FEATURE

Simple calculations, principles,

and techniques to prevent
reactive chemicals events
in the laboratory
Most chemical reactions are exothermic and have the potential for an uncontrolled runaway if not
conducted properly. Understanding how much heat is released, the potential consequences of an adiabatic
temperature rise, the rate heat is released, and the rate heat can be removed can help prevent a runaway and
its potential undesired consequences. Simple calculations to estimate the heat of reaction and potential
consequences, and a review of some principles that affect reaction rates and rates of heat loss are examined.
Experimental techniques are presented to minimize risks when limited data are available.

By Gary R. Buske
INTRODUCTION
Whether following an established pro-
cedure or exploring new chemistry,
there are some simple things to do to
greatly reduce the probability of having
a reactive chemicals incident. Even
simple changes to a presumably safe
established procedure could result in a
runaway reaction and undesired con-
sequences. Most laboratory processes
are run either as batch reactions,
where all the reactants, solvents, etc.
are loaded into the reactor and heated
(or cooled) to the desired reaction tem-
perature until done, or semi-batch
where one reactant is slowly added
to the others. A reaction is generally
run in semi-batch mode in order to
control the heat of reaction, and/or
because a low concentration of the
added reactant is desired to prevent
unwanted side chemistry. Sometimes
two or more batch reactions are run
sequentially in the same reactor. For
example, a base may be added to
deprotonate a substrate, then an elec-
trophile may be added to complete the
Gary R. Buske, Ph.D., is a retired
process chemist from Dow Chemical in
Midland, MI;
e-mail: buskegr@charter.net.
sequence. Either procedure can lead to
a reactive chemical runaway, but since
there is less control in a batch process,
it is the more likely one to cause pro-
blems.
There are four questions to consider
when trying to assess the reactive che-
mical hazard potential of a reaction.
(1) How much heat will be released by
the desired reaction? (2) What are the
potential consequences of this heat
release such as adiabatic temperature
rise, pressure increases, or gas volume
generated due to solvent vaporization?
(3) How fast is the heat released? (4)
How quickly can the heat be removed?
This paper will not consider competing
reactions which may occur at higher
than normal temperatures, or reactive
chemistry events associated with
shock sensitive materials or explosives.
DISCUSSION
In order for a reaction to proceed
spontaneously, the free energy change
(DG, Eq. (1)) must be negative.
DG ¼ DH  TDS
In most cases, the entropy change
(DS) is small, and the free energy is
dominated by the enthalpy change
(DH), which therefore must also be
negative.1 The enthalpy change (heat
of reaction) can be determined calor-
imetrically,2,3 but it can also easily be
estimated using either bond energies or
heats of formation.4 In the first method
you sum the bond energies of all the
new bonds formed and subtract that
from the sum of the bond energies of all
the bonds broken (Eq. (2)).
X
DHrxn ¼ Bond Energiesðbonds brokenÞ
X
 Bond Energiesðbonds formedÞ
(2)
The second method requires the sub-
traction of the sum of the standard
heats of formation of the reactants
from the sum of the standard heats
of formation of the products (Eq. (3)).

X
DHrxn ¼ ½DH fðproductsÞ 
X
 ½DH fðreactantsÞ  (3)
Because the bond energy method
uses average bond dissociation ener-
gies in the gas phase and does not
account for changes in strain energy
and resonance energy, the latter
method is generally more accurate.
Neither method accounts for solvation
energy changes. Often, standard heats
of formation cannot be found for the
(1)
exact reactants and products of inter-
est. In that case, a model reaction using
simpler reactants and products that
still incorporate the desired functional
group transformations can be used.
Bond energies and standard heats of
formation can be found in a variety of
common sources.4–8

1871-5532/$36.00 ß Division of Chemical Health and Safety of the American Chemical Society 9
doi:10.1016/j.jchas.2009.08.001 Elsevier Inc. All rights reserved.
 Once a standard heat of reaction has
been estimated, the potential adiabatic
temperature rise (Dt) can be calculated
using Eq. (4).
nDH rxn ¼ q ¼ cmDt (4)
The q is the heat released, and is cal-
culated by multiplying the standard
heat of reaction by the moles (n) actu-
ally being used. The total mass of all
reactants, solvents, etc. is m, and c is
the specific heat of the reaction mix-
ture. Since c is generally not known,
the specific heat of the solvent can be
used to get an estimate of Dt. The
specific heat of water is 1 cal/g 8C,
while the specific heats of many
organic solvents are about 0.5 cal/
g 8C.5,6,8 This calculation assumes
adiabatic conditions. It also assumes
nothing else happens, such as solvent
vaporization, before the final tempera-
ture rise is achieved. If the solvent boils
before the final temperature rise is
reached, then the excess heat will go
into the heat of vaporization of the
solvent (DHv).5,6,8 The amount of sol-
vent vaporized can be calculated
(Eq. (5)), as well as the volume the
solvent vapor would occupy (Eq. (6)).
q ¼ DHv m (5)
PV ¼ nRT (6)
As an example, consider the simple
amine alkylation reaction of n-butyl
bromide with di-n-propylamine to
make a tertiary amine (Eq. (7)).
n-C4 H9 Br þ 2ðn-C3 H7 Þ2 NH
! ðn-C4 H9 Þðn-C3 H7 Þ2 N
þ ðn-C3 H7 Þ2 NH2 þ Br (7)
Assume this is to be run on a 0.1 mol
scale at a concentration of about 0.5 M
n-butyl bromide in acetonitrile at
72 8C, 10 8C below the solvent boiling
point to allow some room for the reac-
tion to exotherm. Twice the amount of
amine required will be used to try to
minimize any reaction of the product
with the n-butyl bromide. Thus, a solu-
tion of 13.70 g (0.10 mol) n-butyl bro-
mide, 40.48 g (0.40 mol) of di-n-
propylamine, and 135 mL (105.71 g)
of acetonitrile are heated to 72 8C.
Since standard heats of formation of
these compounds might not be readily
available, the simple case of methyl
10
bromide reacting with dimethylamine
to form trimethylamine and dimethy-
lammonium bromide is used as a
model as shown in Eq. (8) along with
standard heats of formation.5,7
CH3 BrðlÞ þ 2ðCH3 Þ2 NHðlÞ ! ðCH3 Þ3 NðlÞ þ ðCH3 Þ2 NH2 þ Br ðaqÞ
14:20 Kcal=mol 10:5 Kcal=mol 11:0 Kcal=mol ð28:74 þ 29:05Þ Kcal=mol
For the ammonium salt, the standard
heats of formation of 1 M aqueous solu-
tions of the dimethylammonium ion
and the bromide ion are summed. Using
Eq. (3), the standard heat of reaction for
this model system is:
DH rxn ¼ ð11:0 þ 28:74 þ 29:05Þ
 ð14:20 þ ð2Þð10:5ÞÞ
¼ 33:6 Kcal=mol
Since the reaction is run on a 0.1 mol
scale, the heat (q) will be 3,360 cal-
ories. From Eq. (4), using the specific
heat of acetonitrile (0.53 cal/g 8C),5
the adiabatic temperature rise (Dt) is:
Dt ¼ 3; 360=0:53=ð13:70 þ 40:48
þ 105:71Þ ¼ 39:6  C
Since Dt is greater than the difference
between the solvent boiling point
(82 8C) and the specified reaction tem-
perature (72 8C), under adiabatic con-
ditions the heat released will first raise
the temperature to the boiling point,
and then vaporize the acetonitrile.
Again from Eq. (4), only 847 cal are
required to raise the temperature to
the boiling point, leaving 2,512 cal to
vaporize the acetonitrile. Since the heat
of vaporization of acetonitrile is
173.7 cal/g,5 14.5 g (0.353 mol) of acet-
onitrile could be vaporized (Eq. (5)).
From the ideal gas law (Eq. (6)), that
corresponds to 10.3 L of gas at one
atmosphere and 82 8C. A reaction of
this size might be run in a stirred
250 mL round bottom flask equipped
with a reflux condenser, and a heating
mantle plugged into a temperature con-
troller. The potential gas volume gener-
ated is 41 times greater than the flask
volume. If the reaction rate is very slow,
the heat loss from the equipment may
be sufficient such that no exotherm is
seen, and the temperature is controlled
Journal of Chemical Health & Safety, March/April 2010
at 72 8C. At some faster rate, the
exotherm could occur and cause the
acetonitrile to reflux. The heat removed
by the reflux condenser may be suffi-
cient to contain and control the reac-
(8)
tion. However if the reaction is very fast,
the reaction would exotherm to the
boiling point where the solvent could
boil more and more vigorously until the
condenser is flooded and overwhelmed.
In an open system, this may result in the
separation of a stopper or a joint, and
allow a mixture of liquid and vapor to
escape. The result is likely a fire. Alter-
natively, if this reaction were run in a
closed 250 mL system, an internal pres-
sure of 41 atmospheres at 82 8C is cal-
culated (Eq. (6)) under adiabatic
conditions. If the reaction apparatus
is glass, it will fail catastrophically
resulting in a severe pressure event
and a fire. These simple calculations
imply that running the reaction as
described might not be safe unless we
can control the kinetics of the reaction
and the rate of heat loss from the equip-
ment.
Anticipating what the rate of any
given reaction might be is difficult.
One usually relies on the conditions
reported in the literature for the desired
reaction or a similar reaction. However,
all one often finds is a reaction tempera-
ture and time, and reaction rates can
vary substantially with changes in
stereoelectronic factors in different sub-
strates.1 The reported conditions might
have been determined by the authors
monitoring the progress of the reaction,
or they may be conditions of conveni-
ence. For example, slowly adding a
reactant to the reaction mixture over
a period of one hour followed by reflux-
ing for 15 h does not make thermody-
namic sense. If the reaction is very fast,
slowly adding one reactant to control
the heat of reaction makes sense, but
then an additional 15 hours of reflux
seems excessive. If the reaction is slow
and requires 15 hours of reflux to com-
plete, slowly adding one reactant seems
unnecessary, as it will all be added
before any significant reaction has
occurred. Such reaction descriptions
are probably a combination of caution
and convenience, and cannot be relied
on as useful information about a reac-
tion rate. The slow addition indicates
caution in case the reaction is fast and
exothermic, and the long reflux is prob-
ably a convenience based on desired
work hours. Certainly when possible,
one should try to monitor the reaction
progress by using standard chromato-
graphic or spectroscopic techniques3 to
try to get some data on the reaction rate.
Understanding how reaction condi-
tions affect reaction rates can prevent
making unsafe changes to reaction
conditions. In general, reaction rates
are proportional to reactant and cata-
lyst concentrations (Eq. (9)) where x
and y usually range from 0 to 2. In the
simplest of cases, x and y are one, and
doubling the concentration of reac-
tants A and B would then quadruple
the reaction rate.
rate ¼ k½reactant Ax ½reactant By (9)
Reaction rates are also affected by
temperature, since the rate constant
(k) is a function of activation energy
(Ea) and temperature (T in Kelvin)
(Eq. (10)).
k ¼ AeEa =RT (10)
An old rule of thumb states that
reaction rates double with each 10 8C
increase in temperature. While useful,
a closer examination of this rule shows
that it can be misleading. For a given
reaction, A and Ea are constant. Using
k1 and T1 for initial conditions and k2
and T2 = T1 + Dt for conditions at some
higher temperature, two equations like
Eq. (10) can each be solved for A and
the resultant functions containing Ea
set equal to each other. Solving for Ea
results in Eq. (11).
RT 1 ðT 1 þ DtÞlnðk2 =k1 Þ
Ea ¼ (11)
Dt
If Dt is set equal to 10 and k2/k1 is set
equal to 2 (i.e., doubling reaction rate),
temperature and activation energy
conditions that meet the rule of thumb
can be generated (Table 1).
At a temperature of 100 8C and an
activation energy of 19.7 Kcal/mol,
a 10 8C temperature increase does
Journal of Chemical Health & Safety, March/April 2010
Table 1. Effects of Changes in Temperature and Activation Energy on Relative Rates.
T1 (8C) Dt (8C)
1 50 7.5
2 100 10.0
3 150 12.9
4 50 10.0
5 50 3.7
double the reaction rate. However, at
50 8C, it takes only a 7.5 8C increase to
double the rate, while at 150 8C, it
takes a 12.9 8C increase to double
the rate. Thus, as the reaction tempera-
ture increases, it takes progressively
larger increases in Dt to double the
reaction rate (Table 1, Entries 1–3).
As activation energy increases, it takes
progressively smaller increases in tem-
perature to double the rate (Table 1,
Entries 4, 1, 5). While the doubling of a
reaction rate with a 10 8C increase in
temperature is a useful rule of thumb, it
only works accurately for specific acti-
vation energy – temperature combina-
tions. Rates could easily double with
less than a 4 8C increase in tempera-
ture.
When the rate of heat released
exceeds the rate at which your equip-
ment can remove it, a point of no
return is passed. The reaction will
become out of control. At this point,
it is sometimes possible in the labora-
tory to increase the heat removal rate
by altering the equipment, such as by
removing the heating source and
immersing the reactor in a water or
ice bath. However, disaster could
strike while in the process of doing so.
The rate of heat transfer is propor-
tional to the available heat transfer sur-
face area and the temperature
difference across that area, as well as
other factors. Heat loss from most
laboratory reactors is due to ambient
losses to the air through glass. With the
use of a heating mantle, the bottom half
of the reactor is essentially insulated by
the mantle, effectively reducing the sur-
face area for heat loss. In the case of a
hot oil bath, the liquid may conduct
heat better than a heating mantle. How-
ever, the oil temperature is usually close
to, but higher than the reaction tem-
perature. If an exotherm occurs the
reaction temperature must go above
the oil bath temperature for any heat
removal to occur to the bath. Then as
k2/k1 Ea (Kcal/mol)
2 19.7
2 19.7
2 19.7
2 14.8
2 39.4
the exotherm continues, the tempera-
ture difference is initially small, again
limiting the rate of heat loss.
The rate of heat loss of a laboratory
reactor can easily be estimated. Load
the reactor with a known weight of
water, heat it to 5 8C above the tem-
perature of interest, and let the tem-
perature stabilize. Turn off the heat
source and measure the time required
for the temperature to drop 10 8C. Use
Eq. (4) to calculate q and divide by the
time to get cal/time. This can be done
around several different operating
temperatures and at several different
water loadings to get a heat loss profile
of the reactor. A liquid other than
water can be used if needed, as long
as the specific heat of the liquid is
known. If the same equipment set up
is being used repeatedly, this is a
worthwhile exercise.
Heat loss will vary considerably
from one piece of laboratory equip-
ment to another. The size of the reactor
plays a significant role in this.9 Heat
generated is proportional to the reac-
tion volume while heat loss is propor-
tional to the surface area available for
heat transfer. In a typical laboratory
round bottom flask, this can be
approximated by assuming the flask
is a sphere of the stated volume with
the corresponding surface area avail-
able for heat transfer. Data for some
typical flask sizes are show in Table 2.
While volume increases with the cube
of the radius (V = 4/3pr3), surface area
increases only with the square of the
radius (S = 4pr2). In going from a
10 mL sphere (flask) to a 100 mL
sphere, the volume increase is a factor
of 10, but the surface area increase is
less than a factor of 5. A reaction that
may proceed with no notable
exotherm on one scale may be out of
control on a larger scale simply
because of slower heat loss due to
the reduction in the surface area/
volume ratio.
11
Table 2. Reduction in Surface Area/Volume Ratio with Increasing Volume.
Sphere Diameter Surface
(Reactor) (cm) Area
Volume (mL) (cm2)
10 2.67 22
50 4.57 66
100 5.76 104
500 9.85 305
1,000 12.41 484
5,000 21.22 1414
If the reaction rate (i.e., rate of heat
generation) and/or the heat removal
capability of the equipment are not
known, a reaction should first be run
on as small a scale as feasible, prefer-
ably 100 mL or less. This greatly
reduces the probability of a runaway,
but does not guarantee safety. For
example, a reaction run on a 1.3 g
(12.9 mmol) scale in a closed 20 mL
vessel was recently reported10 to occa-
sionally explode with no obvious
cause. This chemistry involved sequen-
tial reactions. The first reaction gener-
ated a gas, and the second reaction
consumed that gas. It also involved
starting the chemistry in an ice bath,
subsequently warming to room tem-
perature, and ultimately heating to
80 8C. The heat of reaction, adiabatic
temperature rise, and potential pres-
sure change calculations were subse-
quently reported11 for the first
reaction, and showed the potential
for the generation of very high tem-
peratures and pressures. The combina-
tion of a rapid first reaction and
insufficient heat transfer probably led
to enough pressure to rupture the glass
vessel. Had these calculations been
done prior to running the experiments,
the explosion hazard would have been
understood, and a different procedure
would probably have been followed.
A technique used successfully to pre-
vent runaway reactions has been to
start a batch reaction at room tempera-
ture on a small scale such as in a
100 mL flask or smaller. Monitor the
temperature for 10 minutes looking for
an exotherm. If no exotherm is
observed, raise temperature 10 8C
and wait again to see if there is an
exotherm. Continue to repeat 10 8C
temperature increases and wait peri-
ods until the highest desired reaction
temperature is reached. If no exotherm
12
Surface Normalized
Area/Volume Surface Area/Volume
(cm1) (cm1)
2.245 1.000
1.313 0.585
1.042 0.464
0.609 0.271
0.484 0.216
0.283 0.126
is observed, the reaction can then be
tried on a 5–10 fold larger scale, again
going through a series of heat wait
cycles. Reflux (82 8C) the reactants in
acetonitrile for 28 hours were the con-
ditions reported12 for a reaction simi-
lar to that in Eq. (7). Using this
technique, no exotherm was observed
up to a 1 L scale. However at a 5 L
scale, an exotherm was observed start-
ing at 65 8C and proceeding up to
80 8C even with removal of the heating
mantle.12 To deal with a reaction like
this on a 5 L scale, one of the reactants
(in this case the alkyl bromide) can be
slowly added to the remaining materi-
als at about 70 8C, keeping the tem-
perature under control by the rate of
addition. Ideally, the rate of addition
would match the rate at which the
reactant is consumed. Operating about
10 8C below the solvent boiling point
allows for some room for the exotherm
to occur and still be controlled.
CONCLUSIONS
While a thorough understanding of the
kinetics and thermodynamics of a reac-
tion, and of the heat transfer capabilities
of the equipment used is desirable, gen-
erating all the necessary data is usually
not practical for most laboratory opera-
tions. However, estimating the enthalpy
of reaction, the potential adiabatic tem-
perature rise, and the potential changes
in pressure or the volume of gas that
may be generated is a simple task that
should be done whenever one is experi-
menting with new chemistry, or run-
ning reactions they are not thoroughly
familiar with. Changes in concentra-
tion, temperature, and the stereoelec-
tronic nature of a substrate will all affect
reaction rate, and thus the rate of heat
generation. Even a temperature change
Journal of Chemical Health & Safety, March/April 2010
as small as 5 8C can double a reaction
rate. Changes in equipment, especially
changes in reaction scale, will change
the rate of heat loss. Remembering these
effects and starting on a small scale and
carefully looking for an exotherm can
greatly increase the safety of lab reac-
tions. Rapid exothermic reactions are
best run by slowly adding one reactant
to the others such that the rate of heat
generation equals the rate of heat loss
from the equipment.
ACKNOWLEDGEMENTS
The author would like to acknowledge
David Frurip, Charles Gartner, and the
Michigan Operations Reactive Chemi-
cals – Process Hazard Analysis team of
The Dow Chemical Company for
many educational discussions and
training in reactive chemicals hazards.
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