Tutorial on the fitting of kinetics models to multivariate spectroscopic

measurements with non-linear least-squares regression
Graeme Puxty
a,

, Marcel Maeder
b
, Konrad Hungerbühler
a
a
Institute for Chemical and Bioengineering, Safety and Environmental Technology Group, ETH Zürich, 8093 Zürich, Switzerland
b
Department of Chemistry, University of Newcastle, University Drive, Callaghan NSW 2308, Australia
Received 22 September 2005; received in revised form 24 November 2005; accepted 1 December 2005
Available online 14 February 2006
Abstract
The continuing development of modern instrumentation means an increasing amount of data is being delivered in less time. As a consequence,
it is crucial that research into techniques for the analysis of large data sets continues. However, even more crucial is that once developed these
techniques are disseminated to the wider chemical community. In this tutorial, all the steps involved in the fitting of a chemical model, based on
reaction kinetics, to measured multiwavelength spectroscopic data are presented. From postulation of the chemical model and derivation of the
appropriate differential equations, through to calculating the concentration profiles and, using non-linear regression, fitting of the rate constants of
the model to measured multiwavelength data. The benefits of using multiwavelength data are both discussed and demonstrated. A number of real
examples where the described techniques are applied to real measurements are also given.
© 2005 Elsevier B.V. All rights reserved.
Keywords: Kinetic modelling; Multivariate data; Spectroscopic data; Non-linear least-squares regression
1. Introduction
In the context of this tutorial, a kinetic study is the
investigation of chemical reactions and encompasses the
identification of the correct reaction mechanism and the
determination of the associated rate constants. We will
concentrate on how to fit a chemical reaction mechanism,
defined using kinetic theory, to measured multiwavelength
spectroscopic data for a reaction of interest. The fitting of
reaction mechanisms to multivariate data began with the work
of Knutson et al. [1] in 1983. They coined the expression
“global analysis” for simultaneously fitted fluorescence decay
kinetics at multiple wavelengths. Further development of
techniques in this field has continued in particular with the
work of Maeder and coworkers [2–4], Bisjma, Smilde and
coworkers [5–7] and Fürusjö and Danielsson [8,9]. With the
introduction of fast scanning and diode array spectrophot-
ometers, kinetic investigations based on multivariate data are
now common place. This type of data fitting has found
application across a broad range of chemistry. Some recent
examples include the complexation kinetics of metals [10–13],
solvent-free organic reactions [14,15], thermal hazard evalua-
tion [16], industrially relevant reactions carried out in
calorimeters [17] and process modelling and optimisation [18].
In the following sections the process of fitting a kinetic
model to multivariate absorption data using non-linear regres-
sion will be described. First, the structure of the multivariate
data will be outlined (Beer–Lambert's law). Next, the
computation of the concentration profiles for a given mecha-
nism and rate constants is described. These computations form
the core of the fitting algorithm which will be described
subsequently. We then present the second-order global analysis
of series of data. A collection of applications will be presented
and discussed at the end of this tutorial. It should be noted that
while absorption data are considered, the techniques described
are applicable to any multivariate data that show a linear
relationship between signal and concentration.
There are several advantages to using multiwavelength data
(as compared to selecting single wavelengths): (a) Appropriate
analysis results in determination of the pure spectra for all
Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
www.elsevier.com/locate/chemolab

Corresponding author. Fax: +41 44 632 1189.
E-mail address: graeme.puxty@chem.ethz.ch (G. Puxty).
0169-7439/$ - see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.chemolab.2005.12.001
reacting species. This enables structural interpretation even for
intermediates that only transiently exist during the reaction. (b)
Multivariate data allow the application of a wide range of
model-free analyses, from simple factor analysis [19] to indicate
the number of reaction species to sophisticated complete
analyses based on evolving factor analysis [20] or the
alternating least-squares algorithm [21]. These model-free
techniques can also be combined with the hard-modelling
techniques described in this tutorial to give the benefits of both
approaches [22,23]. (c) The need to determine a “good”
wavelength to follow the reaction is eliminated. (d) The analysis
of multiwavelength data is often significantly more robust. The
disadvantages of multiwavelength data include the large
number of data that are acquired in a short time and the large
number of parameters that need to be fitted. Readily available
personal computers with large memory solve the first problem;
appropriate algorithms solve the second.
The most recent development, and not yet widely
accepted, is the globalisation of the analysis of several sets
of kinetic data. The investigation of reasonably complex
mechanisms requires the measurement of data acquired under
different conditions, e.g., variation of initial concentrations.
Global analysis of the complete collection of data invariably
results in increased robustness, reduced model ambiguity and
also significantly less operator input as only one analysis has
to be performed.
All of the algorithms and analyses described in this tutorial
were completed using the commercially available software
package Pro-KII [24] or in-house Matlab® [25] software. Other
software packages offering some similar features have also been
reported in the literature or are available commercially such as
OPKINE [26], KINAJDC (MW) [27,28] and SPECFIT/32™
[29].
2. Multivariate absorption data and Beer–Lambert's law
Light absorption spectroscopy is a common technique used
for chemical reaction monitoring, with the ultraviolet-visible
(UV–Vis, practical range of 190–700 nm) and near-infrared
(near-IR, range of 700–3000 nm) wavelength regions com-
monly used. While measurements in the mid-IR (3000–12,500
nm) are less commonly used for kinetic studies, the use of this
region is increasing with the development of faster scanning
instruments. Any of the above wavelength ranges can be used to
follow the time-dependent spectral changes during chemical
reactions and for the subsequent determination of reaction
mechanisms, its kinetic parameters and the spectra of the
absorbing reacting species. These spectra can be used evaluate
the structure of intermediates and products. Instruments for
making absorbance measurements are widely available with
bench-top spectrophotometers now being sold covering a large
portion of the UV–Vis to near-IR wavelength range in a single
device. Generally, experiments are made using stopped-flow
techniques for rapid reaction kinetics (milliseconds–minutes),
and manually mixed or batch reactor measurements for slower
kinetics (minutes–hours).
To follow the evolution of a reaction, spectra are acquired as
a function of the reaction time. This type of measurement results
in data that can be arranged into a two-dimensional matrix
which will be named Y. If each measured spectrum is arranged
as a row, then the resulting row dimension is the number of
measured spectra (nt rows) and the column dimension is the
Fig. 1. Structure of multivariate absorbance data arranged into a matrix Y.
150 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
number of measured wavelengths (nλ columns). This arrange-
ment is shown in Fig. 1.
According to Beer–Lambert's law the absorbance of a
solution at one particular wavelength λ at time t is the sum of
the contributions from all absorbing species. Each element in Y
represents this sum for a specific time t and wavelength λ. The
contribution from each species to the absorbance is linearly
proportional to the concentration and the optical path length (the
distance travelled through the solution by the incident light
beam). If the path length and proportionality constant are
expressed by the single constant ε
i
(λ) then Beer–Lambert's law
and each element in Yis represented by Eq. (1) (for nc absorbing
species).
yðt;kÞ ¼ c
1
ðtÞe
1
ðkÞ þ c
2
ðtÞe
2
ðkÞ þ
: : :
þ c
nc
ðtÞe
nc
ðkÞ
¼
X
nc
i¼1
c
i
ðtÞe
i
ðkÞ ð1Þ
The structure of Eq. (1) is such that when spectra are
arranged according to the matrix Y, Beer–Lambert's law can be
elegantly expressed using matrix notation [4].
Y ¼ CA þ R ð2Þ
This equation is represented graphically in Fig. 2. The
columns of the matrix C contain the concentration profiles c
i
of
the nc absorbing species at the nt measurement times. The rows
of the matrix A contain the molar absorptivities ε
i
(λ) for each
species at the nλ measured wavelengths. These will be referred
to as pure component spectra. Because measurements are never
perfect, the matrix Y will contain some measurement noise and
as such cannot be perfectly represented by the product of C and
A. This difference is captured in the matrix of residuals R,
which shares the same dimensions as Y. The fact that each
element in Yis an application of Beer–Lambert's law of Eq. (1)
is illustrated by the shading of Fig. 2. Each element in Y is the
vector product of the corresponding row in C and column in A
plus the noise component in the matrix R. Also shown are
typical plots of the type of data contained in each matrix. They
were produced by simulation of simple first-order kinetics.
3. Calculation of kinetic concentration profiles
The central step in the fitting of a kinetic model to
multivariate absorbance data is being able to calculate the
concentration profiles of all the species involved in a chemical
reaction. The concentration profile of a species is its change in
concentration with time. The concentration profiles of all species
are arranged into column vectors and they correspond to the
columns of the matrix C in Fig. 2. According to kinetic theory,
the concentration profiles of the species in a reaction mechanism
are defined by a system of ordinary differential equations
(ODEs) [30]. With knowledge of the initial conditions, ODEs
can be integrated to any time point, allowing the calculation of
the concentration profiles corresponding to data acquisition
times.
For a number of simple first- and second-order reactions, it is
possible to explicitly integrate the resulting system of ODEs.
For example, consider the reaction mechanism of Eq. (3).
Shown is the system of ODEs and their integrated form for this
second-order mechanism.
2AY
k
2A
B
d½AŠ
dt
¼ −2k
2A
½AŠ
2
;
d½BŠ
dt
¼ k
2A
½AŠ
2
A ½ Š ¼
½AŠ
0
1 þ 2½AŠ
0
k
2A
t
Fig. 2. The matrix Y of multivariate absorbance data expressed using Beer–Lambert's law. A plot of typical data is given below each matrix.
151 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
B ½ Š ¼ ½BŠ
0
þ
½AŠ
0
−½AŠ
2
ð3Þ
For the majority of multiple step reaction mechanisms, it is
not possible to explicitly integrate the resulting systems of
ODEs. To overcome this, numerical integration is used.
Numerical integration allows an approximation to the explicit
solution to be calculated for any system of ODEs, within limits
of numerical accuracy and computation time [31]. Numerical
integration routines are, at least in basic principle, based on
Euler's method [31]. Euler's method uses a form of the Taylor
series expansion truncated to the first derivative (see the
Appendix for details of the Taylor series expansion).
The principle of Euler's method is represented graphically in
Fig. 3. Starting with the concentration at time t, the
concentration at t +Δt is estimated by moving along the tangent
(the derivative
dc
i
ðtÞ
dt
) at t. It can be seen that the accuracy of the
approximation is dependent on the magnitude of the increment
size Δt and the shape of the function. The greater the curvature
and the steeper the tangent, the smaller the increment size that
must be used to give an accurate approximation.
Eq. (4) formalises the graph and Eq. (5) shows the equation
as would be applied to calculate the concentration profiles of
species A and B from Eq. (3).
c
i
ðt þDtÞcc
i
ðtÞ þ
dc
i
ðtÞ
dt
Dt ð4Þ
½AŠ
tþDt
c½AŠ
t
−2k
2A
½AŠ
2
t
Dt; ½BŠ
tþDt
c½BŠ
t
þ k
2A
½AŠ
2
t
Dt ð5Þ
In practice, Euler's method as described here is not used in
modern numerical integration routines due to its lack of
accuracy. Some of the modern strategies include using higher-
order terms from the Taylor series expansion or calculating the
first derivative at multiple points within an increment. Adaptive
increment size control is also used to achieve a specified level of
accuracy. The most robust of the modern numerical integration
routines use the idea of extrapolating from a particular result to
the value that would have been obtained if a much smaller,
ideally infinitesimally small, increment size were used [31].
A system of ODEs can be considered either non-stiff or stiff
depending upon the relative difference in the rate of change of
the concentration profiles. If the rate of change of each
concentration profile is similar, the system of ODEs is said to
be non-stiff. For non-stiff systems of ODEs, the fourth-order
Runge–Kutta method [31] is the “workhorse” of numerical
integration and it was used in this tutorial. It is called fourth
order because the first derivative is calculated at four points
along the increment of integration, allowing much larger
increments and thus dramatically reduced computation times
compared to the simple Euler method. Alternatively, if one
concentration profile changes rapidly while another does not,
the system of ODEs is said to be stiff. Such a situation can occur
if either rate constants or concentrations vary by orders of
magnitude or the mechanism is a mixture of elementary steps
with different reaction orders. In this case, if a traditional
method is used the increment size must be reduced to such a
small value to yield accurate integration of the rapidly changing
concentration profiles, that the computation time becomes
excessive for the more slowly changing concentration profiles.
A modified approach to carrying out the integration is then
required. For stiff systems the Bulirsch–Stoer method using
semi-explicit extrapolation [31] was used.
To carry out numerical integration, it is first necessary to
construct the system of ODEs that represent a given reaction
mechanism. This can be done manually, however such an
approach is both error-prone and cumbersome for mechanisms
of any complexity. Rather, an automated method commonly
used to construct ODEs from chemical equations can be adopted
[32]. Firstly, the number of species present in the reaction
mechanismand the stoichiometry of each reactant and product is
determined. Consider the reaction mechanism of Eq. (6).
A þ BY
k
A
B
C
2CY
k
2C
D ð6Þ
Two matrices are then constructed; one containing the
reactant stoichiometries X
r
, and one containing the product
stoichiometries X
p
. Each matrix has ns columns, representing
all the reacting species in the mechanism (A, B, C and D as
distinct from the number of absorbing species nc≤ns), and np
rows, representing reactions or rate constants (k
B
A
and k
2C
). X
r
contains the stoichiometry of each species as a reactant and X
p
contains the stoichiometry of each species as a product. If X
r
is
subtracted from X
p
, the result is the matrix of stoichiometric
coefficients X (see Fig. 4).
Fig. 3. Application of Euler's method to the calculation of a concentration
profile.
Fig. 4. Reactant and product matrices for the reaction mechanism of Eq. (6).
152 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
Once X
r
and X have been determined, the differential
equations can be constructed in a completely generalised way,
according to Eq. (7). The expression defining v
j
is the rate law of
the j-th elementary step in the mechanism [30].
v
j
¼ k
j
Y
ns
i¼1
c
x
rj;i
i
where j ¼ 1 to np
dc
i
dt
¼
X
np
j¼1
x
j;i
v
j
where j ¼ 1 to ns ð7Þ
The ODEs that result from the application of Eq. (7) to the
reaction mechanism of Eq. (6) are given by Eq. (8). The result of
integrating the ODEs in Eq. (8) with [A]
0
=1, [B]
0
=0.8, k
B
A
=2
and k
2C
=1 from 0 to 10 time units in 100 increments is shown in
Fig. 5.
v
1
¼ k
A
B
½AŠ
1
½BŠ
1
½CŠ
0
½DŠ
0
v
2
¼ k
2C
½AŠ
0
½BŠ
0
½CŠ
2
½DŠ
0
d½AŠ
dt
¼
d½BŠ
dt
¼ 1v
1
þ 0v
2
d½CŠ
dt
¼ 1v
1
−2v
2
d½DŠ
dt
¼ 0v
1
þ 1v
2
ð8Þ
4. Linear and non-linear least-squares regression
4.1. Linear parameters
Once the concentration profiles have been calculated, the
pure component spectra can be calculated in a single step. This
is because they are linear parameters, and as such, there is no
need to pass them through the non-linear optimisation routine
[4,33].
Fig. 5. Integrated concentration profiles for the mechanism of Eq. (6) using the
ODEs of Eq. (8).
Fig. 6. Flow diagram of the Newton–Gauss–Levenberg/Marquardt (NGL/M) method.
153 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
Recall that a multivariate spectroscopic measurement Y
can be expressed as the product of C and A plus a matrix of
residuals (Eq. (2)). This is a system of linear equations and,
for such systems, there is an explicit least-squares solution
[34]. Given Y and C, the best estimate for A can be
calculated as shown in Eq. (9). C
+
is called the pseudo-
inverse of C. It is necessary to use the pseudo-inverse as C is
not a square matrix precluding direct calculation of its
inverse.
C
þ
¼ ðC
T

−1
C
T
A ¼ C
þ
Y ð9Þ
C
+
can be calculated as shown in Eq. (9); this, however, is
not recommended as there are numerically superior methods
[31].
4.2. Non-linear parameters
The non-linear parameters to be fitted are the rate
constants of the reaction mechanism that define the matrix
of concentration profiles C. The rate constants are refined
so as to minimize the sum of squares of the residuals
matrix of Eq. (2) (ssq, the sum over the all elements in
R
2
). The parameters are non-linear because the relationship
between the parameters and the residuals is not linear. A
vast range of non-linear regression algorithms exists. One of
the most commonly chosen methods of non-linear regres-
sion is the Newton–Gauss–Levenberg/Marquardt (NGL/M)
method [4,35,36], and it will be described in detail here.
This method is a gradient method, which means it relies on
calculation of the derivative of the function being optimised
(the residuals). Methods also exist that do not rely on
calculation of the derivative, such as the Simplex method
[37] or genetic algorithms [38]. In general, the convergence
of gradient methods is superior to other methods if the
initial parameter estimates lie in the region of the global
optimum. Fig. 6 is a flow diagram showing the NGL/M
method. The NGL/M method is able to vary smoothly
between an inverse Hessian method and a linear decent
method. It evolved in essentially two stages. The inverse
Hessian Newton–Gauss method was developed first; this
will be the starting point for a description of the NGL/M
method.
4.2.1. Newton–Gauss method
The first step in any gradient method is to define initial
estimates for the non-linear parameters, the rate constants, to
be refined. The next step is to evaluate the target function to
be minimised, the ssq over the residuals. To do this, the
concentration profiles must be calculated according to
Section 3 using the initial rate constants. The linear
parameters, the pure component spectra, can then be
calculated by Eq. (9). This gives the matrices C and A.
The residuals matrix and its ssq can now be calculated by
rearranging Eq. (2) to yield Eq. (10).
R ¼ Y−CA
ssq ¼
X
nt
i¼1
X
nk
j¼1
r
2
i;j
ð10Þ
Once the ssq has been determined, the next step is to
calculate a shift in the non-linear parameters in such a way that
the ssq moves towards its minimum value. To do this, it needs to
be emphasised that R, and subsequently the ssq, are functions of
the non-linear parameters only. By substituting Eq. (9) into Eq.
(10), R can be written as a function of C only, which is itself a
function of the rate constants. If the non-linear parameters to be
fitted, p
1
to p
np
, are arranged into a vector p=(p
1
, p
2
, …, p
np
),
this relationship is given by Eq. (11).
RðpÞ ¼ Y−CC
þ
Y ð11Þ
If the initial parameter estimates are given by the vector p
0
,
the Taylor series expansion can be used to estimate R following
a small shift in the parameters Δp=(Δp
1
, Δp
2
, …, Δp
np
) (see the
Appendix for details of the Taylor series expansion). If only the
first derivative of R is used a linear expression results and is
given by Eq. (12).
Rðp
0
þDpÞcRðp
0
Þ þ
ARðp
0
Þ
Ap
1
Dp
1
þ
ARðp
0
Þ
Ap
2
Dp
2
þ
: : :
þ
ARðp
0
Þ
Ap
np
Dp
np
ð12Þ
While this is a crude approximation, the fact that it is a linear
expression makes it easy to deal with. The goal is to determine
the vector of parameter shifts that moves R(p
0
+Δp) towards
zero. So, if R(p
0
+Δp) is replaced by zero and Eq. (12) is
rearranged, Eq. (13) results.
Rðp
0
Þc−
ARðp
0
Þ
Ap
1
Dp
1

ARðp
0
Þ
Ap
2
Dp
2

: : :

ARðp
0
Þ
Ap
np
Dp
np
ð13Þ
R(p
0
) is calculated as described and the partial derivative
ARðp
0
Þ
Ap
i
can be calculated by the method of finite differencing
according to Eq. (14). To calculate the partial derivative for
parameter p
i
, p
i
is shifted by a small amount Δp
i
and the
residuals are calculated to yield R(p
0
+Δp
i
).
ARðp
0
Þ
Ap
i
is then
calculated by subtracting R(p
0
+Δp
i
) from R(p
0
) and dividing
Δp
i
(equivalent to calculating the tangent in two dimensions).
ARðp
0
Þ
Ap
i
c
Rðp
0
þDp
i
Þ−Rðp
0
Þ
Dp
i
ð14Þ
In its current form, it is not clear how Δp can be calculated
using Eq. (13) as it is not a single matrix–vector product. One
solution to this problem is to vectorise (unfold into long column
vectors) the residuals and partial derivative matrices. This
expression can then be easily collapsed into a matrix–vector
product. This procedure is illustrated graphically in Fig. 7. The
154 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
matrix of vectorised
ARðp
0
Þ
Ap
i
matrices is called the Jacobian J and
results in Eq. (15).
rðp
0
Þ ¼ −JDp ð15Þ
This equation is now in a form that has a structure that can be
solved by the linear least-squares method for Δp. This solution
is given in Eq. (16).
J
þ
¼ ðJ
T

−1
J
T
Dp ¼ −J
þ
rðp
0
Þ ð16Þ
Since both the truncated Taylor series expansion and the
partial derivatives used are only approximations, the calculated
parameter shifts of Eq. (13) will not be perfect. Thus, an
iterative procedure is adopted, where the approximations are
successively improved. The calculated shifts are applied to the
parameters (p
0,j+1
=p
0,j
+Δp going from the j-th to the j +1-th
iteration) and the process of calculating C through to Δp is
repeated. This process is iterated until the relative change in the
ssq from one iteration to the next falls below some threshold
value (ssq
old
≈ssq). A relative change of less then 10
−4
is
generally appropriate.
4.4. The Marquardt modification
Generally, the Newton–Gauss method, as described so far,
converges rapidly, quadratically near the minimum. However, if
the initial estimates are poor, the functional approximation by
the Taylor series expansion and the linearization of the problem
becomes invalid. This can lead to divergence of the ssq and
failure of the algorithm.
The modification suggested by Marquardt [36], based on the
ideas of Levenberg [35], was to add a certain number, the
Marquardt parameter mp, to the diagonal elements of the
Hessian matrix, H=J
T
J, during the calculation of the parameter
shifts, as shown in Eq. (17).
H ¼ J
T
J
Dp ¼ −ðH þ mp  IÞ
−1
J
T
rðp
0
Þ
where I ¼ the identity matrix ð17Þ
When the value of mp is significantly larger than the elements
of H, the expression H+mp×I becomes diagonally dominant.
This means the inverse is effectively a diagonal matrix, with
1
mp
in the diagonal elements. This causes Eq. (17) to collapse to Eq.
(18), which has the form of the linear descent method.
Dp ¼
1
mp
 I

J
T
rðp
0
Þ ð18Þ
When the value of mp is small, Eq. (17) reverts to that of the
inverse Hessian method. The Marquardt parameter is initially set
to zero. There are many strategies to manage the Marquardt
parameter, ours is the following. If divergence of the ssq occurs,
then the Marquardt parameter is introduced (given a value of 1)
and increased (multiplication by 10 per iteration) until the ssq
begins to converge. Once the ssq converges the magnitude of the
Marquardt parameter is reduced (division by
ffiffiffiffiffi
10
p
per iteration)
and eventually set to zero when the break criterion is reached.
4.5. Error estimates and correlation coefficients
A spin-off from the NGL/M algorithm is that it allows
direct estimation of the errors in the non-linear parameters.
The inverted Hessian matrix H
−1
, without the Marquardt
parameter added, is the variance–covariance matrix of the
parameters. The diagonal elements contain information on the
parameter variances and the off-diagonal elements the
covariances. The formula for the standard error σ
i
in
parameter p
i
is given by Eq. (19).
r
i
¼ r
Y
ffiffiffiffiffiffiffi
h
−1
i;j
q
ð19Þ
h
− 1
i,i
is the i-th diagonal element of the inverted Hessian
matrix H
− 1
and σ
Y
is the standard deviation of the residuals
R (see Eq. (20)).
r
Y
¼
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ssq
nt  nk−ðnk þ nc  nkÞ
r
ð20Þ
The denominator of σ
Y
is the number of degrees of freedom.
This equals the number of experimental values, the number of
elements in R (nt ×nλ), minus the number of fitted parameters
Fig. 7. Vectorising and collapsing Eq. (13) into a matrix and vector product [39].
155 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
(np+nc×nλ, that is the number non-linear and linear para-
meters). If H is normalised to one in the diagonal elements, this
yields the correlation coefficients between parameters [40]. The
element h
i,j
of the normalised H is the correlation coefficient
between parameter i and j. This is the cosine of the angle between
the columns in J for these parameters. The closer the value of the
correlation coefficient to one (the cosine of 0°) the more
correlated the parameters. High correlation between parameters
means that the two parameters cannot be distinguished from one
another and one needs to be removed from the fit.
5. Second-order global analysis
Up to this point, the analyses discussed have involved a
single multivariate measurement. This approach has been
dubbed first-order global analysis [1,4]. A powerful extension
of this approach is second-order global analysis [2,41]. In
second-order global analysis, the procedures already described
are applied simultaneously to multiple measurements of the
same system made under different conditions. Typically,
measurements where the initial concentrations have been
varied. Thus, a global model is simultaneously fitted to multiple
measurements. This has a number of advantages, including
more robust determination of the parameters, determination of
parameters that are not defined in any single measurement and
the breaking of linear dependencies [2,42]. Also, by fitting a
global model to multiple measurements made under different
conditions, more confidence can be had in the model.
A convenient way of organising a second-order global
analysis process is to organise the data sets in such a way that
existing matrix based software can be adapted. If nm
multivariate measurements have been made, the first step for
carrying out second-order global analysis is to concatenate
(stack one atop the other) the data matrices to form one large
matrix Y
tot
. It is assumed that each measurement covers the
same wavelength range, and thus, each data matrix has the same
number of columns. The individual concentration profile
matrices are then concatenated in a similar manner to the data
matrices, to form one large matrix C
tot
. Although multiple
multivariate measurements have been concatenated, because
each measurement obeys the same reaction mechanism, Eq. (2)
can still be applied using Y
tot
and C
tot
(see Eq. (21)).
Y
tot
¼ C
tot
A þ R
tot
ð21Þ
This equation is represented in Fig. 8. This means calculation of
the linear parameters, and fitting of the non-linear parameters,
can be carried out in the same manner as previously described
by replacing Y with Y
tot
and C with C
tot
.
Second-order global analysis is at its most powerful when a
single matrix of pure component spectra, A, can be calculated
for Y
tot
and C
tot
, as shown in Fig. 8. This is known as the global
spectra mode of analysis. It is not always possible however. If
there is baseline drift, or some other inconsistency between the
measurements such as temperature-dependent spectra, a single
A matrix cannot be used. This is because all measurements will
no longer share the same pure component spectra. In this
situation, a separate A matrix is calculated for each measure-
ment. This arrangement is shown in Fig. 9, and is known as the
local spectra mode of analysis.
To illustrate the power of second-order global analysis,
consider the second-order reaction Eq. (22) where the concen-
tration profiles for a single measurement are linearly dependent.
A þ B Y
k
A
B
¼1
C ð22Þ
For a single multivariate measurement of this mechanism,
starting with the initial concentrations [A]
0
and [B]
0
, the
concentration profiles of the species A, B and C are linearly
dependent. The smallest number of linearly independent terms
that can be used to represent the data is called the rank of the data.
The rank of the data can be estimated by carrying out factor
analysis [19] and in this case the rank of Cand subsequently Yis
two and the calculation of C
+
and thus A, Eq. (9), is not possible.
However, if a second measurement of the same reaction, having
different initial concentrations for A and B, was also made the
linear dependence can be broken. By fitting the mechanism
Fig. 8. Application of second order global analysis using a single matrix of pure
component spectra A (global mode).
Fig. 9. Application of second order global analysis where an individual A
i
is
calculated for each measurement (local mode).
156 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
using second-order global analysis to both measurements, using
a single Amatrix, the pure component spectrumof all the species
can be resolved. The rank of the resulting combined data matrix
Y
tot
is three as it can no longer be represented by two linearly
independent terms.
This is illustrated in Fig. 10, which shows simulated
concentration profiles and data for the mechanism of Eq. (22),
with one set of initial concentrations in part (a) and with two
different sets and second-order global analysis in part (b). Both
concentration profiles have [A]
0
=0.5 and for the first [B]
0
=0.2
and the second [B]
0
=0.4. A single Gaussian peak was used for
the pure component spectrum of each species and the
absorbance data was calculated as Y=CA. If one single data
file and matrix of concentration profiles are used to calculate the
pure component spectra according to Eq. (9) ((a) of Fig. 10), the
pure component spectra cannot be resolved. However, if both
data files and concentration profiles are used according to
second-order global analysis ((b) of Fig. 10), the spectra of all
three species can be calculated and are well defined.
6. Examples
In this section a number of examples are given where the
techniques described have been applied, first to a complex
simulated example, and then to three real examples. Each
example will be used to highlight particular benefits of the
global analysis of multivariate data. This tutorial does not deal
directly with how to discriminate between different models.
However, in summary, the basic approach adopted is that the
residuals are used as an indication of the validity of the
Fig. 10. Calculation of pure component spectra using (a) one single measurement and (b) two measurements and second order global analysis using global spectra.
157 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
Fig. 11. Reaction scheme used for the chlorination of benzene. The chlorination reagent is omitted.
1
5
8
G
.
P
u
x
t
y
e
t
a
l
.
/
C
h
e
m
o
m
e
t
r
i
c
s
a
n
d
I
n
t
e
l
l
i
g
e
n
t
L
a
b
o
r
a
t
o
r
y
S
y
s
t
e
m
s
8
1
(
2
0
0
6
)
1
4
9

1
6
4
underlying model. In all cases, the simplest model (in terms of
number of parameters) that yields residuals with a noise level
and error structure expected from the instrumentation is chosen.
The identifiabilty of model parameters is estimated based on the
error values and correlation coefficients calculated during the
non-linear regression. If the estimated error in a parameter is
large or two parameters are highly correlated then this is used to
indicate that the model is incorrect or overly complex.
Convergence of the model parameters to the same values
from different starting guesses is also used as an indication of
model correctness and parameter identifiability. For a discus-
sion of this topic, see Vajda and Rabitz [43].
6.1. Simulated chlorination of benzene
As a first example of the power of fitting kinetic models to
multivariate data a simulation will be considered. The
chlorination of benzene to hexachlorobenzene involves a
complex series of reactions. The scheme is represented in Fig.
11. To highlight the complexity of the mechanism, consider the
third chlorination step. Three dichloro isomers react to produce
three trichloro isomers. 1,2-dichlorobenzene reacts only to the
1,2,3- and 1,2,4-trichlorobenzenes; 1,3-dichlorobenzene reacts
to form all three isomers and 1,4-dichlorobenzene reacts only to
form 1,2,4-trichlorobenzene. Data were generated for the
mechanism by assigning hypothetical rate constants defined
by the probability of the reaction given by the number of
substitution possibilities that leads to a particular product. For
example, for 1,3-dichlorobenzene to 1,2,4-trichlorobenzene
there are two possibilities so k
1,3–1,2,4
was assigned a value of
2 and for 1,3,5-trichlorobenzene to 1,2,3,5-tetrachlorobenzene
there are three possibilities so k
1,3,5–1,2,3,5
=3. This model
ignores electronic effects of the substituents which in reality
slow down additional substitutions. This is not relevant for the
present purpose. There are a total of 13 species and 20 rate
constants in the mechanism.
Data were generated by modelling the pure spectra of the
benzenes as severely overlapping Gaussian peaks. The
chlorination reagent was assumed to be non-absorbing.
Absorbance data was generated by multiplying simulated
concentration profiles by the simulated pure spectra. White
noise with a standard deviation of 0.001 (a realistic value for
UV–Vis spectrophotometers) was added to the data. An
example of the generated data is shown in Fig. 12. Due to the
complexity of this system it cannot be resolved from a single
measurement, even with perfect noise-free data as serious rank
deficiencies result and simplified models can be fit. 10
measurements were generated, each one starting with the
unsubstituted benzene and with one of the isomers in the steps
involving three isomers (di-, tri- and tetra-chloro isomers). This
was necessary to break the rank deficiencies in the concentra-
tion profiles. A concentration of 1 with a ten-fold excess of
chlorination reagent was used, with 100 spectra generated at
equal intervals between 0 and 0.3 time units.
All 10 measurements were analysed globally using second-
order global analysis. The determined rate constants were
essentially correct (exactly correct to two significant figures).
Such an analysis would be practically impossible without the
use of multivariate data and second-order global analysis. Due
to the severely overlapped spectra, there is no single wavelength
that could be chosen to follow a single species. Furthermore,
due to the complexity of the mechanism, there is no single
measurement or subset of the measurements that could be made
to elucidate all the rate constants and spectra due to the severe
rank deficiencies of the concentration profiles.
6.2. Complexation of Cu(II) by cyclam using stopped-flow and
standard spectrometry
In this example the reaction between Cu(II) and the
macrocyclic ligand cyclam (1,4,8,11-tetraazacyclotetradecane)
in aqueous solution was investigated. The details of the
Fig. 12. Generated data for the benzene example with a 1: 10 ratio between benzene and the chlorination reagent: (a) calculated concentration profiles and pure spectra
(inset) and (b) calculated absorbance data.
159 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
experiments and results can be found elsewhere [13]. Cyclam is
a tetradentate ligand and forms a 1: 1 complex with Cu(II) in
aqueous solution. The reaction rate depends upon the level of
protonation of cyclam, and as such is strongly pH-dependent.
Multiwavelength kinetic data of the reaction was collected
using both stopped-flow and manually mixed measurements
with [Cu
2+
]
0
=3.9×10
−3
M and [cyclam]
0
=4.3×10
−3
M and
different starting acid concentrations (1×10
−7
−0.057 M). The
kinetic model given in Eq. (23), coupled to the protonation
equilibria given by Eq. (24) (L-cyclam), was fitted simulta-
neously to all the measurements. A description of the method
used to couple the kinetic model and protonation equilibria is
beyond the scope of this tutorial. The reader is referred to
Maeder et al. [13] for details. However, beyond some
modification to the method used to calculate the concentration
profiles, the fitting was done as described in this tutorial.
Cu

þ LH
þ
Y
k
Cu
LH
CuL

þ H
þ
Cu

þ LH

2
Y
k
Cu
LH
2
CuL

þ 2H
þ
ð23Þ
L þ H
þ
W
K
1
LH
þ
LH
þ
þ H
þ
W
K
2
LH

2
LH

2
þ H
þ
W
K
3
LH

3
LH

3
þ H
þ
W
K
4
LH

4
ð24Þ
The calculated concentration profiles, calculated pH as a
function of reaction time (calculated as −log
10
([H
+
])), fits of the
absorbance data at two wavelengths and the calculated pure
component spectra of the absorbing species are shown in Fig.
13. In this case, it was necessary to calculate the pure
component spectra in the local mode due baseline shifts
between measurements. However, because of the multiwave-
length data and the fact that only Cu
2+
and CuL
2+
absorbed the
calculated pure component spectra were well defined for all the
measurements. This allowed measurement to measurement
comparison as well as comparison with independently deter-
mined spectra for verification purposes. However, the real
benefit for the study of this system comes from the fitting of a
global reaction model to a number of measurements simulta-
neously. All the parameters associated with this mechanism
cannot be defined by a single measurement due to the effect of
pH on the reaction velocity. Only through fitting multiple
multivariate measurements simultaneously are all the para-
meters defined.
6.3. Acid-induced dissociation of tris(ethylenediamine)
nickel(II)
In this example, the acid-induced dissociation of tris
(ethylenediamine) nickel(II) (Ni(en)
3
2+
) in aqueous solution is
considered. This reaction has been studied in detail [44–47],
and in the presence of an excess of acid the Ni(en)
3
2+
complex
undergoes irreversible dissociation in the three first-order steps
given by Eq. (25).
NiðenÞ

3
Y
H
þ
k
NiðenÞ
3
NiðH
2

2
ðenÞ

2
þ en
NiðenÞ

2
Y
H
þ
k
NiðenÞ
2
NiðH
2

4
ðenÞ

þ en
NiðenÞ

Y
H
þ
k
NiðenÞ
3
NiðH
2


6
þ en ð25Þ
The reaction proceeds as the bidentate en ligand becomes
protonated and dissociates from the metal centre.
Multiwavelength kinetic data of this reaction was measured
using a stopped-flow spectrophotometer. Initially a 0.040 M
solution of Ni(en)
3
2+
was prepared by dissolving Ni
2+
in the
presence of an excess of en and 1 M sodium perchlorate. This
solution was then mixed with a 1 M solution of perchloric acid
in the stopped-flow and the reaction was followed between 430
and 640 nm for 10 s. Experimental details can be found
elsewhere [48]. The reaction mechanism of Eq. (25) was fitted
Fig. 13. Fit results for a manually mixed measurement with [Cu
2+
]
0
=3.9×
10
−3
M, [LH
2
2+
]
0
=4.3×10
−3
M and [H
+
]
0
=1.0×10
−7
M. (a) Calculated
concentration profiles and pH and (b) measured (•••) and calculated (—)
absorbance data and calculated pure component spectra (inset).
160 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
to the data and Fig. 14 shows the resulting calculated
concentration profiles and fits at selected wavelengths.
For this example the benefits of using multivariate data are
significant and three-fold. Firstly, without knowledge of the
spectrum of the intermediate species selection of a single
wavelength to follow the reaction is difficult. Choosing a single
wavelength below 500 nm results in k
Ni(en)
being poorly defined
and choosing a wavelength above 640 nm means k
Ni(en)
3
is
poorly defined. The second advantage is related to the fact that
the mechanism consists of three first-order consecutive
reactions. The parameter values determined for the mechanism
are k
Ni(en)
3
=99.0±0.3 s
−1
, k
Ni(en)
2
=4.10±0.01 s
−1
and k
Ni(en)
=
0.184±0.001 s
−1
. Swapping of the values of k
Ni(en)
3
and k
Ni(en)
2
or k
Ni(en)
2
and k
Ni(en)
results in fits of identical quality. This fast-
slow ambiguity exists for all consecutive first-order reactions
and it has been well documented in literature [49]. However, the
correct ordering of the rate constants is immediately apparent
upon examination of the pure component spectra, as can be seen
in Fig. 15. When the wrong ordering is used, severely distorted
and often negative spectra will result. When using single
wavelength data, such physically impossible spectra may not
occur or may not be detected. For example, using 640 nm and
swapping the values of k
Ni(en)
3
and k
Ni(en)
2
still results in all
positive molar absorptivities and reasonable values. The last
advantage is that the calculated pure component spectra allow
structural determination of the intermediate species. In this case,
the determined spectrum of Ni(en)
2
2+
indicates that it is in the cis
form [50].
6.4. Epoxidation of 2,5-di-tert-butyl-1,4-benzoquinone
As a final example the epoxidation of 2,5-di-tert-butyl-1,4-
benzoquinone (TBB) is considered. The experimental details
can be found elsewhere [17]. In summary, TBB and tert-butyl-
hydroperoxide (TBH) were added to a small volume (b45 mL)
stirred and thermostated reactor. The solvent used was a mixture
of 1,4-dioxane, ethanol and water. The reaction was initiated by
addition of a catalyst, Triton-B (benzyltrimethylammonium
hydroxide), in methanol. The two-step epoxidation reaction was
then followed by IR spectroscopy using an in situ ATR probe.
Fig. 15. Calculated pure component spectra for all species with (a) the rate
constants in the correct order and (b) with the values of k
Ni(en)
3
and k
Ni(en)
2
swapped.
Fig. 14. (a) Calculated concentration profiles and (b) measured (•••) and
calculated (—) absorbance data for the dissociation of Ni(en)
3
2+
. The time axis
has been plotted with a logarithmic scale so initial fast changes are visible.
161 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
Calorimetry data were measured simultaneously but were not
considered here.
To highlight the ability of second-order global analysis to
break rank deficiencies two measurements made at 30 °C, with
different initial concentrations of reagents have been chosen.
The reaction mechanism used to fit the data is shown in Fig. 16.
The reaction was fitted as irreversible (TBH is in excess) and
third order in each step (with the Triton-B catalyst as a reactant
and product) to allow inclusion of the catalyst.
If the reaction mechanism of Fig. 16 is fitted to a single
measurement with TBB, TBH, monoEp and diEp set as
absorbing species ([TBB]
0
=0.22 M, [TBH]
0
=2.2 M and
[Triton-B]
0
=0.064 M), the calculated pure component spectra
of Fig. 17(a) result. The poor outcome is due to linear
dependencies amongst the concentration profiles. The rank of
the concentration profiles matrix is three, but four species have
been set as absorbing. To address this, one of the species could
be set as non-absorbing. The resulting calculated pure
component spectrum would then represent a mixture of multiple
species. A better alternative is to include a second measurement
into the analysis, with different initial concentrations
([TBB]
0
=0.24 M, [TBH]
0
=1.5 M and [Triton-B]
0
=0.072 M),
and calculate a global pure component spectra matrix according
to the method of second-order global analysis. The result of
doing this is shown in Fig. 17(b). The linear dependence of the
concentration profiles is now broken and the pure component
spectrum of all the species can be resolved.
7. Conclusion
The methods required to carry out the fitting of a kinetic
chemical model to measured multivariate spectroscopic data
have been outlined in detail. From the postulation of the model
and the derivation of the differential equations, through the
numerical integration of the model to yield the concentration
profiles and finally the calculation of the pure component
spectra and fitting of the model's rate constants to measured
data.
The benefits of fitting kinetic models to multivariate data
have been explained and demonstrated by simulated and real
examples. These benefits include: more robust model and
parameter determination; calculation of pure component
spectra; the breaking of linear dependencies (second-order
global analysis); and elimination of the need for single
wavelength selection and a reduction in the number of
measurements required for analysis. Probably the most
important point of all is that, particularly with the
Fig. 17. Calculated pure component spectra with TBB, TBH, monoEp and diEp
as coloured for (a) calculation with a single measurement and (b) calculation
using two measurements with different initial concentrations and global spectra
(shaded area shown in inset). NB: The absorbance data has not been divided by
the optical path length for visual clarity so the absorptivity is in M
−1
rather than
M
−1
cm
−1
.
Fig. 16. Reaction mechanism for the epoxidation of TBB by TBH with Triton-B as a catalyst.
162 G. Puxty et al. / Chemometrics and Intelligent Laboratory Systems 81 (2006) 149–164
availability of instrumentation capable of delivering multi-
variate data, there is no reason not to take advantage of the
techniques that exist for their treatment. Furthermore, a
number of simulated and real examples have been
considered to illustrate the benefits.
An additional point to note is that although the techniques
described in this tutorial relate directly to absorbance data, they
can be applied to any multivariate data that shows a linear
response to the concentration of species in the reaction
mechanism. For example the techniques can just as easily be
applied to fluorescence or time resolved NMR data. It is also
straightforward to extend the kinetic models used for non-
isothermal conditions using either Arrhenius of Erying based
rate constant temperature dependencies [3,15] (although careful
attention must be paid to the temperature dependence of
spectra). It is also possible to mix measurements of different
types (for example, absorbance data covering different
wavelength ranges or absorbance and fluorescence data) or
use different types of modelling to calculate the concentration
profiles (for example, equilibria models [42]).
Appendix A. The Taylor series expansion
The Taylor series expansion [51] is a mathematical means of
approximating the value of a function that cannot be explicitly
calculated. It is used both for the numerical integration of a
kinetic model and during the calculation of parameter shifts
during non-linear regression. It relies on knowing the value
taken by a function at some point x. The derivative(s) of the
function at x is (are) then used to extrapolate the value taken by
the function at some other nearby point, x+Δx (Δx is some
small increment in x). As an example, consider some function f,
for which the value of f(x) is known. The full form of the Taylor
series expansion as would be used to calculate its value at f(x
+Δx), and its truncated form as used in Euler's method and the
Newton–Gauss–Levenberg/Marquardt method, are shown in
Eqs. (26) and (27), respectively.
f ðx þDxÞ ¼ f ðxÞ þ
1
1!
df ðxÞ
dx
ðDxÞ þ
1
2!
d
2
f ðxÞ
d
2
x
ðDxÞ
2
þ
: : :
þ
1
n!
d
n
f ðxÞ
d
n
x
ðDxÞ
n
ð26Þ
f ðx þDxÞ ¼ f ðxÞ þ
1
1!
df ðxÞ
dx
ðDxÞ ð27Þ
For practical reasons, generally only the first or second
derivative of the function is used. However, the higher the order
of derivative that is used, the greater the accuracy with which
the prediction of f(x+Δx) is made.
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