Phase equilibrium studies on N-oxidation
systems to identify inherently safer
operating conditions
Sunder Janardanan
Mary Kay O’ Connor Process Safety Center
Chemical Engineering Department,
Texas A&M University,
College Station, TX
4/28/2016
Sunder Janardanan
Born in Mumbai, India
B. Ch. E., Chemical Engineering (2008 - 2012),
Institute of Chemical Technology ( Formerly U.D.C.T),
Mumbai, India
Ph.D., Chemical Engineering (2012 - present),
Mary Kay O’Connor Process Safety Center,
Artie McFerrin Department of Chemical Engineering
Texas A&M University,
College Station, USA
2
Inherent Safety
Four major principles
3
New concepts Description
Ensure Dynamic Stability Design processes with wider operating limits
Limit Hazardous Effects Increase separation distance between units
Hybridization Make reactions inherently safer by adding inert
chemicals
E.g. Addition of water to cyclohexane renders the
vapor mixture inflammable during oxidation
(Chen et al. , (2004))[47]
Minimization Substitution Moderation Simplification
Use lower
quantities of
hazardous
chemicals
Replace
hazardous
chemicals with
safer ones
Operate at
conditions
which are less
hazardous
Reduce design
complexities to
reduce operator
errors
Introduction: N-oxidation of alkylpyridines
Commonly used in pharmaceutical industries
Current industrial practices:
Catalyst used : Phosphotungstic acid hydrate (PTA)
Reaction temperature : 85-100 οC
Decomposition reaction [6]:
2H2O2 2H2O + O2
o Rate is affected by temperature and presence of impurities
o Reduces the overall safety of the process
2,6-dimethylpyridine
(2,6-lutidine)
2,6-dimethylpyridine N-oxide
(2,6-lutidine-N-oxide)
+ H2O2 ------> + H2O
(30%)
PTA
ΔHdec = -98.3 kJ/mole
4
Previous incidents due to
peroxide decomposition
Rocky Flats Inc., Colorado (1957)[7]
Hydrogen peroxide was used to precipitate plutonium from
nitric acid solution
Feed solution contained impurities like iron, copper, chromium
and nickel
Sudden increase in pressure due to uncontrolled addition of
50% H2O2 solution leading to an explosion
Elf Atochem North America Inc., Minnesota (1997)[9]
Hydrogen peroxide was used to epoxidize vegetable oil
Incompatible material entered the fluid transfer line containing
a mixture of acetic acid, hydrogen peroxide and water leading
to an explosion
5
Previous work on N-oxidation
Kinetic models for the N-oxidation reaction [6,17-21, 26]
Effect of catalyst and temperature on the reaction
Increasing the catalyst concentration favored the N-oxidation
Operating the reaction at 110 -125 οC reduces the peroxide
decomposition in case of methylpyridine N-oxidation
Effect of aqueous - organic phase separation during the reaction:
Dimethylpyridines are immiscible in the aqueous phase leading to
formation of two phases
Peroxide decomposition was significant during dimethylpyridine N-
oxidation
However, product N-oxide increases the miscibility of
dimethylpyridine in the aqueous phase
Phase equilibrium studies can identify the region of homogeneity
6
Objective: To study the phase equilibrium of aqueous solutions
of 2,6-dimethylpyridine, catalyst and 2,6-dimethylpyridine N-
oxide
Motivation: Adding product N-oxide to initial reactant mixture
to ensure homogeneity during N-oxidation reactions - an
example of Hybridization
7
Research Highlights
FTIR
RC1e Calorimeter
Phase equilibrium study
System components
2,6-dimethylpyridine (DMP)
2,6-dimethylpyridine N-oxide (N-oxide)
Water
Phosphotungstic acid (PTA)
Various types of equilibrium
8
S-L-L-V S-L-V L-L-V L-V
A A
O O
V V V V
L L
PTA
V – Vapor
O – Organic
A – Aqueous
Research plan
Effect of N-oxide on DMP-Water phase separation:
Mixtures containing known concentrations of DMP and
N-oxide were heated to the desired temperature
Step-wise addition of water to this system
System was allowed to equilibrate
after each addition
FTIR probe was used
to collect the absorption spectrum
Difference in the spectrum of a
two phase system from a
single phase system was used
to determine phase separation
DMP + N-oxide
Water
DMP + N-oxide +Water
9
Mettler Toledo’s RC1e Reaction Calorimeter
10
11
DMP and N-oxide
mixture
Water
Research procedure
Effect of N-oxide on DMP-Water phase separation at 110 οC
12
RC1e Results
Component Concentration
(w/w %)
DMP 80
N-oxide 20
Step DMP
(w/w %)
N-oxide
(w/w %)
Water
(w/w %)
1 74.15 18.43 7.42
2 69.03 17.16 13.81
3 64.57 16.05 19.38
4 60.65 15.08 24.27
5 57.18 14.22 28.60
6 54.09 13.45 32.47
7 51.31 12.76 35.93
8 48.80 12.13 39.06
Component Concentration
(w/w %)
DMP 60
N-oxide 40
Step DMP
(w/w%)
N-oxide
(w/w%)
Water
(w/w%)
1 55.64 36.97 7.39
2 51.81 34.42 13.76
3 48.48 32.21 19.32
4 45.54 30.26 24.20
5 42.95 28.53 28.52
6 40.63 26.99 32.38
7 38.55 25.61 35.84
15 16.31 10.84 72.85
20g -
Water
Preliminary results
Component Concentration
(w/w %)
DMP 85
N-oxide 15
Step DMP
(w/w %)
N-oxide
(w/w %)
Water
(w/w %)
1 78.57 13.87 7.40
5 60.64 10.70 28.53
6 58.95 10.40 30.52
7 57.36 10.12 32.39
Component Concentration
(w/w %)
DMP 75
N-oxide 25
Step DMP
(w/w %)
N-oxide
(w/w %)
Water
(w/w %)
1 66.55 22.40 11.05
2 59.93 20.17 19.90
3 54.51 18.35 27.15
4 49.99 16.82 33.19
5 47.99 16.15 35.85
6 46.16 15.53 38.31
7 44.45 14.96 40.59
8 42.87 14.43 42.70
9 41.54 13.98 44.83
10 40.16 13.52 46.67
13
Component Concentration
(w/w %)
DMP 90
N-oxide 10
Step DMP
(w/w %)
N-oxide
(w/w %)
Water
(w/w %)
1 86.31 9.85 3.84
5 72.42 8.27 19.31
6 68.04 7.77 24.19
7 64.16 7.33 28.51
Analytical tool – Fourier Transform
Infrared Spectroscopy
Interaction of infrared radiations with chemical moieties
leads to absorption
Absorption spectrum of a molecule consists of
characteristic peaks
Benefits of an ATR-FTIR system
Analysis of multicomponent mixtures
In-situ analysis
Surface measurements
Study the solubility of paracetamol in aqueous solutions
in batch crystallization units [34]
14
Mettler toledo’s ATR-FTIR
Single phase system
Two phase system
15
16
DMP-Water-N-oxide ternary plot
Temp – 110 oC
0.00 0.25 0.50 0.75 1.00
0.00
0.25
0.50
0.75
1.000.00
0.25
0.50
0.75
1.00
N-oxide (w/w)
Dimethylpyridine (DMP)
(w/w)
Water
(w/w)
Homogeneous
Heterogeneous
Binodal curve 75-25
80-20
85-25
90-10
Thermodynamic Models
Equilibrium conditions for a heterogeneous closed system [39]
T1 = T2 = T3 =……..=Tm
P1 = P2 = P3 =……..=Pm
fi1 = fi
2 = fi3 =……… =fi
m
Current System:
Components: DMP, N-oxide, Water
Two liquid phases and one vapor phase
Liquid - Liquid Equilibrium
Vapor - Liquid Equilibrium
17
xiIg IiiPi
sat = yiP = x IIi g iIIPi
sat
xiIg Iii = x
II
i g iII
m – phases,
i – components
g i - Activity coefficeint of species i
Pisat -Vapour pressure of pure species i
x, y - Liquid /Vapor mole fractions
UNIQUAC Activity Coefficient Model
Activity coefficient (γi) accounts for the deviations from
ideal behavior in a mixture
It arises due to the interaction between unlike pairs of
molecules in a mixture
Universal QuasiChemical Model (UNIQUAC) of
Abrams and Prausnitz[39]:
18
lng i = lng i (combinatorial)+ lng i (residual)
lng i (combinatorial) = lnfixi
-z
2qi ln
fiqi
+ li -fixi
x jl jj
å
lng i (residual) = qi 1- ln q jt ji
j
åæ
èçç
ö
ø÷÷-
q jt ij
qkt kjk
åj
å
é
ë
êêêê
ù
û
úúúú
UNIQUAC Activity Coefficient Model
19
where li = (ri - qi )z
2- (ri -1)
z = Average coordination number
ri = volume parameter for species i
qi = Surface area parameter for species i
qi = Area fraction =xiqi
x jq jj
å
fi =Volume fraction =xiri
x jrjj
å
Volume (Ri) and Surface
area (Qi) parameters for
various functional groups
are available
lnt ij = -(uij -u jj )
RT
uij - average interaction energy for i- j
u jj - average interaction energy for j - j
(τ12 and τ12) Two adjustable
parameters for each binary
pair
Determined by regression
of experimental data
Estimation of interaction energies
through computational chemistry
Sum and Sandler studied the phase behavior for many binary systems
(methanol+water, ethanol+water, acetic acid + water)
Average interaction energies were estimated using ab intio quantum
mechanics and used in activity coefficient models (UNIQUAC and
Wilson)
20
Figure 1: Phase diagram for methanol and water at T = 323.15 oK[43]
Computational Chemistry - Overview
Computational chemistry
Molecular Mechanics
Electronic Structure Methods
Semi-Empirical
Ab initio
Density Functional
Theory
21
Basic types of calculations involve[1] –
Computing energy of a particular molecular structure or a group of
molecules
Optimizing the structure of a molecular cluster or a single molecule
(Geometric optimization)
Estimating the vibrational frequencies of molecules resulting from
interatomic motion within the molecule
Electronic Structure Methods
Time independent Schrodinger equation
Solutions to the equation corresponds to different stationary
states (Ψ) of the system
Models are classified based on the various mathematical
approximations applied to the Schrodinger's equation
Theoretical Models/Level of Theory : HF, MP2, B3LYP
Basis set - Mathematical description of molecular orbitals within
a system (3-21G, 6-31G(d), 6-31+G(d,p) 6-311G(d))
Gaussian 09 software
22
HY =EY
Y -Wavefunction Function of the positions of the electrons and
the nuclei within the molecule
Computational Procedure
Step 1 – Construction of a molecular cluster that
represents the desired system
Compromise between computational cost and a reasonable
representation of the fluid
Calculated interaction energies should be independent of the
starting geometry
Step 2 – Geometric optimization of the cluster
Selection of a theoretical method and a basis set:
Step 3 – Selection of directly interacting molecular pairs
(like and unlike) from this optimized cluster
Decision is based on the separation distances and relative
orientations of the various molecules in the cluster
23
Step 4 – Compute the energy of each molecular pair
Interaction energy is given by the following formula:
Step 5 – Linearly average the the energies of the molecular
pairs to obtain the interaction parameters in the activity
coefficient models
Procedure will be repeated for multiple initial geometries to
get consistent results
Computational Procedure
E1-2
int = E1-2 -E1 -E2
24
Preliminary Results
RN..H
10 molecule cluster
Hartree Fock (HF),
6-31G(d)
25
DMP-DMP Water-Water DMP-Water
Dimer clusters
Future Work
Using activity coefficient models to construct the phase
diagram (UNIQUAC, Wilson)
Selection of appropriate theoretical model and basis set
Study the effect of temperature and catalyst on the N-oxide-
DMP-Water phase behavior
Preliminary study on N-oxide-Water-Catalyst mixtures
suggested that N-oxide could dissolve the catalyst
Implementation of the ISD concept – Hybridization:
Reduction in peroxide decomposition due to addition of
product N-oxide to the initial reactant mixture
26
References
27
[1] Foresman, J. B., et al. (1996). Exploring chemistry with electronic structure methods, Gaussian, Inc.
[2]A. I. o. C. E. C. f. C. P. Safety, Guidelines for safe storage and handling of reactive materials: American Institute of Chemical Engineers,
1995.
[3]U. S. C. S. a. H. I. Board, "FIRE AND EXPLOSION: HAZARDS OF BENZOYL PEROXIDE," ed, 2003.
[4]C. W. Jones, Applications of Hydrogen Peroxide and Derivatives: Royal Society of Chemistry, 1999.
[5]J. M. Campos-Martin, G. Blanco-Brieva, and J. L. G. Fierro, "Hydrogen Peroxide Synthesis: An Outlook beyond the Anthraquinone
Process," Angewandte Chemie International Edition, vol. 45, pp. 6962-6984, 2006.
[6]A. L. Pineda Solano, "Design of Inherently Safer Complex Reactive Processes: Application on the N-Oxidation of Alkylpyridines," 2014.
[7]W. Conner, "Hydrogen peroxide safety issues," EG and G Rocky Flats, Inc., Golden, CO (United States). Rocky Flats Plant. Funding
organisation: USDOE, Washington, DC (United States)1993.
[8]M. Kumasaki, "An explosion of a tank car carrying waste hydrogen peroxide," Journal of loss prevention in the process industries, vol. 19,
pp. 307-311, 2006.
[9]B. Greene, D. L. Baker, and W. Frazier, "Hydrogen peroxide accidents and incidents: What we can learn from history," 2005.
[10]E. F. V. Scriven and R. Murugan, "Pyridine and Pyridine Derivatives," in Kirk-Othmer Encyclopedia of Chemical Technology, ed: John
Wiley & Sons, Inc., 2000.
[11]S. Shimizu, N. Watanabe, T. Kataoka, T. Shoji, N. Abe, S. Morishita, et al., "Pyridine and pyridine derivatives," Ullmann's Encyclopedia
of Industrial Chemistry, 1993.
[12]I. Kozhevnikov, A. Sinnema, and H. Van Bekkum, "Proton sites in Keggin heteropoly acids from17O NMR," Catalysis letters, vol. 34,
pp. 213-221, 1995.
[13]I. Kozhevnikov, "Advances in catalysis by heteropolyacids," Russian Chemical Reviews, vol. 56, p. 811, 1987.
[14]I. Kozhevnikov, "Sustainable heterogeneous acid catalysis by heteropoly acids," Journal of Molecular Catalysis A: Chemical, vol. 262,
pp. 86-92, 2007.
[15]M. Misono, I. Ono, G. Koyano, and A. Aoshima, "Heteropolyacids. Versatile green catalysts usable in a variety of reaction media," Pure
and applied chemistry, vol. 72, pp. 1305-1311, 2000.
[16]A. Palomo-Coll, "A process for the preparation of omeprazol, ES 2026761 (A6)," European Patent Office, 1992.
[17]J. Sempere, R. Nomen, J. Rodriguez, and M. Papadaki, "Modelling of the reaction of N-oxidation of 2-methylpyridine using hydrogen
peroxide and a complex metal catalyst," Chemical Engineering and Processing: Process Intensification, vol. 37, pp. 33-46, 1998.
References
28
[18]M. Papadaki and J. Gao, "Kinetic models of complex reaction systems," Computers & chemical engineering, vol. 29, pp. 2449-2460,
2005.
[19]J. Gao and M. Papadaki, "Global kinetic model: A case study on the N-oxidation of alkylpyridines," Journal of hazardous materials,
vol. 130, pp. 141-147, 2006.
[20]M. Papadaki, V. Stoikou, D. Mantzavinos, and J. R. Miranda, "Towards improved reaction runaway studies: kinetics of the N-
oxidation of 2-methylpyridine using heat-flow calorimetry," Process Safety and Environmental Protection, vol. 80, pp. 186-196, 2002.
[21]L. R. Saenz-Noval, "Evaluation of alternatives for safer and more efficient reactions: a study of the N-oxidation of alkylpyridines,"
Chemical Engineering Department, Texas A&M University, College Station, TX, 2011.
[22]R. Andon and J. Cox, "896. Phase relationships in the pyridine series. Part I. The miscibility of some pyridine homologues with
water," J. chem. Soc., pp. 4601-4606, 1952.
[23]V. Bassiloua, L. Ghaicha, M. Privat, R. Bennes, and E. Tronel-Peyroz, "Activities and thermodynamic excess properties of aqueous
2, 5-dimethylpyridine mixtures near the critical demixing point: Comparison with 2, 6-dimethylpyridine-water mixtures," Journal of
solution chemistry, vol. 24, pp. 935-952, 1995.
[24]R. M. Stephenson, "Mutual solubility of water and pyridine derivatives," Journal of Chemical and Engineering Data, vol. 38, pp.
428-431, 1993.
[25]J. Cox and E. Herington, "The coexistence curve in liquid-liquid binary systems," Trans. Faraday Soc., vol. 52, pp. 926-930, 1956.
[26]A. Pineda-Solano, L. R. Saenz, V. Carreto, M. Papadaki, and M. S. Mannan, "Toward an inherently safer design and operation of
batch and semi-batch processes: The N-oxidation of alkylpyridines," Journal of Loss Prevention in the Process Industries, vol. 25, pp.
797-802, 9// 2012.
[27]Mettler-Toledo, "RC1e High Performance Thermostat. Operating Instructions," 2012.
[28]J. Coates, "Interpretation of infrared spectra, a practical approach," Encyclopedia of analytical chemistry, 2000.
[29]F. Lewiner, G. Févotte, J. P. Klein, and F. Puel, "Improving batch cooling seeded crystallization of an organic weed-killer using on-
line ATR FTIR measurement of supersaturation," Journal of Crystal Growth, vol. 226, pp. 348-362, 6// 2001.
[30]F. Lewiner, J. P. Klein, F. Puel, and G. Févotte, "On-line ATR FTIR measurement of supersaturation during solution crystallization
processes. Calibration and applications on three solute/solvent systems," Chemical Engineering Science, vol. 56, pp. 2069-2084, 3//
2001.
[31]F. R. van de Voort, A. A. Ismail, J. Sedman, J. Dubois, and T. Nicodemo, "The determination of peroxide value by fourier transform
infrared spectroscopy," Journal of the American Oil Chemists’ Society, vol. 71, pp. 921-926, 1994/09/01 1994.
29
References
[32]N. B. Colthup, L. H. Daly, and S. E. Wiberley, Introduction to infrared and Raman spectroscopy: Academic Press, 1975.
[33]F. ULBERTH and H. J. HAIDER, "Determination of low level trans unsaturation in fats by Fourier transform infrared spectroscopy,"
Journal of food science, vol. 57, pp. 1444-1447, 1992.
[34]M. Fujiwara, P. S. Chow, D. L. Ma, and R. D. Braatz, "Paracetamol Crystallization Using Laser Backscattering and ATR-FTIR
Spectroscopy: Metastability, Agglomeration, and Control," Crystal Growth & Design, vol. 2, pp. 363-370, 2002/09/01 2002.
[35]J. S. Oliveira, R. Montalvão, L. Daher, P. A. Suarez, and J. C. Rubim, "Determination of methyl ester contents in biodiesel blends by
FTIR-ATR and FTNIR spectroscopies," Talanta, vol. 69, pp. 1278-1284, 2006.
[36]P. C. Painter, M. M. Coleman, R. G. Jenkins, P. W. Whang, and P. L. Walker, "Fourier transform infrared study of mineral matter in coal.
A novel method for quantitative mineralogical analysis," Fuel, vol. 57, pp. 337-344, 1978.
[37]A. Al‐Alawi, F. R. van de Voort, and J. Sedman, "A new FTIR method for the analysis of low levels of FFA in refined edible oils,"
Spectroscopy letters, vol. 38, pp. 389-403, 2005.
[38]G. E. Swann and S. Patwardhan, "Application of Fourier Transform Infrared Spectroscopy (FTIR) for assessing biogenic silica sample
purity in geochemical analyses and palaeoenvironmental research," Climate of the Past, vol. 7, pp. 65-74, 2011.
[39] S. I. Sandler, Chemical, biochemical, and engineering thermodynamics vol. 4: John Wiley & Sons Hoboken, NJ, 2006.
[40]Mettler-Toledo, "Hardware Manual: ReactIR15 - Improve Chemistry Understanding," 2012.
[41]Y.-X. Yu, G.-H. Gao, J.-L. Daridon, and B. Lagourette, "Prediction of solid–liquid equilibria in mixed electrolyte aqueous solution by the
modified mean spherical approximation," Fluid Phase Equilibria, vol. 206, pp. 205-214, 4/30/ 2003.
[42]U. o. C. Davis. Instrument Calibration. Available:
http://chemwiki.ucdavis.edu/Analytical_Chemistry/Data_Analysis/Instrument_Calibration_over_a_regime
[43] Sum, A. K. and S. I. Sandler (1999). "A Novel Approach to Phase Equilibria Predictions Using Ab Initio Methods." Industrial &
Engineering Chemistry Research 38(7): 2849-2855
[44]D. D. Dunuwila and K. A. Berglund, "ATR FTIR spectroscopy for in situ measurement of supersaturation," Journal of Crystal Growth,
vol. 179, pp. 185-193, 8/1/ 1997.
[45]A. Rohman, Y. B. C. Man, A. Ismail, and P. Hashim, "Application of FTIR spectroscopy for the determination of virgin coconut oil in
binary mixtures with olive oil and palm oil," Journal of the American Oil Chemists' Society, vol. 87, pp. 601-606, 2010.
[46]Y. C. Man, M. Moh, and F. Van de Voort, "Determination of free fatty acids in crude palm oil and refined-bleached-deodorized palm
olein using Fourier transform infrared spectroscopy," Journal of the American Oil Chemists' Society, vol. 76, pp. 485-490, 1999.
[47]J. R. Chen, "An inherently safer process of cyclohexane oxidation using pure oxygen—an example of how better process safety leads to
better productivity," Process safety progress, vol. 23, pp. 72-81, 2004.
Acknowledgements
Dr. M. Sam Mannan
Committee members
Dr. James Holste
Dr. Benjamin Wilhite
Dr. Debjyoti Banerjee
Dr. Kenneth Hall
Dr. Lisa Perez
Dr. Samina Rahmani
Dr. Maria Papadaki
Dr. Simon Waldram
Dr. Alba Pineda
Members of the Steering Committee
Members of the MKOPSC
30
31
Thank You
Questions and Comments