~ )

Pergamon

Computers"chem. Engng, Vol. 21, Suppl., pp. $959-$964, 1997

1997 Elsevier Science Ltd
All rights reserved
Printed in GreatBritain

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0098-1354/97 $17.00+0.00

Reaction Path Synthesis For

Environmental Impact Minimization
A. Buxton, A.G. Livingston and E.N. Pistikopoulos*
Centre for Process Systems Engineering, Dept. of Chemical Engineering
Imperial College, London, SW7 2BY, U.K.
A b s t r a c t - Reaction path synthesis, the generation of a network of alternative reaction routes for the
manufacture of a desired product and the selection of an optimal route, represents a key step in arriving
at environmentally sound process designs. In this paper a systematic procedure for organic reaction path
synthesis is described in which minimum environmental impact considerations are incorporated in order
to exploit the earliest opportunities for waste reduction. The size of the reaction path synthesis problem
is reduced by decomposing it into a series of steps, each of which is approached in a guided way. This is
achieved by first introducing a group based computer aided raw material and stoichiometric co-product design
step. With the raw materials, stoichiometric co-products and product known, the reaction path synthesis
problem is no longer open ended. Feasible stoichiometries between these materials are determined and
promising candidates are identified according to the Methodology for Environmental Impact Minimization
(Pistikopoulos et al., 1994).

INTRODUCTION

concentrated on technological alternatives with predetermined chemistry (Linninger et al., 1995; DouReaction path synthesis is a very large and comglas, c1994).
plex problem. In order to identify promising reaction
routes, reaction path synthesis tools must deal with a The central ideas behind our procedure are to relarge number of alternative chemistries and sufficient duce the size of the reaction path synthesis problem by decomposing it into a series of steps, each
information to evaluate each one.
Traditional approaches to reaction path synthesis of which is approached in a guided way, and to inhave concentrated on generating chemistries (Corey corporate environmental considerations in the route
and Wipke, 1969; Ugi and Gillespie, 1971; Rotstein et selection exercise in order to exploit the earliest opal. 1982). Agnihotri and Motard (1980) divided these portunities for waste reduction. We adopt a group
methods into two categories - logic-based systems, based approach to reaction path synthesis, achieving
with their roots in mathematics and information- problem size reduction principally by introducing a
based systems, with their roots in chemistry. How- raw material and co-product design step, exploiting
ever, the relationships between the desired product the relationship between these compounds and the
and the raw materials and stoichiometric co-products desired product. Our procedure includes both logic
(which we will refer to collectively as co-materials) and information-based chemistry representation syshave not been exploited so that within these tools, tems in a way which capitalises on the advantages of
the co-materials are not developed in a systematic both.
way. Furthermore, there is a trade-off between the Aspects of the Methodology for Environmental Imgenerality of the tools (the ability to represent many pact Minimization, MEIM (Pistikopoulos et al.,
alternatives) and their predictive power (the ability to 1994) provide the framework for the environmental
represent specific distinct reactions in detail) (Govind evaluation of alternatives. Using this approach, we
and Powers, 1981), according to the representation incorporate environmental considerations and prinsystem employed.
ciples from life cycle analysis in the route selection
Recently, the issue of route selection, with or with- problem, so that the wastes associated with the inout explicit environmental objectives, has come puts to a process (raw materials, energy consumpto the forefront (Crabtree and E1-Halwagi, 1994; tion, capital, etc.) as well as the conventional process
Fornari and Stephanopoulos, 1994; Knight, 1995; emissions are accounted for. This is achieved by (i)
Mavrovouniotis and Bonvin, 1995). However, the expanding the conventional process boundary to inpotential of environmental evaluation of alternative clude all processes associated with raw material manreaction routes has not been fully explored. Other ufacture and energy generation, (ii) defining a set of
synthesis approaches for waste minimization have pollution metrics (such as air, water pollution, global
*To whom correspondence should be addressed; e-marl: e.pistikopoulos@ic.ac.uk
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PSE '97-ESCAPE-7 Joint Conference

warming, ozone depletion etc.) in order to transform

all process emissions (output and input) into a common currency with respect to environmental damage
and (iii) embedding these metrics into our procedure.
In this paper we introduce the foundations of our
procedure and we concentrate on the issues of comaterial design and stoichiometry determination and
evaluation. We illustrate the application of our
method with an example problem: the synthesis
of production routes for the pesticide 1-naphthyl-Nmethyl carbamate, also known as carbaryl.
PROBLEM STATEMENT
The reaction path synthesis problem for minimum
environmental impact may be stated as follows:
Given a desired product

Determine a set of candidate reaction routes and corresponding process technologies for the production
of a fixed amount of the desired product which are
promising both economically and in terms of minimum environmental impact.
This problem has two key elements: (i) the generation of a set of alternative reaction routes with corresponding technologies and (ii) the evaluation of these
routes and the selection of a subset of economically
attractive, environmentally benign candidates. Each
of these subproblems is very large because of the
many alternative reaction routes and corresponding
alternative process configurations which may be employed to produce the desired product.
It is desireable to solve the subproblems simultaneously. However, this is difficult to achieve, as the traditional reaction path synthesis tools have revealed.
Therefore, we propose a structured, stepwise procedure in which we decompose the reaction path synthesis problem in order to deal with its size.
OUTLINE OF PROCEDURE
The steps of our methodology are as follows for a fixed
desiredproduct: (i) select co-material groups, (ii) determine a set of candidate co-materials using group
based molecular design techniques, (iii) identify a set
of promising candidate stoichiometries using a logicbased representation system and an optimization selection procedure incorporating aspects of the MEIM,
(iv) generate corresponding mechanisms using functional group transformations and so introduce competing reactions, (v) evaluate the mechanism steps in
detail using the MEIM to make a final selection.
The key to our procedure is the introduction of the
co-material design steps. Recognising that much organic chemistry essentially consists of reorganising
functional groups (through additions, substitutions
and eliminations), we expect our co-materials to contain (at least) the group structures present in the desired product. Accordingly, we systematically design
our candidate co-materials according to the group
structure of the product, the types of chemistries we
wish to consider (e.g. aliphatic or aromatic) and other
considerations (such as property constraints) using a
group based computer aided molecular design technique.

We use groups, rather than atoms, as our molecular building blocks for several reasons. First of all,
this considerably reduces the combinatorial size of
the molecular generation problem without much loss
of generality - very many organic compounds can be
constructed using only a small number of groups.
Secondly, with appropriate group bonding restrictions (see Co-Material Desi#n) such a method provides a short cut to structurally and chemically feasible molecules, so significantly reducing molecular
screening requirements. Finally, a suitable choice of
groups gives direct access to the thermodynamic and
environmental properties we need through group contribution methods.
With the co-materials and product known the reaction path synthesis problem is no longer open ended
and is therefore considerably reduced. Now we must
bridge the gap between these materials with feasible stoichiometries and corresponding reaction mechanisms and then make our final route selection.
The first step towards this is to identify feasible overall stoichiometries, without mechanisms, involving
our co-materials and leading to our product. In order to achieve this we employ a logic-based chemistry
representation system and an optimization based procedure, incorporating aspects of MEIM, to identify
good candidate stoichiometries among the alternatives according to economic, thermodynamic and environmental impact criteria (see Stoichiometry Selection).
Now we have a set of promising stoichiometries involving some of our candidate raw materials, our
product and some stoichiometric co-products. From
this position we can employ an information based approach in order to generate the underlying reaction
mechanisms using functional group transformations
based on real chemistry. We can then use the MEIM
in its full form to analyse our candidate routes within
an optimization framework and make the final selection.
In this work we concentrate on the identification of
economically attractive and environmentally benign
candidate stoichiometries, divorced from any process
technology. In future publications we will consider
the problem of determining the underlying chemical
mechanisms and the optimal process configurations
corresponding to our candidate stoichiometries.
CO-MATERIAL DESIGN
Co-material design is the key in reducing the reaction
path synthesis problem to a manageable size. Our
aim is to select a set of co-material groups (see New
Rules for Co- Material Design) and then to generate a
set of structurally and chemically feasible co-materials
from these groups with the minimum screening requirement. We must also introduce additional structural restrictions which are pertinent to the reaction
path synthesis problem.
We employ the molecular design algorithm within the
CAMD approach of Gani et al. (1991), later updated
by Constantinou et al. (1995), incorporating some

PSE '97-ESCAPE-7 Joint Conference

new rules of our own to design our set of co-materials.
CAMD is based on a system of group classification
and categorisation. The class of each group represents the number of free attachments available to the
group and the category signifies the level of restriction for bonding with other groups - the higher the
category the tighter the restrictions.
The molecular design algorithm is based on a set of
conditions which ensure structural and chemical feasibility, firstly by ensuring that the complete compound has zero valency and secondly that it obeys the
principles of chemistry. These principles have been
embodied in a set of rules which determine the maximum permissible number of groups from any category
which can be present in a molecule and the permissible combinations of groups from the different categories.
These rules are divided into three sets; a set each for
acyclic, cyclic and aromatic molecules. The molecular design algorithm has been developed to systematically generate all molecules which satisfy these conditions.

New Rules for Co-Material Design

Gani's approach includes over one hundred groups
and can potentially generate thousands of feasible
molecules (Constantinou et al., 1995), not all of which
are interesting from a reaction path synthesis point
of view. In order to reduce the number of molecules
which are passed to the stoichiometry selection step
we introduce three new sets of rules for co-material
.design. Our rules are based mainly on engineering
and chemical insight, rather than on property constraints, as in the conventional molecular design problem.
The first set of rules is aimed at group pre-selection.
Group pre-selection is the first step towards designing co-material molecules and has the most direct effect on the number of molecules we generate. We
use the following simple rules to guide our group preselection: (i) include the groups present in the product, (ii) include groups present in any existing industrial raw materials, co-products or by-products,
(iii) include groups which provide the basic building
blocks for the functionalities of the product or of similar functionalities, (iv) select the group sets for the
desired chemistry (cyclic, acyclic or aromatic), (v)
reject groups which violate property restrictions (e.g.
chloro groups may violate environmental restrictions
- Gani et al., 1991).
The second set of rules provides additional structural
restrictions on the co-material molecules according to
the structure of the product. This set is incorporated
in the co-material design procedure so that undesireable structures are not generated only to be rejected
later: (i) upper limit on the number of groups in the
co-materials according to the number in the product - industrial co-materials are generally not signif-

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icantly larger than the product, (ii) upper limit on

the number of substituents, substituted sites or functionalities - in general industrial co-materials are not
significantly more complex than the product.
The third set of rules are chemistry based screening
rules, applied after the molecules have been generated. Rules (iii) and (iv) are in fact implemented
within the stoichiometry selection procedure: (i)
since we restrict ourselves to reactions involving only
functional group transformations we reject molecules
in which the carbon skeleton must be altered in order to achieve the product, (ii) restrict the number of
members from any homologous series, (iii) disallow
certain combinations of raw materials, (iv) impose
role specification constraints on molecules (e.g. a particular species may be designated as a raw material
only).

Additional Molecules
During addition, substitution and elimination reactions some simple molecules which do not feature in
CAMD may be generated or consumed. We introduce
the following set of additional co-material molecules
from which we may select a subset to be included in
our stoichiometries.

a) H20

b) O2

c) H2

d) CO2

e) HCI

a) water b) oxygen c) hydrogen

d) carbon dioxide e) hydrogen chloride
STOICHIOMETRY

SELECTION

At this stage, our aim is to identify stoichiometries

which link our co-materials to our product and which
exhibit minimum environmental impact subject to
economic and thermodynamic constraints. In order to do this, we examine the environmental performance of the stoichiometries at the reaction equilibrium position.
The equilibrium position is located using the relationship between the Gibbs free energy change of reaction
and the reaction equilibrium constant, the value of
which is determined by the composition of the reaction mixture. The equilibrium position indicates the
best possible conversion for any stoichiometry and
therefore the maximum economic potential. We employ a cost constraint to reject reactions which do
not exhibit promising economics (i.e. profit _> 0) at
equilibrium.
The overall mathematical model for stoichiometry selection (omitted here due to space limitations) corresponds to a large, non-convex, mixed-integer nonlinear programming (MINLP) problem. While ongoing research is aimed directly at solving this problem
globally, a two step sequential solution strategy is
adopted in this work to the determination and evaluation of stoichiometries, as follows.

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PSE '97-ESCAPE-7 Joint Conference

Stoichiometry Determination
The first step - stoichiometry determination - can
be achieved with a linear formulation. We write an
atom balance for our co-materials and product as a
system of linear equations (Rotstein et al, 1982) of
which the solutions are vectors of stoichiometric coefficients. We then employ guided enumeration to extract stoichiometries from this system.
From a process point of view we are more interested
in simple stoichiometries, with few reactants and coproducts, than in complex ones. Clearly, the more
molecules we have the more complex the reaction
and particularly the separation processes must become. Accordingly, we formulate the stoichiometry
determination problem as an optimization problem
in which our objective is to minimise the sum of the
magnitudes of the stoichiometric coefficients and we
impose a (case dependent) upper limit on the number
of molecules to be involved in the stoichiometries.
We introduce constraints so that the stoichiometric
coefficients take whole number values, integer cuts
to exclude side reactions and we solve the problem
iteratively, introducing integer cuts to exclude previous solutions as we go. In this way, we enumerate
the stoichiometries starting with the simplest first.
This formulation represents our guided enumeration
approach.

following the Bhopal disaster. UCIL's process involved the raw materials 1-naphthol and methyl isocyante, a toxic substance with a PEL of 0.02ppm.
Under disputed circumstances, 45 tons of methyl isocyanate underwent a chemical reaction and were released, killing approximately 2,500 people in the vicinity of the plant and resulting in some 300,000 additional casualties.
The search for a production route involving more
innocuous reactants is the motivation for this case
study (Crabtree and E1-Halwagi, 1994).

Group Pre-selection
Carbaryl can in fact be made with or without methyl
isocyanate (Worthy, 1985). The two alternative industrial chemistries are shown below (Figures 1 and
2).
CH3NH2

"J"

COCI2

Methyl Amine

CH3 - N ffiC ffiO

Phosgene

"{-

"J"

2 HCI

Methyl Isocysaate

CH3-- N~CffiO

O--H

O--C ~ ~CH 3
n
O .

I-Naphthol

Cat'beryl (l-NaphthaJenyl Methyl Carbamate)

Figure 1: Methyl Isocyanate (Bhopal) Route

Stoichiometry Evaluation
The second step - stoichiometry evaluation - involves
equilibrium analysis of each reaction stoichiometry.
Since the stoichiometries are now known, this reduces
to a non-linear programming (NLP) problem. Our
objective is the minimization of the environmental
impact associated with each stoichiometry, subject
to the aforementioned cost and thermodynamic constraints. In order to estimate the impact we assume
5% loss of reactor effluent by unavoidable leakage.
We measure the impact in terms of the critical water
mass (CTWM, Pistikopoulos et al., 1994).
We solve the problem to determine the equilibrium
composition and reaction temperature which correspond to the minimum environmental impact for each
stoichiometry. The thermodynamic and environmental properties we require are calculated from group
contributions (Van Krevelen et al., 1951; Gao et al.,
1992).
Finally we rank our stoichiometries according to economics and environmental impact in order to identify
the most promising candidates. The mathematical
details of our approach are reported elsewhere (Buxton et al., 1996).

COCI~

O--H

+
_

It
O

"t-

HCI

O--C ~CI
II
O
1-Naphthalenyl Chloroformate

CI

CH3Nll:2

H
l

O _ C ~ N~CH3
fl
O
Carlmryl

Figure 2: Non-Methyl Isocyanate Route

We make our group pre-selection according to our
New Rules for Co-Material Design (see Co-Material
Design), restricting ourselves to the simplest set of
groups which represent these molecules and the functional groups of interest. Employing the functional
group definitions of Gani et al. (1991), our set of selected groups (12 in all) is then: (i) aromatic groups
AC-, ACH, ACC1, ACOH; (ii) other groups CH3,
CH3NH<, C H 3 N H 2 - , - C O O - , - C H O , - C O 2 H , - O H ,
-C1.

Co-Material Design

We construct our co-material molecules according to

Gani's molecular design procedure, (Gani et al., 1991)
EXAMPLE PROBLEM
PRODUCTION
incorporating our new rules. Specifically, we introOF 1-NAPHTI-IALENYL METHYL
duce the following structural and chemistry-based reCARBAMATE
strictions: (i) we impose upper limits on the numProduct Identification
bers of groups in our non-aromatic molecules so that
1-naphthalenyl methyl carbamate, also known as 'car- we retain the simplest set of non-aromatic molecules
baryl' was employed as a pesticide (Worthy, 1985). It which contain functional groups of interest, (ii) we
was manufactured under the trade name SEVIN by impose an upper limit of 14 groups within our aroUnion Carbide India, Limited (UCIL) in Bhopal un- matic molecules since it is unlikely that we would
til December, 1984 when production was terminated synthesise our product from a more complex molecule
-

PSE '97-ESCAPE-7 Joint Conference

(earbarvl contains 14 groups), (iii) we allow only monosubstituted aromatic molecules (since the product is
monosubstituted), (iv) we eliminate all molecules of
which the carbon skeleton must be altered in order
to achieve the product (e.g. we reject all benzyl (single ring) structures since we do not wish to be concerned with contructing the naphthyl (double ring)
group). By applying these criteria we reduce our set
of molecules to fifteen in total (see Figures 3 and 4).

S963

in any feasible stoichiometry. Thirteen stoichiometries meet this constraint, these routes are shown in
Table 1, ranked according to their economic potential.
The original Union Carbide industrial chemistry and
one of the routes generated by Crabtree and E1Halwagi (1994) were reproduced, the other two routes
put forward by Crabtree and E1-Halwagi were eliminated by our cost constraint.

&o-Material Design Results

:~

CI
a)

OH

b)

H~N~cH3
d)

c)

_ C ~ OH
n
O

O_c~CI
II
O
13

e)

~ ~. ~ ~ t.- ~. ~ ~. ~ .~ ~ e~ "~

O--C ~ ~CH 3
II
O
g)

Figure 3: Aromatic Molecules

a) Naphthalene, b) 1-Chloronaphthalene
c) 1-Naphthol, d) N-Methyl-l-Naphthylamine
e) 1-Naphthalenyl Hydroxyformate
f) 1-Naphthalenyl Chloroformate
g) Carbaryl

CI2

CH3C |

CH3OH

CI--C~ H

a)

b)

c)

d)

H-- C ~ N ~ CH 3
II

CH3NH2

CI~C_. O
CI

e)

CH3-- N = C = O

f)

,.7

"7"7"7"7

"77

"7,

"7,

h)

g)

Figure 4: Aliphatic and Other Molecules

a) Chlorine, b) Methyl Chloride, c) Methanol
d) Chloromethanal, e) Methylamine, f) Phosgene
g) Methyl Isocyanate, h) Methyl Formamide

1
2
3
4

The isocyanate group and phosgene do not appear

in Gani's method, so we add methyl isocyanate and
phosgene to class zero (complete molecules).

Additional Molecules
We introduce four additional co-material molecules:
a) H 2 0

b) 02

c) H2

d) HC1

a) water b) oxygen c) hydrogen

d) hydrogen chloride

6
7

8
9
10

Oxygen
Hydrogen
Hydrogen Chloride
1-Naphthol
Chloroformate
Methyl Formamide
Water
Methylamine
Phosgene
Methyl Isocyanate
1-Naphthol

11
12
13
14
15
16
17
18
19

Carbaryl
Naphthalene
1-Chloronaphthalene
N-methyl-l-Naphthyl
Amine
1-Naphthalenyl
Hydroxyformate
Chlorine
Chloromethane
Methanol
Chloromethanal

Table 1: Stoichiometry Selection Results

All of the alternative stoichiometries exhibit more

promising economics than the Bhopal chemistry and
more than half also exhibit lower environmental imStoichiometry Selection Results
pact. Stoichiometries 5,6 and 12 represent the best
The solutions from the stoichiometry selection pro- compromise solutions, with both promising economics
grams are presented below in the form of a table of and low environmental impact.
stoichiometric coefficients; blank spaces indicate zero Stoichiometries involving methyl isocyante (specie 9)
coefficients. A basis production rate of 1 mol/hr of and/or 1-chloronaphthalene (specie 13) as raw macarbaryl was employed. An upper limit of six was im- terials exhibit relatively high environmental impact,
posed on the number of molecules Nmot to be involved and should therefore be avoided.

PSE '97-ESCAPE-7Joint Conference

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APPENDIX

This work has employed the following assumptions

(i) we assume that the Gibbs free energies of formation and of reaction are linear with temperature, (ii)
we assume that the group contribution techniques we
have used to obtain the Gibbs free energies of formation and toxicities of our molecules are suitable for all
of our molecule (iii) we assume 5% of reactor effluent flow by mass is released by unavoidable leakage,
(iv) we assume that all emissions are to the water
phase, we do not model pollutant fate (v) we do not
consider wastes which do not arise directly from the
process chemistry (e.g. solvents and wash water), (vi)
all generated molecules are chemically feasible, (vii)
group based raw material design provides all interesting co-materials, (viii) we have applied limits to the
numbers of groups to be allowed in any co-material
and the number of functionalities, (ix) the additional
molecules we require to complete our stoichiometries
are not systematically designed or selected, (x) we apply an upper limit to the number of molecules which
may be involved in any stoichiometry, (xi) side reactions are excluded by integer cuts, (xii) do not consider competing reactions at this stage, (xii) we assume low pressure (1 atm) gas phase reaction and we
make the perfect gas assumption, (xiii) we employ
a hierarchical screening procedure: economics, thermodynamics, then environmental impact, (xiv) we
cost only the products and the reactants, no process
equipment or operating costs (xv) we do not consider
solvents, catalysts or reagents. Current research efforts are aimed at relaxing some of these assumptions.

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