Telescoped flow process for the syntheses of N-aryl pyrazoles

Article abstract of DOI:10.1021/op300209p

N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl₂ to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N-aryl pyrazole.

Full text of DOI:10.1021/op300209p

Article
pubs.acs.org/OPRD
Telescoped Flow Process for the Syntheses of N‑Aryl Pyrazoles
Bryan Li,* Daniel Widlicka, Steven Boucher, Cheryl Hayward, John Lucas,† John C. Murray,
Brian T. O’Neil, David Pfisterer, Lacey Samp, John VanAlsten,‡ Yanqiao Xiang, and Joseph Young
Worldwide Research & Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to
give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn
reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl2 to
give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and
potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The
heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was
employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the
purification of the final N-aryl pyrazole.
their surrogates (Scheme 1). The commercial availability of
ketoenamines, RC(O)CHCHNMe2 (R = H, Me, Ph, OEt)
INTRODUCTION
■
The pyrazole moiety has been shown as a key pharmacophore
in many pharmaceutically active agents. Naturally occurring
Pyrazofurin (1), a C-nucleoside isolated from Streptomyces
candidus in 1969, possessed broad-spectrum antiviral activity.1
Multiple blockbuster drugs celecoxib (2, Celebrex), rimonabant
(3, Acomplia), sildenafil (4, Viagra) (Figure 1), and the
recently approved lung cancer drug crizotinib (5, Xalkori)
feature a pyrazole substructure.
Scheme 1. Knorr Cyclocondensation
A number of synthetic methods have been developed for the
formation of pyrazoles.2,3 Among them, the Knorr4 cyclo-
condensation offers direct entry to the pyrazole via cyclo-
condensation of hydrazines with 1,3-dicarbonyl compounds or
and the accessibility of hydrazines make the Knorr reaction one
of the most attractive methods for the preparation of pyrazoles.
Importantly, when the nitrogen groups of hydrazines are
electronically or sterically biased, reasonable regioselectivity can
be achieved in the pyrazole formation.5
We adopted such an approach in the synthesis of N-aryl
pyrazole 6, a key intermediate for an ongoing research program
(Scheme 2). The synthesis started with diazotization of 2-
amino-4-bromophenol (7), followed by reduction of the
diazonium salt 8 to give the hydrazine 9. The isolation of 9
was complicated by the presence of tin oxides in the reaction
mixture. After cumbersome extractive workup, crude 9 was
isolated and purified by forming the tosylate salt (10).
Subsequently, 10 was reacted with ketoenamine 11 to give
the aryl pyrazole 6. The regioisomer 12 (8−10% by HPLC)
was formed as a byproduct and was removed by silica gel
chromatography. While the synthesis was relatively straightfor-
ward on small scale, the involvement of energetic intermediates
(diazonium 8 and hydrazine 9) with low differential scanning
calorimetry (DSC) onset temperatures6 presented potential
safety hazards for scale-up. Thus, we turned our attention to
developing a continuous flow process to address the safety
concerns in scale-up. Continuous flow technology offers many
Special Issue: Safety of Chemical Processes 12
Received: July 31, 2012
Published: August 23, 2012
Figure 1. Compounds with a pyrazole moiety.
© 2012 American Chemical Society
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Scheme 2. Original Synthesis of N-Aryl Pyrazole 6
Scheme 3. New Synthesis of N-Aryl Pyrazole 6
a
(a) NaNO2, aq HCl, 0 °C. (b) SnCl2, EtOH, AcOH, 0 °C to RT;
then extractive workup. (c) TsOH·H2O. (d) AcOH, RT.
a
(a) t-BuONO, BF3·THF in 2-MeTHF; RT. (b) SnCl2, 2-MeTHF/
water, 0 °C. (c) 0−20 °C. (d) PhBCl2, toluene, 95 °C, 3 h;
recrystallization in iPrOH/water.
advantages over batch methods, including precise control of
stoichiometry, reaction time, and temperature; high reprodu-
cibility; and often better reaction yields.7 The much higher
surface area to volume ratio under flow conditions renders
highly efficient heat transfer. When coupled with the much
smaller volume in the reaction train, safety hazards in handling
exothermic reactions associated with explosive intermediates
are minimized.8
reaction rates for the diazonium reduction and the cyclo-
condensation steps occurred within minutes, neither energetic
intermediates 14 and 15 would be accumulated in a telescoped
process.
2. First Generation Flow Design. Since the diazonium
intermediate 14 was observed to react further with the aniline
starting material to give azo coupling byproduct, we wanted to
avoid back mixing in a flow reactor. Thus, a plug flow design
was selected (Figure 2) instead of a continuous stirred tank
RESULTS AND DISCUSSION
■
1. Adapting the Batch Chemistry to Continuous Flow.
As an industrial process of vast importance, the diazotization of
aromatic amines has been well studied.9 A continuous
diazotization of anilines was reported in 1965 from the dye
industry.10 More recently, there have been several reports on
generating diazonium salts as reactive intermediates using flow
technology.11 In the design of a continuous flow process for the
synthesis of 6, our objectives were to avoid the accumulation
and isolation of both energetic intermediates 8 and 9. We
envisioned that appropriate reaction conditions in a telescoped
process would satisfy these objectives. Thus, we set to enable
reaction conditions for each transformation and explore
telescoping opportunities. As expected, the diazotization of
aniline 7 worked well under either aqueous (NaNO2, aqueous
HCl) or nonaqueous (t-BuONO, BF3·THF)12 conditions.
Though it was highly desirable to eliminate SnCl2 from the
synthesis, our efforts to find alternative reducing agents to
replace SnCl2 were fruitless.13 When crude diazonium 8 was
carried to the SnCl2 reduction, it failed to convert cleanly due
to the presence of a number of impurities generated from the
diazotization. This profile led to low overall yields when the
hydrazine reaction mixture was subjected to the pyrazole
formation. The use of SnCl2 also complicated the workup and
isolation, as a large amount of tin oxide byproduct gave a milky
mixture. Tin oxides are only soluble in either highly acidic or
basic aqueous media that were not suitable for the isolation of
zwitterionic 9 or 6. With that in mind, we turned to the methyl
ether protected aniline 13 (less expensive than 7) as the
starting material. It offered a cleaner reduction step and resulted
in a much more convenient isolation of hydrazine 15 or
pyrazole 16, as high pH conditions that solubilized tin oxides
could be applied during the workup (Scheme 3).
Figure 2. First generation flow setup for a three-step telescoped
reaction to form pyrazole 16.
reactor (CSTR). Aniline 13 was combined with BF3·THF in
THF as one feed stream. The resulting solution was evaluated
for its stability, and it revealed no concerns for prolonged
storage (24 h). tert-Butyl nitrite in THF was introduced as a
separate stream. The two streams were pumped into a T-mixer
followed by a PTFE coil to achieve a 10 min residence time for
the diazotization reaction. The coil was submerged in a
sonication14 bath to allow the diazonium salt formed in the coil
to move smoothly out of the PTFE coil without clogging.
Crystallization of diazonium fluoroborate salt (14) in the
reaction mixture resulted in a systemic pressure of 30−45 psi. It
was noted that 14, as a light and fluffy solid, was well suspended
in THF. The effluent was directly added to a receiving flask
containing SnCl2 and ketoenamine 11 in ethanol. This design
worked successfully for up to at least 100 g scale. After an
extractive workup, pyrazole 16 was isolated by chromatography
15
and underwent methyl ether deprotection using PhBCl2 to
give the desired product 6 in 35−40% overall yield.
To streamline the process, we next examined if ketoenamine
11 was stable in SnCl2 (1 equiv)/EtOH, and we were pleased
to observe no appreciable degradation at 20 °C. Since the
3. Second Generation Flow Design. While the first
generation flow design allowed the successful scale up to meet
the initial demands, isolation of the final product still required
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silica gel chromatography. As the program progressed, larger
quantities of 6 were demanded, and it became evident a more
robust synthesis was needed. Since most impurities16 from the
three-step sequence were generated in the diazotization step,
and an excess of tert-butyl nitrite was found to give rise to high
levels of impurities in the reduction, we envisioned an
opportunity to introduce a continuous extraction to allow the
separation of the water-soluble diazonium salt 13 from the
organic-soluble impurities. This idea was demonstrated by
isolating a small amount of purified 13 and carrying it forward
to 16 with high purity and good yield, leading to the second
generation flow design (Figure 3). The flow setup used two
Figure 4. Continuous extraction in the second generation flow design.
tert-butyl nitrite feed stream solutions, a back pressure of ∼30
psi was observed due to the diazonium solids present in the
PTFE tubing. A picture of the 400 mL reaction coil used in the
production run is shown in Figure 5. After approximately 3 min
Figure 3. Second generation flow setup for a three-step telescoped
reaction to form pyrazole 14..
Fluid Metering Inc. (FMI) pumps (with the mechanism of
valveless rotating and reciprocating piston metering) to
introduce the feed streams. A stainless steel T-union was
used as a mixer, which was joined by PTFE tubing to provide
the required residence time. Considering the upper pressure
limit of the pumps recommended by the manufacture is 100
psi, we used an automatic pressure shut-down device and set
the trigger point at 100 psi. The effluent (out of the PTFE
tubing) from the diazotization reaction was mixed with a water
stream using a two staged continuous stirred tank reactor
(CSTR); the resulting biphasic mixture then entered a glass
standpipe decanter (Figure 4) for phase separation. The
organic layer was continuously removed as a waste stream,
while the aqueous phase was directed into a reaction vessel
containing SnCl2.
Some modifications of the chemistry were required to enable
this new design. In order to facilitate the continuous extraction,
the diazotization solvent was changed to 2-MeTHF to
accelerate separation from the aqueous layer. We also realized
that the residence time could be reduced from 10 to 8 min.
Second, the SnCl2 pot receiver was held at 0−5 °C during the
reduction to provide a better purity profile, and ethanol was
eliminated for more streamlined workup and isolation. Third,
with water introduced to the system, the aqueous hydrazine
intermediate presented a low hazard in thermal stability testing
and it was deemed safe to accumulate hydrazine 15 in a solvent
mixture of water/2-MeTHF. Ketoenamine 11 was added after
the flow run was complete and then warmed to 20 °C for a
cleaner reaction. Using this protocol, we executed two runs
(800−1000 g) and obtained 51−55% overall yield of 6. With
flow rates of 25 mL/min for both the BF3−aniline adduct and
Figure 5. Diazonium fluoroborate salt crystallization in the reaction
coil (1/8′′ i.d., PTFE, 400 mL).
of residence time, diazonium salt started to crystallize from the
reaction mixture. The solids were light and fluffy and moved
through the coil smoothly. Liquid segments were noted as the
solid segregated in mother liquor from the crystallization. The
FMI pumps were able to handle the slurry formed in the 400
mL PTFE tubing (1/8′′ i.d., 1/4′′ o.d., rated to handle 320 psi of
pressure @ 23 °C) in a continuous ∼8 h operation. It is
plausible that the pulsating effect generated from the FMI
pumps might have helped in moving the slurry. A process
hazard analysis (PHA) was conducted, and the following was
recommended and followed: (1) All tubing and fittings used
should be rated for much higher pressure at the operating
temperature. The whole system was tested to ensure it could
withstand up to 250 psi pressure with no leaks detected. (2)
Each run should be closely monitored despite the implementa-
tion of an automatic shut down device at 100 psi. (3) In the
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event of pressure buildup due to solid agglomeration, the coil
containing the diazonium intermediate was to be flushed with
water immediately and kept from exposure to air. Fortunately
we did not run into a need to use the contingency plan in the
kilogram scale flow run.
as mobile phase (1.2 mL/min) and detection at 210 nm
wavelength.
1-(5-Bromo-2-methoxyphenyl)-5-methyl-1H-pyrazole
(16). Boron trifluoride−tetrahydrofuran complex (972 g, 6.95
mol) was added over 20 min to a solution of 5-bromo-2-
methoxyaniline (1.00 kg, 4.95 mol) in 2-methyltetrahydrofuran
(6 L), and the mixture was filtered through Celite. The filtrate
was brought to a volume of 10 L with additional 2-
methyltetrahydrofuran. In a separate container, tert-butyl nitrite
(546 g, 5.29 mol) was dissolved in 2-methyltetrahydrofuran
(9.0 L); the volume was then adjusted to 10 L by addition of 2-
methyltetrahydrofuran. To effect diazotization (CAUTION:
solid diazonium salts will form in the tubing; conduct this work
only in a properly designed flow setup with the approval of
process safety engineers), the two solutions were pumped by
two Ismatec pumps (model C.P. 78020-50) equipped with FMI
heads at 25 mL/min flow rate per stream into a T-mixer (1/8′′
OD T-union) connected to a 400 mL PTFE coil (1/8′′ ID; 1/4′′
OD). At a combined flow rate of 50 mL/min, the reaction
mixture had a total residence time of 8 min in the coil. The
pumps were started simultaneously, and the effluent exiting the
reaction coil was sent to a two-stage continuous stirred-tank
reactor (CSTR), where diazonium fluoroborate (12) was mixed
with water (introduced continuously at a flow rate of 37 mL/
min). The aqueous layer was continuously separated in a stand
pipe decanter and sent to a jacketed 75 L reactor containing a
mixture of tin(II) chloride dihydrate (2.82 kg, 14.9 mol), 2-
methyltetrahydrofuran (10 L), and water (5 L) at 0 °C. After 2
h, the reduction was deemed complete, as determined by
HPLC analysis. (3E)-4-(Dimethylamino)but-3-en-2-one (562
g, 4.97 mol) was charged, and the jacket temperature was
adjusted to 20 °C. After 12 h, the layers were separated and the
organic layer was washed with 1 N aqueous NaOH solution (3
× 20 L). The organic layer was concentrated (35 °C, 100
mbar) in a 20 L rotovap bulb containing silica gel (1.5 kg) until
a free-flowing powder was obtained. The material was loaded
onto a pad of silica gel (2.0 kg), and elution was carried out
with 2-methyltetrahydrofuran (12 L). The eluent was
concentrated in vacuo (45 °C, 60 mmHg) and was displaced
with toluene and then was concentrated to give the crude
product as a dark red oil (1.202 kg), as a mixture of the title
product (16) and the regioisomeric pyrazole in a roughly 9:1
It is noteworthy that the continuous separation worked
extremely well for this chemistry. The standpipe decanter vessel
(100 mL) could accommodate flow rates of 120 mL/min per
stream with facile layer separation. The emulsion zone between
1
the phases was less than /2′′ during the course of both flow
runs (Figure 4).
With crude 16 in hand, we sought an efficient workup and
isolation method. Upon complete conversion of the hydrazine
15 to the pyrazole 16, the aqueous phase was removed, and the
organic phase was washed with 6 N aqueous NaOH. The
mixture was filtered, and the filtrate was concentrated and
treated with silica gel. This method effectively reduced the
residual tin level to less than 10 ppm. The crude product was
then subjected to demethylation using PhBCl2 in toluene.
Finally, a crystallization method was developed to remove the
regioisomer 12 using a mixture of isopropanol and water.
CONCLUSION
■
We have described a flow process allowing the safe handling of
the energetic intermediates. The maximum amount of
diazonium 14 present in the system was 99 mmol (29.6 g,
assuming 100% conversion) for the scale up using 400 mL coil.
For comparison, a batch reaction of 1.0 kg scale would generate
4.9 mol of diazonium salt 14. Under the worst case scenario of
decomposition of all diazonium salt in the reaction system,
approximately 2.2 L of nitrogen (under 1 atm pressure) would
be generated in the continuous production scale. Whereas the
batch reaction would generate 110 L of nitrogen upon
decomposition.
In the diazotization step, while the feed streams were
homogeneous solutions in the flow operation, the product
stream became a slurry after ∼3 min of residence time. The
solid/liquid heterogeneous reaction mixture (5−7 wt % solids)
was successfully handled at kilogram scale production scale
(400 mL PTFE 1/8′′ i.d. coil) without sonication. The
continuous extraction employing a simple stand pipe decanter
effectively removed organic-soluble impurities from the
diazonium salt (14), which also resulted in higher throughput
in the three step telescoped process.
Despite the successful outcome of the flow runs demon-
strated in the preparation of N-aryl pyrozole 6, the robustness
of the process on any scale larger than 1 kg of 13 and longer
duration is yet to be tested. We plan to further investigate the
flow design if the need arises for greater demand of the aryl
pyrazole 6. Additionally, process improvements on the product
isolation and the demethylation step will also be necessary.
1
ratio (as assessed by H NMR). Quantitative-NMR analysis
indicated the crude product contained 56 wt % of 16 (677 g,
2.53 mol, 51% yield). HRMS: m/z (M + H)+ calcd for
C11H15rN2O: 267.0133/269.0133; found: 267.01269/
1
269.01038. H NMR (400 MHz, d6-DMSO): 7.66 (1H, dd, J
= 8.8, 1.8 Hz), 7.55−7.45 (2H, m), 7.21 (1H, d, J = 8.8 Hz), 6.2
(1H, d, J = 0.8 Hz), 3.77 (3H, s), 2.08 (3H, s). 13C NMR (400
MHz, d6-DMSO) 153.49, 140.24, 139.71, 132.79, 131.18,
129.42, 114.67, 111.19, 105.48, 56.02, 10.79.
4-Bromo-2-(5-methyl-1H-pyrazol-1-yl)phenol (6). A 20
L jacketed glass reactor was fitted with a recirculating scrubber
charged with water (0.40 L), methanol (1.20 L), and
ethanolamine (0.40 L). To the 20 L reactor were charged
crude 16 (677 g active, 2.53 mol, 1.2 kg of total mass from
above), and toluene (8.4 L) to afford a dark red solution that
was stirred at 25 °C. Dichlorophenylborane (0.75 kg) was
charged via a dropping funnel over 15 min while maintaining
the temperature below 30 °C. The reaction mixture was heated
to 95 °C for 3 h, then concentrated (60 °C, 60 mmHg) to ∼8
L, and then cooled to 20 °C. The mixture was quenched with 1
N aqueous NaOH solution (13.8 L). After the mixture was
EXPERIMENTAL SECTION
■
PTFE tubing was purchased from Omegaflex (this flexible
tubing offers good transparency for applications that require
1
1
visual inspection; the /4′′ o.d., /8′′ i.d. tubing is designed to
withstand 320 psi of pressure at 23 °C). LCMS was recorded
with an HP-1100MSD using API-ES ionization mode. HPLC
analyses were carried out in HP-1100 using a Water Atlantis T3
column (stable-bond C18) (3 μm, 3 mm ×75 mm) with
acetonitrile:0.1% TFA aqueous buffer (95/5 to 5/95 in 8 min)
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(8) (a) Van Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel,
D. J. Org. Process Res. Dev. 2008, 12, 989. (b) Kulkarni, A. A.; Kalyani,
V. S.; Joshi, R. A.; Josh, R. R. Org. Process Res. Dev. 2009, 13, 999.
(c) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron
2009, 65, 6611. (d) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.;
Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017.
(9) For a review, please see: Zollinger, H. Diazo Chemistry I: Aromatic
and Heteroaromatic Compounds; VCH Verlagsgesellschaft mbH: D-
69451 Weinheim, 1994.
stirred for 30 min, the layers were separated and the toluene
layer was extracted with additional 1 N aqueous NaOH
solution (4.0 L). The aqueous layers were combined and were
charged back to the 20 L reactor. The pH of the aqueous
mixture was adjusted to 9.2 with concentrated HCl (0.65 L),
resulting in a precipitation. The solids were collected by
filtration in a Buchner funnel. The filter cake was charged back
into the 20 L reactor and taken up in 2-propanol (6.72 L). The
mixture was heated to 50 °C and stirred for 1 h and then
cooled to 20 °C. Water (6.72 L) was slowly added over a 1 h
period, and the resulting product slurry was stirred at 20 °C for
2 h. The product was filtered, rinsed with water (4.2 L), and
dried (40 °C, 50 mmHg) for 24 h to give pure 6 (0.488 kg, 1.92
mol, 76% yield) as a white solid. HRMS: m/z (M + H)+ calcd
for C10H10BrN2O: 252.9977/254.9977; found: 252.99726/
(10) Kindler, H.; Schuler, D. Application FR 1964-996369, 1965;
Chem. Abstr. 65, 91168.
(11) (a) Fortt, R.; Wootton, R. C. R.; de Mello, A. J. Org. Process Res.
Dev. 2003, 7, 762. (b) Malet-Sanz, L.; Madrzak, J.; Ley, S. V.;
Baxendale, I. R. Org. Biomol. Chem. 2010, 8 (23), 5324. (c) Martin, L.
J.; Marzinzik, A. L.; Ley, S. V.; Baxendale, I. R. Org. Lett. 2011, 13 (2),
320.
(12) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
(13) Commonly used reducing conditions (Pd catalyzed hydro-
genation, hydrides, H3PO2, Et3SiH) were known to lead to
dediazoniation. Na2SO3 and NaHSO3/aq NH3 gave poor results.
Ascorbic acid was attempted, but it would require the isolation of the
hydrazine intermediate: (a) Norris, T.; Bezze, C.; Franz, S. Z.;
Stivanello, M. Org. Process Res. Dev. 2009, 13, 354. (b) Ashcroft, C. P.;
Hellier, P.; Pettman, A.; Watkinson, S. Org. Process Res. Dev. 2011, 15,
98. (c) Browne, D. L.; Baxendale, I. R.; Ley, S. V. Tetrahedron 2011,
67, 10296.
(14) Process safety of aryl diazonium salts in PTFE tubing under
sonication was not evaluated, as this approach was used for scale up.
(15) Demethylation using BCl3 was not clean, probably due to fact
that the methyl chloride formed was trapped under the reaction
conditions.
(16) A dark brown mixture was noted invariably for the diazotization
step. LCMS indicated the presence of dediazoniation, azo coupling,
triazenes, and other polymeric substances. The continuous extraction
also removed any excess tert-butyl nitrite from the diazotization step.
These impurities along with the excess tert-butyl nitrite were removed
as a waste stream in the continuous separation.
1
254.99463. H NMR (400 MHz, d6-DMSO) 10.39 (1H, s),
7.50 (1H, s), 7.46 (1H, dd, J = 8.8, 2.3 Hz), 7.38 (1H, d, J = 2.3
Hz), 7.01 (1H, d, 8.8 Hz), 6.18 (1H, s), 2.13 (3H, s).13C NMR
(400 MHz, d6-DMSO) 151.88, 140.21, 139.56, 132.43, 131.05,
128.35, 118.55, 109.33, 105.37, 10.92.
ASSOCIATED CONTENT
* Supporting Information
Details of the DSC the results. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: bryan.li@pfizer.com.
■
Present Addresses
†Amgen, 40 Technology Way, West Greenwich, RI 02817.
‡Chemical Development Department, Vertex Pharmaceuticals,
130 Waverly St., Cambridge, MA 02139.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Jim Hallissey, Brian Morgan, and Asaad
Nematalla for Kilo Lab production support. We also thank Drs.
Chris J. Helal, Russell J. Linderman, and Mr. Michael Fichtner
for their valuable input in preparing the manuscript.
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