgia 30322, USA.
e-mail: menger@emory.edu
References
1. Weaver, W. Am. Sci. 36, 536 (1948).
2. Heinrich, A. J., Gupta, J. A., Lutz, C. P. & Eigler, D. M. Science
306, 466–469 (2004).
3. Yang, H. Curr. Opin. Chem. Biol. 14, 3–9 (2010).
4. Popper, K. Conjectures and Refutations (Routledge and
Keagan Paul, 1963).
5. Hayek, F. Nobel Lectures (World Scientific, 1992).
6. Menger, F. M., Eliseev, A. V. & Migulin, V. A. J. Org. Chem.
60, 6666–6667 (1995).