Dynamic Clustering and Ion Microsolvation

CHAPTER FOUR
Dynamic Clustering and Ion

Microsolvation
W. Scott Hopkins1
Department of Chemistry, University of Waterloo, Waterloo, ON, Canada
1
Corresponding author: e-mail address: shopkins@uwaterloo.ca
Contents
1. Introduction 83
2. The Effect of the Asymmetric Field 84
2.1 Differential Mobility in a Hard Sphere Environment (Type C Behaviour) 86
2.2 Introduction of Solvent Vapour (Type A and Type B Behaviour) 93
2.3 Exotic Dispersion Curves (Type D and Type E Behaviour) 104
3. Using DMS Clustering Behaviour to Assess Molecular Properties 106
3.1 Correlating Type B Critical Points With Molecular Properties 106
3.2 Application of Supervised ML 112
Acknowledgements 118
References 118
1. INTRODUCTION
The inception of differential mobility spectrometry (DMS) can be
traced back to the Gas Analyser of Ions reported by Gorshkov [1]. Over
the decade following this initial report, the development of differential
mobility devices proceeded along two different directions based on device
geometry. One direction, driven by Gorshkov and his research team, sought
to utilize cylindrical device geometry with curved electrodes to generate
inhomogeneous electric fields at the device output so as to focus the trans-
mitted ions into a detector. This implementation would later be referred to
as high-field asymmetric waveform ion mobility spectrometry (FAIMS)
[2–4]. The other direction of device development sought to utilize a planar
device geometry which could transmit all ions without discrimination when
the separation voltage (SV) was set to 0 V, and transmit cations and anions
simultaneously during operation [5,6]. This implementation became known
as DMS [7]. As these technologies matured, there arose an impetus towards
Comprehensive Analytical Chemistry, Volume 83 # 2019 Elsevier B.V. 83

ISSN 0166-526X All rights reserved.
https://doi.org/10.1016/bs.coac.2018.10.002
84 W. Scott Hopkins
miniaturization, and the first microscale DMS (μDMS) device was reported
in the year 2000 [8]. While these different implementations of device geom-
etry impart different analytical properties, DMS (both macro- and microscale)
and FAIMS employ the same fundamental principle for physically separating
analytes—an ion’s coefficient of mobility has a very specific, nonlinear
electric field dependence typically described by:

E E
K ¼ K0 1 + α (1)
N N
where K0 is the mobility coefficient under low-field conditions and α is
a function that describes how the mobility depends on the ratio E/N
(expressed in Townsend, Td) where E is electric field and N is concentra-
tion of neutral particles.
Chapter “Tandem ion mobility spectrometry with drift tubes at ambient
pressure” by Eiceman, Section 2.2, provides an excellent overview of the
underlying theory for DMS, and the keen reader is directed to review
articles by Schneider et al. [9] and Kabir and Donald [10] for additional
perspectives. Of pertinence to the discussion which follows in here is the
observation that DMS separations can be substantially improved (in some
cases enabled) by the addition of a low partial pressure of polar solvent
vapour to the collision gas [11–24]. It is generally thought that this behaviour
is a result of dynamic ion–solvent clustering and declustering, which occurs
during the ion’s transit through the DMS cell. Consequently, it is useful to
revisit the principle of operation for DMS paying particular attention to
ion–molecule interactions. This is done in Section 2. We then describe
how one can use clustering propensities as measured by DMS to assess a
variety of gas and condensed-phase molecular properties in Section 3.
2. THE EFFECT OF THE ASYMMETRIC FIELD

A planar DMS cell consists of two parallel planar electrodes separated
by a gap which is on the order of d ¼ 1 mm [25]. To these electrodes one
may supply an asymmetric AC waveform, known as the SV, and/or a DC
compensation voltage (CV). The SV waveform is chosen such that the area
under the curve in the high-field portion of the waveform is equal to that
under the curve during the low-field portion of the waveform. Under these
conditions, the ions adopt a zig–zag motion whereby they first migrate
quickly towards one of the planar electrodes during the first half-cycle of
Dynamic Clustering and Ion Microsolvation 85
Gas flow
To detector
Unstable trajectory
Stable trajectory
SV CV
0 0
Time, t Time, t
Fig. 1 A schematic diagram showing ion trajectory in a DMS cell. The ion’s differential
mobility coefficient, α, is encoded in the compensation voltage (CV) required for optimal
transmission at a given separation voltage (SV). Adapted from W.S. Hopkins, Determining
the properties of gas-phase clusters, Mol. Phys. 113 (21) (2015) 3151–3158.
the SV waveform, then more slowly return to their original distance from
said electrode during the second half-cycle of the SV waveform. Upon
introducing a collision gas, the ion’s differential mobility between the
high- and low-field conditions results in migration towards one of the planar
electrodes as determined by the α parameter (see Eq. 1). To correct the ion’s
trajectory such that it may be transmitted through the DMS cell, one can
apply an appropriate CV. Thus, the ion’s differential mobility coefficient is
encoded in the CV required for optimal transmission at a given SV. Fig. 1
provides a schematic diagram describing this phenomenon. It is important
to note that at the molecular scale the curved electrodes of the FAIMS
implementation appear planar, and that the discussion that follows also
applies to FAIMS and μDMS devices.
By recording the optimal CV for ion transmission as a function of SV,
one can generate a dispersion plot. Dispersion plots may be thought of as a
visual representation of the α parameter and they provide insight as to the
behaviour of an analyte in a given gaseous environment. Fig. 2 shows the
dispersion plot for tributylammonium in a pure N2 environment at a pres-
sure of 1 atm (black curve), a N2 environment seeded with a 1.5% mole ratio
of methanol vapour (red curve), and a N2 environment seeded with a 1.5%
mole ratio of acetonitrile vapour (blue curve) [14]. Clearly, the differential
mobility exhibited by tributylammonium varies from one gaseous environ-
ment to another. The three dispersion plots shown in Fig. 2 are exemplary
of the three common behaviours observed for ions in DMS experiments.
86 W. Scott Hopkins
20 N2 Type C
MeOH
10 ACN
0
CV (V)
Type B
–10
–20
–30
Type A
–40
0 1000 2000 3000 4000
SV (V)
Fig. 2 Dispersion plots for tributylammonium as recorded in (black curve) a pure N2
environment, (red curve) a N2 environment seeded with a 1.5% mole ratio of methanol
vapour, and (blue curve) a N2 environment seeded with a 1.5% mole ratio of acetonitrile
vapour. The experiments were conducted at a pressure of P ¼ 1 atm and a temperature
of T ¼ 150°C. Adapted from J.L. Campbell, M. Zhu, W.S. Hopkins, Ion-molecule clustering in
differential mobility spectrometry: lessons learned from tetraalkylammonium cations and
their isomers, J. Am. Soc. Mass Spectrom. 25 (9) (2014) 1583–1591.
Type C behaviour, whereby increasing CV is necessary to correct cation

trajectory as a function of increasing SV, is observed for weakly interacting
(i.e. hard sphere) collision environments. This behaviour indicates that ion
mobility decreases with increasing electric field (i.e. the α parameter is neg-
ative). In contrast, Type A behaviour is associated with decreasing CV as
a function of increasing SV, indicating that ion mobility increases with
increasing electric field (i.e. the α parameter is positive). Interestingly, for
Type B behaviour, the CV initially decreases with increasing SV, but then
reverses its trend and increases with increasing SV at higher field. For this
behaviour, the α value is initially negative, but changes sign at high field.
To understand the origins of these types of ion behaviour, it is necessary
to consider differential mobility from the molecular perspective.
2.1 Differential Mobility in a Hard Sphere Environment

(Type C Behaviour)
Before considering the simplest differential mobility condition, that of
an ion in a hard sphere (Type C) environment, it is useful to think about
how an ion moves in a DMS cell under vacuum conditions. Fig. 3 shows
a separation waveform which is the sum of the first and second harmonics
of a sinusoidal function, V0sin(ωt), where the amplitude of the second
harmonic is scaled by a factor of ½. For additional details on the DMS
f(t) = sin(w t) + sin(2wt)
sin(2wt)
sin(wt)
Fig. 3 A DMS waveform produced by adding two sinusoidal functions. Note that the
shaded areas above and below SV ¼ 0 V are equal.
mode of operation, see chapter “Tandem ion mobility spectrometry with

drift tubes at ambient pressure” by Eiceman, Section 2.2, or Refs [9, 25].
Key to this discussion is the fact that the average value of the separation
field over a period is zero. This of course has important bearing on ion
motion. If one performs the simple approximation of equating the
! !
Coulomb force acting on the ion, F ¼ q E , with the Newtonian force,
! !
F ¼ m a , one arrives at:
!
qE !
a¼ (2)
m
Thus, under CV ¼ 0 V conditions, the average field-induced accelera-
tion and velocity are zero, and over the course of the full SV waveform ions
migrate off the longitudinal axis of the DMS cell, then back again.
With gas present in the DMS cell, ion motion is dampened via collisions
as described by the mobility coefficient (see Eq. 1). The field-dependent
nature of ion mobility is not well understood. However, it is clear that
the underlying phenomena giving rise to differential mobility must be
described by kinetic gas theory and dynamic ion–molecule interactions.
For the case of Type C behaviour, the collision gas is weakly interacting
and the molecules of the collision gas may be approximated as hard spheres.
Assuming this ideal behaviour, one can draw from kinetic gas theory to cre-
ate a qualitative model for ion motion based on the frictional mechanism of
fluid viscosity. Consider, for example, a knife which has been inserted into
in a jar of honey normal to the surface of the honey (as shown in Fig. 4). If
the knife is removed along an axis perpendicular to the surface, the friction
88 W. Scott Hopkins
Fig. 4 The viscosity of fluids like honey is governed by the momentum transfer between
molecular layers. The force required to overcome the interactions between fluid layers is
proportional to the velocity gradient, ν0/d.
between the knife’s surface and the molecules in the fluids that are in a layer
directly adjacent to the knife drag the molecules of the fluid along in the
direction of the knife’s movement. This behaviour extends out into the fluid
away from the surface of the knife. Molecular collisions transfer momentum
between the fluid layers; faster molecules collide with slower molecules
causing the slower molecules to speed up; and the faster molecules to slow
down. This effect is often observed at the macroscopic level at ice skating
rinks and stock car ovals. At the microscopic level, this effect gives rise to
fluid viscosity. The friction between the fluid layers originates from the
interactions between molecules as they slide past one another.
In liquids, the proximity of the molecules gives rise to relatively strong
intermolecular interactions (compared to gases). Consequently, a relatively
large shear force is required to cause the layers of the liquid to move past one
another. In our honey example, the force required to overcome the inter-
actions between fluid layers is proportional to the velocity gradient, ν0/d, in
the region of the knife:
F ν0
¼η (3)
A d
where F/A is the force per unit area of plate (i.e. knife) and η is the coefficient
of viscosity [26]. For liquids, η decreases with increasing temperature—at
higher temperatures the high-kinetic energies of the molecules allow them
to overcome the intermolecular forces between the fluid layers allowing the
layers to slip past one another with greater ease. In contrast to the behaviour
of liquids, the viscosity of gases increases with increasing temperature.

Because the intermolecular distances between molecules in gases are
relatively large, intermolecular forces between molecules are relatively
weak, and the fluid layers of the gas can slide past one another without much
effort. However, as the temperature of the gas increases, the faster moving
molecules transfer more momentum between the layers thereby increasing
the viscosity of the fluid. From the kinetic theory of gases, one arrives
at the result that the viscosity of a gas is proportional to the square root
of the gas temperature. Specifically [27],
1=2
m 8kB T
η ¼ pffiffiffi (4)
3 2σ πm
where m is the particle mass, kB is Boltzmann’s constant, T is temperature,

and σ is the collision cross section (CCS) of the gas particles. If one considers
DMS from this perspective, one can qualitatively explain the phenomenon
of differential mobility. As the electric field increases, the relative velocity of
the ions in the gas increases, leading to an increase in the rate of collision as
described by [28]:
N
z ¼ σ hvrel i (5)
V
where hvreli is the average relative velocity of the particles and N/V is the gas
number density. It is clear from this description that the increased collision
frequency is a local effect for the ion since the neutral, hard sphere collision
gas is affected to only a relatively minor extent by application of the electric
field. In other words, as the applied electric field increases, the instantaneous
relative velocity and collision frequency of an ion in the field also increases.
This increases the momentum transfer to the bath/collision gas and results in
an increased fluid viscosity in the region of the ion. This scenario is depicted
schematically in Fig. 5. Because local fluid viscosity increases with increasing
electric field, ion mobility decreases with increasing electric field, and a pos-
itive voltage offset (i.e. CV) is required to correct ion trajectory and ensure
ion transmission. This gives rise to the observed Type C behaviour.
Given the earlier qualitative model of differential mobility, one might
naı̈vely expect that a quantitative model should be forthcoming. However,
there are two major challenges that must be overcome en route to developing
a quantitative model of differential mobility: [1] How does one determine
the local temperature of the ions from first principles? [2] How does one
90 W. Scott Hopkins
Fig. 5 The local viscosity experienced by the ion (red hexagon) depends on the applied
electric field.
determine the field-dependent behaviour of the ion’s CCS? With regards to

the question of local temperature, statistical mechanics shows that in three
dimensions [28]:
mv2
T¼ (6)
3kB
where m is the particle mass and v is the root mean square of the total veloc-
ity. That is,
v2 ¼ vx2 + vy2 + vz2 (7)
For a Maxwell–Boltzmann distribution, vx ¼ vy ¼ vz. However, if we

define the x-axis to be the electric field axis in the DMS cell, the x-component
of the ion velocity has a contribution due to the time-dependent electric
field.
vx ðtÞ ¼ vMB + vfield ðtÞ (8)
The velocity (and therefore temperature) contribution due to the electric
field is not readily calculated from first principles since it depends on collision
frequency, CCS, gas number density, and the partitioning of total energy
between the internal energy states of the molecules and their kinetic energies
following collision. Consequently, the field-dependent temperature can
vary from one system to another.
The CCS of an ion can also potentially vary as a function of the applied
electric field. At relatively low temperature, an ion is constrained to sampling
the relatively few nuclear configurations that are accessible at the energy
available to the system. Generally, these configurations occupy a similar
region of the potential energy landscape and so exhibit similar structures.
Note that this does not discount the possibility of observing multiple isomers
or conformers in a sample since the same argument holds for high energy
species kinetically trapped in a different region of the potential energy sur-
face than the global minimum structure (provided that the barrier to isom-
erization to the ground state is relatively high) [29–31]. As the electric field
increases, the local temperature (viz. thermal energy) of the ion can increase
to the point where substantially different nuclear configurations are acces-
sible. If the ion can adopt a higher energy configuration on the timescale of
the DMS asymmetric waveform (100 s of nanoseconds), the orientationally
averaged CCS of the molecular ion can change. Ultimately, to address
the two major issues outlined earlier, accurate molecular dynamics (MD)
simulations and detailed knowledge molecular partition coefficients are
necessary.
It is also worth noting that the assumption of hard sphere behaviour for a,
e.g., N2 environment, is not necessarily valid. Because N2 has a polarizability of
1.710 Å3 [32], it can form relatively strongly bound charge/induced-dipole
complexes. For example, the dispersion- and counterpoise-corrected D0
value (i.e. dissociation from the vibrational ground state) for the (H2O•N2)+
complex is 78.1 kJmol1 at the B3LYP/6-311++G(d,p) level of theory. In
comparison, the neutral water dimer, (H2O)2, has a similarly calculated D0
value of 24.3 kJ mol1. Thus, ions can exhibit Type A or Type B behaviour
even for environments in which they might be expected to exhibit Type
C behaviour. For example, Fig. 6 shows the dispersion plots for tetramethyl-
ammonium, tetraethylammonium, and tetrapropylammonium in a pure N2
environment at P ¼ 1 atm and T ¼ 150°C [14]. While the tetraethyl and
tetrapropyl analogues exhibit Type C behaviour (as expected), the tetramethyl
analogue clearly exhibits Type B behaviour. Moreover, there are examples of
elemental ions (K+, Cs+) which exhibit Type A behaviour in N2 environments
[33]. However, it should be noted that the purity of the transport gas in these
92 W. Scott Hopkins
R4N+ in N2
R = CH3
= CH2CH3
= CH2CH2CH3
Fig. 6 Dispersion plots for (black) tetramethylammonium, (red) tetraethylammonium,

and (blue) tetrapropylammonium in a pure N2 environment at P ¼ 1 atm and
T ¼ 150°C. The green highlighted region indicates negative CV values. Adapted from
J.L. Campbell, M. Zhu, W.S. Hopkins, Ion-molecule clustering in differential mobility spec-
trometry: lessons learned from tetraalkylammonium cations and their isomers, J. Am.
Soc. Mass Spectrom. 25 (9) (2014) 1583–1591.
experiments was not stated, and it is possible that the clustering behaviour arose
from interactions between the analyte ions and trace levels of water vapour.
Given the apparent importance of ion–solvent clustering in DMS, a detailed
discussion is warranted and is presented in Section 2.2.
As a final point of consideration regarding ion CCSs in DMS, it is also
important to highlight the fact that the impact of dynamic field-dependent
dipole alignment (and therefore hindered molecular rotation) is not well
understood. Most relatively, small molecules are expected to experience
an essentially free rotation even under the high-field conditions of most
commercial DMS instruments. Consequently, the trajectories of these ions
are influenced by their orientationally averaged CCS, Ωave, with the buffer
gas molecules. However, Shvartsburg et al. showed that permanent electric
dipoles of >400D are oriented by the electric field under typical experimen-
tal conditions [34]. Dipole moments of this magnitude are found for many
macroions, such as proteins with masses in excess of c. 30 kDa. Rather than
Ωave, the ion trajectories of these dipole-aligned species instead depend on
directional CCSs, Ωdir. While direct evidence of dipole alignment in DMS
studies has yet to be reported, ions with masses above 29 kDa have been
shown to exhibit a substantial increase of mobility under high-field condi-
tions, a behaviour which is consistent with dipole alignment [34]. Eventu-
ally, spectroscopic studies and/or high-level MD simulations could shed
light on this phenomenon.
2.2 Introduction of Solvent Vapour (Type A and

Type B Behaviour)
Adding a small partial pressure of polar solvent vapour to the collision gas in
the DMS cell can result in significant deviations in the observed ion trajecto-
ries when compared to those of the pure N2 (i.e. hard sphere) environment.
The Type A dispersion curve (see Fig. 2), wherein a negative CV is required
for optimal ion transmission through the DMS cell, implies that ion mobility
increases with increasing SV. This is in contrast to the Type C behaviour dis-
cussed in Section 2.1, which can be thought of in terms of field-induced
heating resulting in increased local viscosity. Instead, Type A behaviour sug-
gests that the ions are able to more easily overcome intermolecular interactions
as the electric field (viz. local temperature) increases, analogous to the situation
outlined earlier for a liquid. In DMS, this scenario is commonly interpreted as
arising from dynamic clustering and declustering during the SV cycle. Ions
move relatively slowly and are relatively cold under low-field conditions,
so upon collision with a solvent molecule a noncovalent ion–solvent bond
can form. The ion–solvent cluster can grow via subsequent collisions with
additional solvent molecules (or solvent clusters). This microsolvation process
artificially increases the CCS of the ion, which in turn reduces the mobility
of the microsolvated ion compared to its mobility as a bare ion. During the
high-field portion of the SV waveform, the ion–solvent cluster is heated,
and solvent molecules evaporate from the cluster, thereby reducing the effec-
tive CCS of the ion and increasing its mobility compared to that observed
under low-field conditions.
The dynamic clustering and declustering process are intimately related to
the interaction potential between the ion and solvent molecules. Subtle
changes in ion structure such as isomerization, tautomerization, or conforma-
tional changes, result in small changes in the strength of ion–solvent interac-
tion, which can dramatically affect the process of microsolvation and
evaporation during the DMS duty cycle. These differences in dynamic
clustering can lead to substantial differences in the DMS behaviours of the
conformeric, isomeric, or tautomeric species. For example, Fig. 7 shows the
dispersion plots recorded for three positional isomers of chloro-2-
methylquinoline in a pure N2 environment and in a N2 environment that
was seeded with 1.5 mol% H2O vapour. Whereas all three positional isomers
exhibit identical Type C behaviour (within error) in the pure N2 environment,
the 8-substituted species exhibits significantly different behaviour from that
observed for the 6- and 7-substituted species in the water-seeded environment
[35]. The explanation for these differences is apparent if one considers that
94 W. Scott Hopkins
6-Chloro
7-Chloro
8-Chloro
Fig. 7 Dispersion plots for protonated (black) 6-chloro-, (blue) 7-chloro-, and (red)
8-chloro-2-methylquinolinine in (left) a pure N2 environment and (right) a N2 environ-
ment seeded with 1.5 mol% H2O vapour. Error bars show 2σ of the Gaussian mean
for the fitted ionogram peaks. Adapted from C. Liu, J.C.Y. Le Blanc, J. Shields,
J.S. Janiszewski, C. Ieritano, G.F. Ye, et al., Using differential mobility spectrometry to
measure ion solvation: an examination of the roles of solvents and ionic structures in
separating quinoline-based drugs, Analyst 14 (20) (2015) 6897–6903.
the site of protonation (the ring nitrogen) is also the site of the strongest inter-
action with the H2O solvent molecules. The microsolvation process of the
methylquinoline derivatives begins when a single H2O molecule forms an
ionic hydrogen bond with the protonated ring nitrogen atom. Subsequent
water molecules hydrogen bond to those previously bound to the ion to create
an extended H-bonding network near the site of protonation [13,35,36]. In the
case of the 8-substituted isomer of chloro-2-methylquinoline, the chlorine
atom sterically hinders the formation of the extended H2O hydrogen
bond network [35]. Consequently, the 8-substituted species are more weakly
bound and decluster at lower temperature (viz. electric field) than do the 6- and
7-substituted isomers. In other words, the 8-substituted isomer spends more
of its time as a bare ion and so it adopts a weak-clustering Type B dispersion
curve whereas the 6- and 7-substituted isomers exist as larger clusters further
into the high-field portion of the waveform leading to strong-clustering
Type B and Type A dispersion curves.
The Type B dispersion curve can be viewed as intermediate behaviour

between Type A and Type C. Under low-field conditions, when there is
insufficient thermal energy to overcome ion–solvent interactions, Type
B molecules exhibit the dynamic clustering and declustering processes that
are described earlier for Type A behaviour. However, as SV increases there
comes a point where enough internal energy is imparted during the high-
field portion of the waveform that the ion is too hot to effectively cluster
under the low-field condition. At SVs above this critical point, the Type B
ion adopts a behaviour analogous to the Type C molecules described in
Section 2.1. Thus, the critical point (CV minimum) in the Type B curve
is associated with the maximum difference in mobility between high-
and low-field conditions, which is associated with the highest degree of
clustering/declustering during the SV cycle.
The dynamic clustering process is governed by the Gibbs’ energy of clus-
ter formation, ΔGform, (i.e. solvent binding energy) of the clusters. This
should not be confused with heat of formation, which is the heat absorbed
or evolved when a compound is formed from its constituent elements.
ΔGform is described in the usual way:
ΔGform ¼ ΔHform T ΔSform (9)
where ΔHform and ΔSform are the enthalpy and entropy of cluster formation,
respectively. Thus, it stands to reason that the dynamic clustering processes
(and therefore DMS behaviours) of ions should be temperature dependent.
Indeed, introducing temperature control to the DMS cell provides an addi-
tional means of fine-tuning ion trajectories (and therefore separations). Fig. 8
shows the dispersion curves for a drug candidate recorded at T ¼ 150, 225,
and 300°C in a N2 environment seeded with 1.5 mol% methanol vapour
[37]. As the temperature of the DMS cell is increased, the ion behaviour
changes from Type A (at 150°C) to Type B (at 225°C), and then to Type
C (at 300°C). These observations provide some insight into the dynamic
ion–solvent clustering process. At T ¼ 150°C, the Gibbs’ energy of the sys-
tem is such that relatively large ion–solvent clusters can form under the low-
field condition, leading to a relatively large difference in ion mobility
between low- and high-field (where the solvent clusters evaporate). When
the temperature is increased to T ¼ 225°C, there is enough thermal energy
in the system to prevent the formation of larger clusters, resulting in a
decrease in the observed differential mobility between low- and high field.
96 W. Scott Hopkins
O
H
N N
N N
O
CF3
300°C
225°C
150°C
Fig. 8 Dispersion plots for a drug candidate molecule (inset) recorded at (black) T ¼ 150°C,
(blue) T ¼ 225°C, and (red) T ¼ 300°C in a N2 environment seeded with 1.5 mol% MeOH
at P ¼ 1 atm. The site of protonation is highlighted in red. Adapted from S.W.C. Walker,
A. Anwar, J. Psutka, J. Crouse, C. Liu, J.C.Y. Le Blanc, J. Montgomery, G.H. Goetz,
J.S. Janiszewski, J.L. Campbell, W.S. Hopkins, Determining Molecular Properties with Differen-
tial Mobility Spectrometry and Machine Learning. Submitted (revision requested) (2018).
At T ¼ 300°C, few (or no) ion–solvent clusters form under the low-field
condition, and the collision gas behaves as a hard sphere environment.
Owing to the difficulties in determining the field-induced temperature
and dynamic CCSs of ions (discussed earlier), it is difficult to develop an
accurate model of dynamic clustering for DMS. However, some insight
can be gained by examining the clustering behaviour of ions under static,
equilibrium conditions. To do so, it is first beneficial to determine the
approximate structures of the ion–solvent clusters that are likely to be present
under the given conditions of the DMS experiment. This can be accom-
plished to a first approximation by conducting NVT MD studies wherein
the number of particles, volume, and temperature of the system are fixed.
Although several varieties of MD simulations/programmes are available
[38,39], the application of basin-hopping (BH) search algorithms has shown
a good deal of success in identifying candidate structures for low-energy iso-
mers of small-to-intermediate-sized ion–solvent clusters [16,30,31,40–43].
The BH–MD methodology is akin to simulated annealing or Monte Carlo
with minimization, and as such it is efficient at locating stationary points on
the cluster potential energy landscape. Furthermore, simulation efficiencies
may be gained by cleverly choosing which cluster degrees of freedom to

explore (e.g. solvent XYZ coordinates, ion dihedral angles).
In general, BH calculations employ inexpensive model chemistries (e.g.
molecular mechanics) because several tens of thousands of geometry optimi-
zation calculations are required for a typical BH search. Consequently, the
candidate structures identified by the BH algorithm must be refined at a
higher level of theory before conclusions about, e.g., global minimum struc-
tures or ion–solvent binding energies can be drawn. Density functional
theory (DFT) usually provides a good balance for calculation time and accu-
racy. However, one should be aware that a suitable functional and basis set
must be chosen, and that, since the ion–solvent clusters are bound predom-
inantly by noncovalent interactions, dispersion corrections may be impor-
tant [44–46]. Moreover, it may be necessary to correct for basis set
superposition error when determining ion–solvent binding energies [47].
Fig. 9 shows the lowest energy structures for methanol solvated, proton-
ated 4-aminobenzoic acid, (4-ABA + H)+(MeOH)n (n ¼ 1–8) as calculated
at the B3LYP/6-311 ++G(d,p) GD3 level of theory [45,46]. (4-ABA + H)+
n=1 n=2 n=3
n=4 n=5 n=6
n=7 n=8
Fig. 9 The lowest energy structures of protonated 4-aminobenzoic acid/methanol clus-
ters, (4-ABA+ H)+(MeOH)n (n ¼ 1–8), as calculated at the B3LYP/6-311++G(d,p) GD3
level of theory. The green highlighted regions indicate hydrogen bonds. Adapted from
J.L. Campbell, A.M.-C. Yang, L.R. Melo, W.S. Hopkins, Studying gas-phase interconversion
of tautomers using differential mobility spectrometry, J. Am. Soc. Mass Spectrom. 27 (7)
(2016) 1277–1284.
98 W. Scott Hopkins
is a well-studied molecular ion, which may be used to illustrates several

important considerations for ionic clusters [48–51]:
1. The site of charge in the gas phase might differ from the site of charge in
the condensed phase. It is therefore important to systematically calculate
all possible sites of ion complexation, protonation, or deprotonation for
the ionic cluster and ensure that the lowest energy structure has been
identified. 4-ABA, for example, protonates on the amine in polar protic
solution, but on the carbonyl oxygen in the gas phase [48–51].
2. The site of charge and ion structure can change with degree of solvation.
As the protonated 4-ABA molecule is sequentially solvated with polar
protic solvent molecules (e.g. H2O, H3COH), protonation at the amine
nitrogen becomes favoured over protonation at the carbonyl oxygen.
Moreover, upon clustering with protic solvent, hydrogen bond net-
works can be established which provide a route for proton transfer
between basic sites via a relay mechanism [13,52–56]. The n ¼ 7, 8 clus-
ters in Fig. 9 are good examples of this phenomenon; the charge-carrying
proton was transferred from the carbonyl oxygen to the amine nitrogen
via the MeOH H-bond network [13]. Such a structural conversion can
affect conclusions based on subsequent MS characterization. For example, con-
version of O-protonated (4-ABA + H)+ to the N-protonated species
results in the observation of ammonia (NH3) loss as the major fragmen-
tation channel via collision-induced dissociation (CID); an observation
which might lead one to conclude that the N-protonated form was gen-
erated at the ion source if solvation effects are not considered.
3. Asymmetric microsolvation, whereby solvent molecules bind to one
another rather than the analyte, is common. Upon binding to a charge
site, the first solvent molecule gains an additional degree of polarization
and becomes the preferred binding site for the next solvent molecule and
so on. The formal charge is then stabilized by partial delocalization
throughout the extended hydrogen bond network as is the case in the
N ¼ 7, 8 clusters in Fig. 9.
4. Solvent evaporation can occur one-at-a-time, or via dissociation of a
small solvent clusters. The latter case, although entropically disfavoured,
can arise due to asymmetric microsolvation and the preferential forma-
tion of magic number clusters [57]. Solvent evaporation can be problem-
atic because in instances where the solvent gas-phase basicity (GB) exceeds
that of the ion charge stripping can occur. Moreover, while differences in
ion and solvent GB may be such that the ion survives a low pressure
(viz., weakly solvating) environment, larger solvent clusters may be
capable of charge scavenging and ion suppression since the GB of a solvent

cluster can change as the cluster grows. For example, the calculated GBs
and proton affinities (PAs) of isopropyl alcohol clusters, (IPA)n (n ¼ 1–5),
are plotted in Fig. 10. The PA and GB of the IPA clusters increase with
cluster size because the extended hydrogen bonding network is increas-
ingly better able to stabilize the additional positive charge.
Having established a procedure for determining representative cluster
structures, one can then conduct normal mode analyses for each cluster size
to determine relative Gibbs’ energies. Two useful parameters are the Gibbs’
energy of solvent binding, ΔGbind, and the Gibbs’ energy of cluster forma-
tion, ΔGform (discussed earlier). ΔGbind provides a measure of how strongly
bound a solvent molecule is to a given cluster, and it can be calculated from
the computed energies via:
ΔGbind ¼ GXsolvðn1Þ + Gsolv GXsolvðnÞ (10)
N=2 N=3
N=4 N=5
Fig. 10 The calculated proton affinities (PAs), gas-phase basicities (GBs), and structures
for isopropyl alcohol clusters, (IPA)n (n ¼ 1–5), as calculated at the B3LYP/6-311 ++G(d,p)
GD3 level of theory.
100 W. Scott Hopkins
where GX•solv(n1), Gsolv, and GX•solv(n) are the Gibbs’ energies of the (n 1)
solvent cluster, the solvent molecule, and the n-solvent cluster, respectively.
ΔGform indicates the relative stability of an n-solvent cluster compared to the
bare ion and n-solvent molecules:
ΔGform ¼ GX + nGsolv GXsolvðnÞ (11)
where GX is the Gibbs’ energy of the bare ion. The cluster with the lowest
Gibbs’ energy of formation for a given pressure and temperature, is the spe-
cies with the highest fractional population within the cluster distribution at
equilibrium. The DMS cell is clearly a perturbed environment compared to
field-free conditions. However, the effect of the dynamic electric field
on ion alignment and polarization is currently an open question. Fortu-
nately, on the timescale of DMS separations, all degrees of freedom
are equilibrated [58–60], so this treatment does yield a coarse estimate
of relative cluster populations. Fig. 11 shows the Gibbs’ energies of forma-
tion for the (4-ABA + H)+(MeOH)n (n ¼ 1–8) species at a pressure of
P ¼ 0.127 atm and a temperature of T ¼ 450 K. This is the partial pressure
of methanol at room temperature (the temperature at which solvent
vapour is typically seeded into the N2 collision gas), and the lowest tem-
perature setting of the DMS cell. Note that the energies in Fig. 11 have
been reported relative to the most stable cluster, (4-ABA + H)+(MeOH)4.
Doing so facilitates estimation of the relative populations for the various
cluster sizes via [61,62]:
Ni ¼ N0 eΔGrel_form =kB T (12)
P = 0.127 atm
T = 450 K
Spontaneous
formation
0 1 2 3 4 5 6 7 8
N
Fig. 11 The relative Gibb’s energies of formation for (4-ABA +H)+(MeOH)n (n ¼ 0–8), as
calculated at the B3LYP/6-311 ++G(d,p) GD3 level of theory with P ¼ 0.127 atm and
T ¼ 450 K.
where Ni is the relative population of the ith cluster, N0 is the relative pop-
ulation of the lowest energy cluster (usually set to 1), ΔGrel_form is the Gibbs’
energy of formation relative to the lowest energy cluster, and kB is
Boltzmann’s constant. By calculating the relative populations of the clusters
as a function of temperature (at a constant pressure of P ¼ 0.127 atm), one
can produce a temperature-dependent relative population plot as constructed
for (4-ABA + H)+(MeOH)n (n ¼ 0–8) in Fig. 12. This plot shows that at the
low-temperature setting of the DMS cell (c. 150°C, 450 K), (4-ABA + H)+
ions favour a microsolvated state with c. four bound methanol molecules.
As temperature increases beyond c. 200°C (c. 500 K), the clusters containing
a single methanol molecule are favoured. At temperatures greater than
c. 700°C, the bare ion is the dominant charged species in the DMS cell.
The relative populations of (4-ABA + H)+(MeOH)n (n ¼ 0–8) species
shown in Fig. 12 again raises the question of the field-dependent tempera-
ture in the DMS cell (described earlier). The two-temperature theory sug-
gests that ion temperature, Tion, may be approximated as [58–60]:
M ðKEÞ2
Tion ¼ T0 + Tfield T0 + (13)
3kB
where E is the magnitude of the electric field, K is the ion mobility, and M is
the molecular mass of the collision gas. Ion mobility is related to the CCS of
the ion via the Mason–Schamp equation [58,60]:
1=2
N0 3 2π q
K ¼ K0 ¼ (14)
N 16 μkB Tion N σ ðTion Þ
N=4 N=0
N=1
N=2
N=3
Fig. 12 Relative populations of (4-ABA+ H)+(MeOH)n (n ¼ 0–8) as a function of temper-

ature at P ¼ 0.127 atm.
Tmax (K+)
Tmax (Cs+)
Tmin = 450 K
Fig. 13 An estimate of ion temperatures for K+ and Cs+ based on the predictions of two-
temperature theory [59,60]. Calculations employed T0 ¼ 450 K, P ¼ 1 atm N2,
Emax ¼ 15 kV cm 1, K0(K+) ¼ 2.47 cm2 V1 s1, and K0(Cs+) ¼ 2.21 cm2 V1 s1.
where N is the gas number density, N0 is the gas number density at standard
temperature and pressure, μ is the reduced mass for the ion/collision gas
molecule system, and q is the ion charge. However, since the ion CCS
(and therefore ion mobility) is temperature dependent, the treatment pre-
scribed by Eq. 13 has an embedded circular reference. Robinson and
coworkers have demonstrated that one can circumvent this problem in stud-
ies of proteins by monitoring structural changes as a function of gas temper-
ature and electric field [58]. Their work showed that the field-dependent ion
temperature (which scales as E2) oscillates with the applied electric field. For
ubiquitin ions with charge states ranging from z ¼ 6–8, fields of up to
20 kV cm1 were studied and maximum field-induced temperature varia-
tions on the order of a few tens of degrees were observed during the SV
cycle. Of course, it is clear by inspection of Eq. 13 that the field-induced
temperature experienced by an ion varies from one species to another
due to changes in CCS and, therefore, mobility. For example, Fig. 13 shows
the field-dependent temperature of K+ and Cs+ in N2 as calculated via
Eq. 13. These calculations assume that the respective K0 values describe
the ion mobility under all E-field conditions. Since, under hard sphere col-
lision conditions, ion mobility decreases with increasing field, the maximum
calculated temperatures (Tmax) should be viewed as an upper bound on the
local temperature experienced by the ion in a DMS cell with P ¼ 1 atm N2
and Emax ¼ 15 kV cm1. Of course, one could arrive at a more accurate esti-
mate of temperature by taking α(E/N) into consideration. By tracking the
maximum temperature of the K+ and Cs+ ions as a function of field strength,
we arrive at the plot shown in Fig. 14. As expected, based on Eq. 13,
K+
Cs+
Fig. 14 The maximum temperatures for K+ and Cs+ for a given maximum DMS field
strength as predicted by two-temperature theory [59,60]. Calculations employed
T0 ¼ 450 K, P ¼ 1 atm N2, K0(K+) ¼ 2.47 cm2 V1 s1, and K0(Cs+) ¼ 2.21 cm2 V1 s1.
K+
Cs +
Fig. 15 The average temperatures for K+ and Cs+ for a given maximum DMS field
strength as predicted by two-temperature theory [59,60]. Calculations employed
T0 ¼ 450 K, P ¼ 1 atm N2, K0(K+) ¼ 2.47 cm2 V1 s1, and K0(Cs+) ¼ 2.21 cm2 V1 s1.
ion temperature increases quadratically with increasing field strength and the
temperature of K+ increases more rapidly with field than does the temper-
ature of Cs+ due to differences in ion mobility.
The ion temperature arguments outlined earlier have important bearing
on the dynamic ion–solvent clustering process. The most obvious impact is
that small ions can experience local temperatures of several hundred degrees
during the high-field portion of the SV waveform. It is also worth noting
that the secondary maxima in temperature (see Fig. 13) also reach relatively
high temperatures at high-field (c. 600 K for K+ at 120 Td). Consequently,
the average temperature that an ion experiences during the SV waveform
can also be substantial (see Fig. 15). In extreme cases, the thermal energies
at high field can induce structural changes or result in ion fragmentation.

The ion temperature analysis shown in Figs 13–15 also aligns with expec-
tation for dynamic ion–solvent clustering. If we consider the relative pop-
ulation diagram shown in Fig. 12, we see that the expected temperature
variations for small ions are such that ion–solvent clusters should completely
evaporate during the high-field portion of the SV waveform at relatively
high peak-to-peak voltages. However, the dynamics of this process is not
necessarily straightforward since the changing effective CCS of the ion
(due to solvent evaporation and condensation) will dynamically impact
the local temperature of the ion.
2.3 Exotic Dispersion Curves (Type D and Type E Behaviour)

In some cases, ions do not exhibit dispersion curves that can be categorized
in either of the common behaviours (Types A–C). Instead, the dispersion
curves exhibit additional features which are not expected based on the
above-described models. An example of Type D behaviour, whereby an
ion exhibits Type C behaviour at low SV but reaches a maximum CV
and subsequently adopts Type A or B behaviour, is shown in Fig. 16 [37].
O
N O
N
O H
150°C
300°C
Fig. 16 Dispersion curves observed for a drug candidate at (blue) T ¼ 150°C and (red)
T ¼ 300°C. The Type D dispersion curve (T ¼ 300°C) occurs when a strongly bound
ion–solvent cluster survives the high-field portion of the SV waveform at low SV volt-
ages. The early part of the Type D dispersion curve is reminiscent of Type
C behaviour. Eventually a critical point is reached where the ion–solvent cluster disso-
ciates at high SV. At SV voltages above this critical point, the ion adopts Type A
behaviour. Error bars show the standard error of the Gaussian ionogram peak fits.
The site of protonation, as determined by calculations at the B3LYP/6-311 ++G(d,p) level
of theory, is highlighted on the inset molecule in red.
This behaviour is observed in instances of very strong ion–solvent binding

whereby ion–solvent clusters survive the high-field portion of the separation
waveform at low SV voltages. The ion–solvent cluster therefore acts as a sin-
gle, rigid species throughout the SV waveform, exhibiting Type C behaviour.
At relatively high SV voltages, the field-induced heating is such that the
ion–solvent complex dissociates during the high-field portion of the SV wave-
form and reforms under the low-field portion; the onset of dynamic cluster-
ing/declustering results in Type A (or Type B) behaviour. The Type D curve
shown in Fig. 16 is observed in a N2 environment seeded with 1.5 mol%
methanol at a temperature of T ¼ 300°C. Also plotted in Fig. 16 is the disper-
sion curve observed when the DMS cell temperature is set to T ¼ 150°C.
In this case, clear Type C behaviour is observed indicating that the ion–solvent
cluster survives the high-field portion of the SV waveform at all SV voltages
when the base temperature of the ion is relatively low.
Fig. 17 provides an example of Type E behaviour. In this case, the
tricarbastannatrane cation is measured in a N2 environment seeded with
1.5 mol% acetonitrile [63]. The Lewis acidic tin centre of the cation binds
an acetonitrile molecule very strongly, and the ion–solvent complex survives
the high-field portion of the SV waveform up to relatively high voltages
150°C
300°C
Fig. 17 Dispersion curves observed for tricarbastannatrane, N(C9H18)Sn+, at (blue)

T ¼ 150°C and (red) T ¼ 300°C. Both curves are associated with Type E behaviour, which
occurs when a strongly bound ion–solvent cluster survives the high-field portion of the
SV waveform and exhibits additional weak-clustering (Type B) interactions at low SV
voltage. At high SV voltages, the cluster dissociates, and the bare ion adopts Type
A behaviour. Error bars show the standard error of the Gaussian ionogram peak fits.
Adapted from J. Crouse, J. Steffen, D. Huang, W.S. Hopkins, A Differential Mobility Study
of Tricarbastannatrane. (in preparation) (2018).
(as was the case for the Type D behaviour described earlier). However, in the
case of tricarbastannatrane (see Fig. 17, inset), the transannular nitrogen centre
also donates electron density to stabilize the positive charge on the tin. Con-
sequently, the nitrogen centre is weakly Lewis acidic and forms weakly bound
clusters with acetonitrile. Dynamic clustering associated with the secondary
nitrogen binding site results in Type B behaviour for the N(C3H6)3Sn+•
NCCH3 complex, which dissociates upon entering the mass spectrometer
and appears in the N(C3H6)3Sn+ ion channel. At high SV voltage, the binding
energy of the Sn-bound acetonitrile molecule is also overcome, and the bare
N(C3H6)3Sn+ ion exhibits Type A behaviour. It is this combination of
Type B and Type A behaviour that gives rise to the Type E curve.
When measuring ion behaviour in a modified environment, the forma-
tion of strongly bound ion–solvent complexes is an important consideration.
Not only can these species exhibit unexpected DMS trajectories but also, in
cases where they fragment prior to mass spectrometric detection, their
behaviours can be confused/convoluted with those of the bare ions. It is
therefore useful to examine ion DMS behaviour at multiple temperatures
and to introduce post-DMS probing techniques [23,24] to ensure the cor-
rect identification of the DMS signal carrier. For example, one can employ
in-source CID via application of a declustering potential (DP) to probe ions
post-DMS, but pre-MS detection. As the DP is ramped up, the signals of
bare ions will deplete due to fragmentation. In contrast, the signal intensity
of ions which are produced from fragmentation of larger weakly bound clus-
ters initially increase with increasing DP. Fig. 18 shows the ionogram for
protonated cytosine at SV ¼ 3500 V as recorded over a series of DP voltages.
Three signals corresponding to the three lowest energy isomers are observed
to depleted as the DP voltage is increased. A fourth peak in the ionogram (at
CV ¼ 4 V) increases in intensity with increasing DP, suggesting that the m/z
112 species associated with this feature is being produced via fragmentation
of a larger cluster/complex [23].
3. USING DMS CLUSTERING BEHAVIOUR TO ASSESS

MOLECULAR PROPERTIES
3.1 Correlating Type B Critical Points With Molecular
Properties
In examining how dynamic clustering in DMS is affected by molecular
structure, the influence of inter- and intramolecular hydrogen bonding
[64], electronic and resonance effects [12,35,36], and steric hinderance of
II
III
II. Iso 2 (5.9) III. Iso 3 (35.5)
I. Global min (0.0)

Fig. 18 The ionogram observed for protonated cytosine at SV ¼ 3500 V at a series of
different declustering (DP) potentials. Signals for bare ions deplete with increasing
DP. Adapted from A. Anwar, J. Psutka, S.W.C. Walker, T. Dieckmann, J.S. Janizewski, J. Larry
Campbell, W.S. Hopkins, Separating and probing tautomers of protonated nucleobases
using differential mobility spectrometry, Int. J. Mass Spectrom. 429 (2018) 174–181.
charge sites has been observed [12,14,65]. It is now becoming clear that the
dynamic clustering environment of the DMS cell provides a means of
statistically sampling molecular interaction potentials. Given that the SV
waveform cycles at a frequency on the order of 1 MHz, and that ion flight
times through the DMS cell are on the order of 10 ms [9], an ion in a solvent-
seeded environment undergoes c. 10,000 cycles of condensation and evap-
oration as it transits the DMS cell. Because of this, strong correlations can be
observed between an analyte’s behaviour in DMS experiments and other
molecular properties which are dependent on the interaction potential
between the analyte and its environment.
The most obvious physicochemical property which depends on the
interaction potential between an ion and a solvent molecule is, of course,
the solvent binding energy. There have been several systematic studies
showing that the clustering propensities of ions as observed by DMS corre-
late strongly with the binding energies of clusters which contain a single
solvent molecule [14,16,35–37]. This makes qualitative sense since, in the

clusters which contain a single solvent molecule, the solvent molecule usu-
ally binds to the ion’s site of charging, and does so with a binding energy that
is substantially larger than those of subsequent solvent molecules (which usu-
ally bind to the first solvent molecule or to other, lower partial charge sites
on the ion). Moreover, if one models the dynamic clustering process quan-
titatively via the method outlined in Section 2 (see Fig. 13) it becomes clear
that, for small molecules, it is clusters containing a single solvent molecule
which dominate the population distribution at the elevated temperatures
generated by the high-field portion of the SV waveform.
The strength of the DMS technique lies in its ability to distinguish ions
based on subtle differences in structure (and therefore solvent binding prop-
erties). As discussed earlier, a slight variation in molecular geometry can have
a dramatic impact on the molecular interaction potential, and therefore the
DMS behaviour of the ion. For example, consider the positional isomers
6-amino-2-methylquinoline and 8-amino-2-methylquinoline are shown
in Fig. 19. Both isomers are protonated on the ring nitrogen and, when
N2
6-Amino
8-Amino
6-Amino-2-methylquinolinium•H2O
H2O
6-Amino
8-Amino
8-Amino-2-methylquinolinium•H2O
Fig. 19 (Left) Molecular orbitals showing the interaction between a water molecule and
the protonation site of (left top) 6-amino-2-methylquinolinium and (left bottom)
8-amino-2-methylquinolinium. Calculations were conducted at the B3LYP/6-311
++G(d,p) level of theory. (Right) Dispersion plots recorded for 6- and 8-amino-2-
methylquinolinium in a pure N2 environment and a N2 environment seeded with
1.5 mol% H2O at P ¼ 1 atm and T ¼ 150°C. Adapted from C. Liu, J.C.Y. Le Blanc, J. Shields,
J.S. Janiszewski, C. Ieritano, G.F. Ye, et al., Using differential mobility spectrometry to mea-
sure ion solvation: an examination of the roles of solvents and ionic structures in separating
quinoline-based drugs, Analyst 14 (20) (2015) 6897–6903.
studied in a pure N2 environment, both exhibit identical dispersion curves.

However, upon seeding the N2 gas with 1.5 mol% water vapour, the 6- and
8-amino derivatives exhibit different dispersion curves, with the
6-substituted species exhibiting behaviour indicative of stronger solvent
clustering than the 8-substituted isomer. Examination of the DFT-
optimized structures of the singly solvated clusters of these species shows that
in both cases the water molecule binds to the site of protonation. In the case
of the 6-amino isomer, the valence molecular orbital (MO) corresponding
to the water valence electron density exhibits a contribution from the NdH
antibonding σ* MO, indicating the presence of an intermolecular hydrogen
bond [66]. Similarly, the analogous MO of the 8-substituted species also sug-
gests the presence of an intermolecular hydrogen bond between the proton-
ated NdH group, and a second intermolecular hydrogen bond with the
amine group in the 8-position (see Fig. 19). Owing to these two different
modes of solvent binding, the dynamic clustering process for the two iso-
mers differs enough to enable separation in the H2O-seeded environment.
In Section 2, the Type B curve was described as an intermediate case
between Type A and Type C, whereby dynamic clustering occurs at low
SV voltages (viz. electric fields), but at high SV voltages the ion is too
hot to effectively cluster and hard sphere collisions occur. Thus, the mini-
mum CV value can be viewed as a “critical point” where dynamic cluster-
ing/declustering is at a maximum, and the SV value at this point as being
indicative of the minimum thermal energy required to completely desolvate
the ion. It therefore stands to reason that the SV at the minimum value of CV
(SV@CVmin) should correlate with ion–solvent binding energies. Fig. 20
shows a correlation plot of the water binding energies for several protonated
2-methylquinoline derivatives and the SV@CVmin values measured for
these species in a N2 environment seeded with 1.5 mol% water at P ¼ 1 atm
and T ¼ 150°C [35]. It is clear that there is a strong correlation between sol-
vent binding energy and DMS clustering behaviour, but there is room for
improvement on this rather simplistic treatment. A more sophisticated treat-
ment that utilizes supervised machine learning (ML) is described below.
Interestingly, the dynamic gas-phase clustering observed in DMS
also correlates with condensed-phase properties. For example, Fig. 21 shows
the correlation between experimentally determined pKb values for
2-methylquinolin-8-ol derivatives and the SV@CVmin values for the pro-
tonated molecules as measured in a N2 environment seeded with 1.5 mol
% methanol [36]. The methylquinoline-8-ol derivatives that are substituted
in the 5- and 6-positions show strong correlations with the pKb values of the
neutral molecule in water, whereas the 7-substituted species exhibits a
Fig. 20 The correlation between calculated solvent binding energies and SV@CVmin for
several derivatives of 2-methylquinolinium. Calculations were conducted at the
CCSD(T)/6-311 ++G(d,p) level of theory. Data were recorded in an N2 environment
seeded with 1.5 mol% H2O at P ¼ 1 atm and T ¼ 150°C. Adapted from C. Liu, J.C.Y. Le
Blanc, J. Shields, J.S. Janiszewski, C. Ieritano, G.F. Ye, et al., Using differential mobility spec-
trometry to measure ion solvation: an examination of the roles of solvents and ionic struc-
tures in separating quinoline-based drugs, Analyst 14 (20) (2015) 6897–6903.
5-Substituted
6-Substituted
7-Substituted
Fig. 21 The correlation between experimentally determined pKb values and SV@CVmin
for several derivatives of 2-methylquinolin-8-ol. (top panel) 5-substituted derivatives,
(middle panel) 6-substituted derivatives, (bottom panel) 7-substituted derivatives where
X ¼ H, F, Cl, Br, CH3, OCH3, NO2. DMS data were recorded in a N2 environment seeded
with 1.5 mol% H3COH at P ¼ 1 atm and T ¼ 150°C. Adapted from C. Liu, J.C.Y. Le Blanc,
B.B. Schneider, J. Shields, J.J. Federico, H. Zhang, et al., Assessing physicochemical properties
of drug molecules via microsolvation measurements with differential mobility spectrometry,
ACS Cent. Sci. 3 (2) (2017) 101–109.
relatively poor correlation. Computational analysis of the probed species

shows that the 5- and 6-substituted derivatives bind a solvent molecule
via the hydroxyl group in the 8-position. In contrast, the 7-substituted
derivatives exhibit two binding motifs—binding via the OH or the NH
groups—with the lower energy motif depending on the size of the group
in the 7-position compared to the methyl group in the 2-position. The steric
hinderance of the methyl group in the 2-position drives solvent binding
to the hydroxyl group in the 5- and 6-substituted derivatives and in
7-substituted derivatives wherein the substituent has a small van der Waals
radius than the methyl group in position 2.
The fact that DMS can assay condensed-phase molecular properties such
as pKa, pKb, solubility, cell permeability, etc. [36,37], in minutes using only
picograms of sample is very compelling. However, it is not necessarily obvi-
ous that the gas-phase clustering behaviour of ionized molecules should cor-
relate with the condensed-phase properties of their neutral counterparts.
The key detail is that the site of charging (protonation/deprotonation) in
the gas phase is at or near the most basic/acidic site of the solution-phase
molecule. Consequently, the principal site of solvent interaction is the same
for the ionized and neutral molecule. This can be visualized with the molec-
ular electrostatic potential for the neutral and protonated versions of a given
molecule. For example, Fig. 22 shows the electrostatic potential as mapped
5-Methoxy-2-methylquinlin-8-ol
Neutral Protonated
Fig. 22 The electrostatic potential mapped onto total electron density for the (left) neu-
tral and (right) protonated forms of 5-methoxy-2-methylquinolin-8-ol as calculated at
the B3LYP/6-311 ++G(d,p) level of theory. Blue regions indicate partial positive charge
and red regions indicate partial negative charge. Adapted from C. Liu, J.C.Y. Le Blanc,
B.B. Schneider, J. Shields, J.J. Federico, H. Zhang, et al., Assessing physicochemical properties
of drug molecules via microsolvation measurements with differential mobility spectrometry,
ACS Cent. Sci. 3 (2) (2017) 101–109.
onto the total electron density for the neutral and protonated forms of
5-methoxy-2-methylquinolin-8-ol. In both cases, the darkest regions of
the potential map—blue indicating electron deficiency and red indicating
electron richness—are in the region of the NH and OH groups. While
the relative energetics of solvation for the ionized species are likely to differ
substantially from those expected for the neutral molecule, the mechanism/
mode of interaction is similar (i.e. H-bonding at the same site of adduction)
and relative trends for the neutral and ionized systems mirror one another
[36,37]. This interpretation is supported by the fact that intermolecular
hydrogen bonding has been identified as the first step in protonation
reactions, and these motifs closely resemble the early stages proton-transfer
processes [67–69]. It is also worth noting that the protonated forms of drugs
(like the quinoline derivatives discussed earlier) may play an important role
in absorption processes in the digestive tract where pH ranges from approx-
imately 6.5 (in the intestines) to approximately 1.7 (in the stomach) [70], and
that condensed-phase measurements conducted under physiological condi-
tions may be probing the ionized versions of these species.
Although there are strong correlations observed when plotting physico-
chemical properties against SV@CVmin, this methodology fails when
treating a large group of molecules which exhibit a wide range of structures
and chemistries. Even in the case of the methylquinoline-8-ol derivatives
discussed earlier, where strong correlations were observed between, e.g.,
SV@CVmin and cell permeability for a series of positional isomers (i.e.
5- vs 6- vs 7-substituted species), correlations across derivatives (e.g. CN
vs NO2 vs F) were poor [36]. The origin of these discrepancies lies in the
fact that DMS ion trajectories rely not only on ion interaction potentials
(viz. clustering with the surrounding environment) but also on the size of
the molecules (i.e. CCS). Thus, a proper treatment of the experimental data
requires fitting in a multidimensional parameter space. This can be accom-
plished through application of supervised ML.
3.2 Application of Supervised ML

Fundamentally, the behaviour of an ion in a DMS cell depends on how the
ion interacts with the surrounding environment. This is determined by the
strength of interaction (i.e. the magnitude of the interaction potential), the
energy of the system (i.e. temperature), and the molecular size (viz. CCS,
mass), which determines the number of collisions/interactions via Eq. (5).
Thus, by measuring an ion’s behaviour in a variety of DMS cell conditions
(i.e. temperature, pressure, composition), one gains a dataset which encodes

how the analyte interacts with its surroundings. Given the correlations
observed between SV@CVmin and molecular properties which depend
on molecular interaction potential, it stands to reason that taking a global
view of the DMS dataset should result in improved predictive capabilities.
Stated another way, a map of the entire DMS parameter space for a given ion
should provide a much better prediction of how the ion interacts and, there-
fore, and its physicochemical properties.
Supervised ML provides the framework necessary to map the DMS
parameter space onto a given output [71]. Supervised learning algorithms
take a set of N training examples of the form {(xi,yi),…,(xN,yN)} where
xi is the parameter (or feature) vector of the ith example and yi is the output
label (or class), and seek a function g: X ! Y that maps the input space X
onto the output space Y. For the purposes of treating DMS data, the param-
eter vector and class might take the form:
By mapping the DMS parameter space of a large training set of ions, one
can then generate a predictive model to estimate, e.g., the water binding
energy of ions based on their DMS behaviours. There are, of course, caveats
of which one should be mindful when taking such an approach to DMS data
processing. First and foremost, the DMS dataset must be representative of
the output onto which the data are being mapped. To date, it has been dem-
onstrated that DMS data can reliably predict properties of small molecules
with relatively simple interaction potentials [37], but work must still be con-
ducted to determine the applicability to larger, more complex systems (e.g.
proteins, DNA). It is also necessary that the training set contains examples
that are representative of the species for which one seeks to estimate phys-
icochemical properties; if an ML model is trained on amino acid data, it is
unlike to perform well in predicting the properties of, e.g., fullerenes.
Finally, in the development of accurate ML models, data are key! The larger
the input space, the more likely the learning algorithm is to infer the correct
mapping function and provide accurate output.
The selection of a suitable learning algorithm is also an important con-
sideration as there are numerous methods available [71,72]. Appropriate ML
models must exhibit a balance between bias and variance while avoiding
overfitting. In an ML model, bias typically results by preselecting the func-
tional description of the data (i.e. the fit is biased to reproduce the model
imposed by the user), and variance, which depends how well the model fits
the data, can depend on how data are partitioned into training sets and test
sets. Overfitting leads to poor applicability of a model outside the data range
used for training. Learning algorithms based on Decision Trees are a good
choice since they are exceptionally unbiased and are easily implemented
[73]. One such algorithm, known as the Random Forest method, employs
an ensemble of random decision trees for training and outputs the mode of
the classes (for classification) or the mean prediction (for regression) with
low variance [74]. Moreover, Random Forest exhibits a relatively low sus-
ceptibility to overfitting. Fig. 23 shows a schematic diagram of the Random
Forest regression algorithm.
Walker et al. have shown that by treating DMS data with the Random
Forest regression algorithm one can create highly accurate models to predict
a variety of molecular properties [37]. For example, Fig. 24 shows the results
of a Random Forest model which uses DMS data, {m/z, charge state, tem-
perature, modifier, SV, CV}, to predict the ion CCS as calculated using the
MobCal programme following geometry optimization at the B3LYP/
6-311 ++G(d,p) level of theory [45,46,75,76]. Note that 10 different
molecular topologies belonging to four different chemical classes were
included in the dataset: (blue) drug molecules exhibiting intramolecular
hydrogen bonding (IMHB), (red) 2-methylquinolin-8-ol derivatives,
(green) 2-methylquinoline derivatives, and (black) acrylamide covalent
xi
Tree #1 Tree #2 Tree #3
3 4 5
}
4±1
Fig. 23 A schematic example of the Random Forest regression algorithm. Each coloured
node on the tree represents a data splitting/binning procedure. For example, if at
SV ¼ 3500 V CV > 0 choose bin A, otherwise choose bin B. Each decision tree yields a
value for the target parameter, Y. By using an ensemble of random decision trees,
one is able to predict the mean value of the target parameter.
Average error = 0.63%
Fig. 24 A Random Forest regression fit of DMS data to calculated collision cross sections
(CCSs) for a training set consisting of 10 topological classes of molecules belonging to
four different chemical classes: (blue) drug molecules exhibiting intramolecular hydro-
gen bonding (IMHB), (red) 2-methylquinolin-8-ol derivatives (MQOH), (green)
2-methylquinoline derivatives (MQ), and (black) acrylamide covalent reactive
groups (CRGs). Adapted from S.W.C. Walker, A. Anwar, J. Psutka, J. Crouse, C. Liu, J.C.Y.
Le Blanc, J. Montgomery, G.H. Goetz, J.S. Janiszewski, J.L. Campbell, W.S. Hopkins, Determin-
ing Molecular Properties with Differential Mobility Spectrometry and Machine Learning.
Submitted (revision requested) (2018).
reactive groups (CRGs). This demonstrates the broad applicability of

using DMS to assess gas-phase molecular properties across a variety of
molecule types. It is also important to reiterate that the DMS data that
went into these fits were not just associated with SV@CVmin or Type
B dispersion curves; CCSs were determined from a wide range of ion
behaviour under a variety of DMS conditions (Types A and C included).
As an additional guard against overfitting, the model was subjected to a
fivefold cross-validation procedure [77]. This involves randomly splitting
the data into five bins, then iteratively training the model with four bins,
and testing predictions against the fifth. This methodology facilitates a
more robust error analysis. Ultimately, the correlation between ML-
predicted CCSs and those calculated via MobCal exhibited a R2 value
of 0.9919 and an average error 0.63% (i.e. the absolute error increases with
increasing molecular size). Similar high-quality models may be generated
for other gas-phase properties such as solvent binding energy [37]. In gen-
eral, the errors of the ML models converge to those of the training set as the
size of the training set increases.
When employing DMS data to create a predictive model of condensed-
phase properties, outcomes are also of very high quality. For example,
Fig. 25 A Random Forest regression fit of DMS data to experimentally determined cell
permeabilities for: (green) drug molecules exhibiting intramolecular hydrogen bonding
(IMHB), (blue) 2-methylquinolin-8-ol derivatives (MQOH), and (black) 2-methylquinoline
derivatives (MQ). Adapted from S.W.C. Walker, A. Anwar, J. Psutka, J. Crouse, C. Liu, J.C.Y. Le
Blanc, J. Montgomery, G.H. Goetz, J.S. Janiszewski, J.L. Campbell, W.S. Hopkins, Determining
Molecular Properties with Differential Mobility Spectrometry and Machine Learning. Sub-
mitted (revision requested) (2018).
Fig. 25 shows the results of a Random Forest fit of DMS data to condensed-
phase cell permeabilities. If only experimental DMS data are employed in
the ML treatment, the coefficient of determination is R2 ¼ 0.889 and the
mean average error of the fit is 1.73 106 cm s1 [37]. However, if one
also includes molecular CCS in the parameter vector, the fit improves to
R2 ¼ 0.989 with a mean average error, MAE ¼ 0.82 106 cm s1. Note
that employing SV@CVmin to predict cell permeability yields a very weak
correlation [36]. Since the rate of passive cell permeability is dependent on
molecular size and on the propensity of the molecule to desolvate and trans-
port across the hydrophobic lipid bilayer [78–80], it stands to reason that
DMS data, which encodes molecular size and interaction potential, should
correlate strongly with this molecular property.
Walker et al. have also shown that, when treated with the Random For-
est method, DMS data can be used to predict pKa, pKb, logD, solubility,
experimental polar surface area, and reaction rates for CRG-based drugs
with glutathione [37]. The strong correlation between DMS data and the
physicochemical properties of small molecules is appealing since it suggests
that the technique can be used to quickly and accurately determine a variety
of molecular properties simultaneously. However, to advance the technol-

ogy, it is necessary to assemble an extensive training set for ML modelling.
This database must include DMS data for a variety of temperature and mod-
ifier conditions, m/z, charge state, CCS, and whichever target properties
one might desire to predict. Construction of such a database, along with
development of an accurate model for ion field-dependent temperature
are (in the author’s opinion) grand challenges for the field.
Ultimately, the goal of building ML models is the prediction of proper-
ties for unknown species. Once the model is constructed, users need only
measure the DMS behaviour (i.e. dispersion plot) of an ion of interest under
a variety of temperature and modifier conditions, then apply the ML model
to estimate the target physicochemical property. Fig. 26 shows the results
of a testing algorithm whereby the 89-member set of small molecule drugs
(shown in Fig. 24) was split into an 88-molecule training set and at
1-molecule test set; the procedure was iterated such that each molecule
appeared in the test set once [37]. In doing so, one finds that the estimated
Fig. 26 Application of the Random Forest ML model shown in Fig. 24. The 89-molecule
set was split into an 88-molecule training set and 1-molecule test set; the procedure was
iterated such that each molecule was left out-of-the-bag as a test (i.e. 89-fold cross val-
idation). The model was used to predict collision cross sections (CCSs) for 10 topological
classes of molecules belonging to four different chemical classes: (purple) drug molecules
exhibiting intramolecular hydrogen bonding (IMHB), (blue) 2-methylquinolin-8-ol deriva-
tives (MQOH), (black) 2-methylquinoline derivatives (MQ), and (green) acrylamide covalent
reactive groups (CRGs). Root mean square error (RMSE), mean average error (MAE), and fit
R2 are provided on the plot. Adapted from S.W.C. Walker, A. Anwar, J. Psutka, J. Crouse,
C. Liu, J.C.Y. Le Blanc, J. Montgomery, G.H. Goetz, J.S. Janiszewski, J.L. Campbell, W.S. Hopkins,
Determining Molecular Properties with Differential Mobility Spectrometry and Machine
Learning. Submitted (revision requested) (2018).
error in ML-predicted CCS is approximately 3%, which accords well with

expected errors for the CCSs used to train the model (calculated using the
MobCal code) [75,81]. There are, of course, caveats for this methodology.
First and foremost, it is necessary that the training set used to build the ML
model contain members that are representative of the unknown target
species—a model that is trained on, e.g., anionic metal clusters, is unlikely
to perform well at predicting the properties of cationic neurotransmitters.
It is also, at this point, unclear as to how this technique will perform for
large biomolecules. Extending the ML methodology to larger, more com-
plex systems will be an interesting direction for future research.
ACKNOWLEDGEMENTS
W.S.H. would like to thank Prof. W. Alex Donald for his help in reviewing this document,
and Professors Pierre-Nicholas Roy and J. Larry Campbell, as well as Doctors J.C. Yves
LeBlanc and Brad B. Schneider for insightful conversations.
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Dynamic Clustering and Ion Microsolvation

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Dynamic Clustering and Ion Microsolvation

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CHAPTER FOUR

Dynamic Clustering and Ion

Comprehensive Analytical Chemistry, Volume 83 # 2019 Elsevier B.V. 83

2. THE EFFECT OF THE ASYMMETRIC FIELD

Type C behaviour, whereby increasing CV is necessary to correct cation

2.1 Differential Mobility in a Hard Sphere Environment

f(t) = sin(w t) + sin(2wt)

mode of operation, see chapter “Tandem ion mobility spectrometry with

of liquids, the viscosity of gases increases with increasing temperature.

where m is the particle mass, kB is Boltzmann’s constant, T is temperature,

determine the field-dependent behaviour of the ion’s CCS? With regards to

v2 ¼ vx2 + vy2 + vz2 (7)

For a Maxwell–Boltzmann distribution, vx ¼ vy ¼ vz. However, if we

Fig. 6 Dispersion plots for (black) tetramethylammonium, (red) tetraethylammonium,

2.2 Introduction of Solvent Vapour (Type A and

The Type B dispersion curve can be viewed as intermediate behaviour

ΔGform ¼ ΔHform T ΔSform (9)

may be gained by cleverly choosing which cluster degrees of freedom to

n=1 n=2 n=3

n=4 n=5 n=6

is a well-studied molecular ion, which may be used to illustrates several

capable of charge scavenging and ion suppression since the GB of a solvent

Ni ¼ N0 eΔGrel_form =kB T (12)

Fig. 12 Relative populations of (4-ABA+ H)+(MeOH)n (n ¼ 0–8) as a function of temper-

at high field can induce structural changes or result in ion fragmentation.

2.3 Exotic Dispersion Curves (Type D and Type E Behaviour)

This behaviour is observed in instances of very strong ion–solvent binding

Fig. 17 Dispersion curves observed for tricarbastannatrane, N(C9H18)Sn+, at (blue)

3. USING DMS CLUSTERING BEHAVIOUR TO ASSESS

II. Iso 2 (5.9) III. Iso 3 (35.5)

I. Global min (0.0)

solvent molecule [14,16,35–37]. This makes qualitative sense since, in the

studied in a pure N2 environment, both exhibit identical dispersion curves.

relatively poor correlation. Computational analysis of the probed species

3.2 Application of Supervised ML

(i.e. temperature, pressure, composition), one gains a dataset which encodes

Tree #1 Tree #2 Tree #3

Average error = 0.63%

reactive groups (CRGs). This demonstrates the broad applicability of

of molecular properties simultaneously. However, to advance the technol-

error in ML-predicted CCS is approximately 3%, which accords well with

[52] H.E. Audier, D. Leblanc, P. Mourgues, T.B. McMahon, S. Hammerum, Catalyzed

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