Design and synthesis of florylpicoxamid, a fungicide derived from renewable raw materials

Article abstract of DOI:10.1039/d0gc02063j

The design and synthesis of the broad-spectrum fungicide, florylpicoxamid, embodies multiple Green Chemistry principles. The active ingredient was strategically designed to deliver maximum biological activity and rapidly degrade after application to minimize its enviromental impact. Unlike many chiral crop protection chemicals, florylpicoxamid was purposely developed as a single stereoisomer to minimize the dose rate of this product in field applications and avoid any potential environmental burdens of its less active stereoisomers. Fortunately, the most efficacious stereoisomer of the natural product-inspired active ingredient can be derived from the natural antipodes of lactic acid and alanine. The principles of Green Chemistry were also used to improve the synthetic route originally developed for structure-activity relationship studies, resulting in a convergent stereoselective synthesis that is more sustainable and cost-effective. The streamlined 2^ndgeneration route decreases the use of protecting groups and utilizes safer reaction solvents. Development of a novel synthetic sequence to the 2,3,4-trisubstituted pyridine motif from furfural further increased the renewable carbon content of the active ingredient to nearly 50%. Throughout process development, improved reaction conditions and industrially-preferred alternatives were identified to replace hazardous reagents for key transformations. In all, the holistic use of Green Chemistry principles in the design and synthesis of florylpicoxamid will provide farmers with a highly sustainable product for crop disease management.

Full text of DOI:10.1039/d0gc02063j

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Design and synthesis of florylpicoxamid, a
fungicide derived from renewable raw materials†
Cite this: DOI: 10.1039/d0gc02063j
Nicholas R. Babij, *a Nakyen Choy,a Megan A. Cismesia, a David J. Couling,a
Nicole M. Hough,a Peter L. Johnson, a Jerzy Klosin,b Xiaoyong Li,a Yu Lu,a
Elizabeth O. McCusker,a Kevin G. Meyer,a James M. Renga,a Richard B. Rogers,a
Kenneth E. Stockman,a Nicola J. Webb,a Gregory T. Whiteker *a and
Yuanming Zhua
The design and synthesis of the broad-spectrum fungicide, florylpicoxamid, embodies multiple Green
Chemistry principles. The active ingredient was strategically designed to deliver maximum biological
activity and rapidly degrade after application to minimize its enviromental impact. Unlike many chiral crop
protection chemicals, florylpicoxamid was purposely developed as a single stereoisomer to minimize the
dose rate of this product in field applications and avoid any potential environmental burdens of its less
active stereoisomers. Fortunately, the most efficacious stereoisomer of the natural product-inspired active
ingredient can be derived from the natural antipodes of lactic acid and alanine. The principles of Green
Chemistry were also used to improve the synthetic route originally developed for structure–activity
relationship studies, resulting in a convergent stereoselective synthesis that is more sustainable and cost-
effective. The streamlined 2nd generation route decreases the use of protecting groups and utilizes safer
reaction solvents. Development of a novel synthetic sequence to the 2,3,4-trisubstituted pyridine motif
from furfural further increased the renewable carbon content of the active ingredient to nearly 50%.
Throughout process development, improved reaction conditions and industrially-preferred alternatives
were identified to replace hazardous reagents for key transformations. In all, the holistic use of Green
Chemistry principles in the design and synthesis of florylpicoxamid will provide farmers with a highly sus-
tainable product for crop disease management.
Received 17th June 2020,
Accepted 21st August 2020
DOI: 10.1039/d0gc02063j
rsc.li/greenchem
egories: (1) the principles that address the manufacturing foot-
print for commercial production of a chemical substance and,
Introduction
A primary goal of modern agriculture is to address the food (2) the principles focused on the environmental impact of that
security needs of a growing global population while decreasing chemical in its intended use.4 For many chemical products,
the impact of food production on our planet’s climate and such as simple commodity chemical building blocks, the
limited natural resources.1,2 Crop protection products are one environmental and safety aspects of the manufacturing
of the tools that help farmers achieve this aspiration by mini- process are the most significant because these substances are
mizing yield loss caused by weeds, insect damage and plant intermediates and not final products.5 However, both sets of
diseases. The sustainability benefits of crop protection techno- principles are highly applicable to agrochemicals because
logies can be maximized by holistically applying the 12 prin- these products are annually produced on thousands of metric
ciples of Green Chemistry during the strategic design and ton scale and then sprayed directly onto crops that enter the
development of new active ingredients.3 The Green Chemistry world’s food supply.6 Due to their widespread global usage,
principles developed by Anastas and Warner fall into two cat- the safety, environmental fate, persistence and toxicity of crop
protection products are much more important than for other
types of chemical products, and regulatory agencies around
aCorteva Agriscience, 9330 Zionsville Road, Indianapolis, IN, 46268, USA.
E-mail: nicholas.babij@corteva.com, greg.whiteker@corteva.com
bDow Chemical Company, 1776 Building, Midland, MI, 48674, USA
†Electronic supplementary information (ESI) available: For detailed experi-
mental procedures, spectral data, & crystallographic data. CCDC 2005098 and
2005099. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0gc02063j
the world set testing requirements to ensure high standards of
product safety.7 As such, the molecular design of agrochemical
active ingredients drives the sustainability profile of these pro-
ducts. Additionally, given the scale of agrochemical pro-
duction, the principles that promote green and safer pro-
duction processes are extremely important and significantly
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impact the environmental footprint of crop protection product
manufacture.
Unlike fenpicoxamid (1a), which is produced by semi-syn-
thesis, florylpicoxamid (2a) is prepared entirely by chemical
Two new picolinamide fungicide active ingredients that synthesis. Described herein is the development of a sustain-
exemplify green design are fenpicoxamid 1a and florylpicoxa- able synthetic route to florylpicoxamid from renewable raw
mid 2a, which have recently been reported by Corteva materials.
Agriscience (Fig. 1).8 Fenpicoxamid is commercially prepared
by alkylation of the natural product UK-2A (1b), which is
obtained from the fermentation broth of Streptomyces sp. 517-
02.9 Fenpicoxamid exhibits exceptional efficacy against
Results and discussion
Zymoseptoria tritici at lower dose rates than commercial fungi- 1st Generation route to florylpicoxamid
cides.10 Fenpicoxamid is a pro-fungicide that is rapidly metab-
To facilitate structure–activity relationship studies, a conver-
olized back to UK-2A, which is the actual species responsible
for anti-fungal activity.11 UK-2A subsequently degrades to mul-
gent route was strategically developed that enabled the coup-
ling of various picolinic acid derivatives and chiral amines, fol-
lowed by installation of various pro-fungicide motifs. In the
stereoselective synthesis of 2a specifically, a benzotriazole-1-yl-
1
tiple species on leaf surfaces (t < 24 h). The pro-fungicide
2
strategy employed in the design of fenpicoxamid enables
effective delivery of the active ingredient and rapid, sub-
sequent degradation in the environment.
oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate
(PyBOP)-mediated amide coupling of picolinic acid derivative,
3, and chiral amine hydrochloride salt, 4, was followed by
acetylation with acetyl chloride in pyridine (Scheme 1).
Florylpicoxamid (2a) was identified by understanding the
key structural elements of 1a which were critical for antifungal
activity. Methodical synthetic deconstruction of the macro-
cyclic bislactone led to the discovery of less-complex acyclic
structures that maintained high efficacy against key plant
pathogens.12 Both 1a and 2a share the same novel biological
target site13 and show activity against fungal isolates which are
resistant to other classes of fungicides.11 To deliver commer-
cial level efficacy, a similar pro-fungicide strategy was devel-
oped for florylpicoxamid. The 3-hydroxypyridine moiety of 2a
is protected as an acetate ester, which undergoes eventual
metabolic hydrolysis to generate 2b.
Although regulations do not currently require chiral crop
products to be produced as single stereoisomers, the relative
and absolute stereochemistry of 2a was a second design
element that was evaluated during the discovery phase with
the goal of maximizing activity and developing a more sustain-
able product.14 The S,S-enantiomer of 2a was the only stereoi-
somer that showed any efficacy against Zymoseptoria tritici in
greenhouse testing.15 As such, we decided to develop florylpi-
coxamid commercially as a single stereoisomer to reduce the
dose rate of the active ingredient in field applications and
avoid potential concerns due to differential metabolism of the
inactive stereoisomers.16 Fortuitously, the biologically active
stereoisomer 2a corresponds to the stereochemistry of chiral
pool inputs, S-lactate and L-alanine, although, this is perhaps
unsurprising given the active ingredient’s natural product
inspiration (1b).
Despite its relatively simple structure, intermediate
3
proved to be surprisingly challenging to prepare on large scale.
In their total synthesis of UK-2A, Shimano et al. prepared 3 via
a series of lithiation steps with tert-butyllithium (t-BuLi) at
−78 °C (Scheme 2).17 Lithiation of the methoxymethyl (MOM)
ether derivative (5) of 3-hydroxypyridine with t-BuLi followed
by bromination with 1,2-dibromoethane introduced a bromine
substituent at the 4-position to give intermediate 6. The SNAr
reaction of 6 with sodium methoxide gave 7. A second ortho-
lithiation reaction, followed by carboxylation of the organo-
lithium intermediate gave 3.
To avoid the safety hazards associated with use of pyropho-
ric t-BuLi and corresponding cryogenic conditions, we devel-
oped an alternate synthesis of 3 from commercially available
3-hydroxypicolinic acid (Scheme 3). Although this synthesis
was scalable to >100-gram preparations, introduction of the
4-methoxy substituent required multiple functional group
manipulations, including protection of the carboxylic acid and
3-hydroxy substituent.18 Following conversion of the acid to
the methyl ester, bromination with Br2 gave dibromide 8.
Protection of 8 with benzyl chloride afforded 9,19 which under-
went methoxylation and hydrolysis in a single-pot to afford 10
as a single regioisomer upon treatment with potassium car-
bonate in methanol. Intermediate 10 was subjected to catalytic
reduction (H2, Pd/C) to remove the 6-bromo substituent and
concomitantly cleave the benzyl ether to afford 3.
Fig. 1 Structures of fenpicoxamid and florylpicoxamid.
Scheme 1 1st generation synthesis of 2a.
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ingredient were prepared from renewable and inexpensive
chiral pool inputs (L-alanine and (S)-ethyl lactate). However,
the 1st generation synthesis of 2a was somewhat lengthy, uti-
lized multiple protecting groups (O-benzyl and N-Boc), and
employed some relatively undesirable reaction conditions for
manufacturing, such as sodium hydride (NaH) in dimethyl for-
mamide (DMF).21 As such, we designed a 2nd generation syn-
thesis to minimize these issues and achieve a more sustain-
able and economical process. The culmination of these efforts
Scheme 2 Synthesis of 3 from 3-hydroxypyridine reported by Shimano
et al.
resulted in
a
convergent twelve-step synthesis of
florylpicoxamid.
2nd Generation route to florylpicoxamid
Similar to the 1st generation route, retrosynthetic analysis
resulted in the identification of the same key bond-forming
steps (amidation and esterification) and strategic intermedi-
ates (picolinic acid 3, L-alanine and chiral alcohol 15) as
shown in Scheme 5. However, we envisioned improved coup-
ling conditions to replace the use of PyBOP and EDC. To
address some of the other shortcomings of the original route,
primarily the use of protecting groups in the syntheses of 3
and 15, we proposed starting from renewable feedstocks fur-
fural and (S,S)-lactide, respectively. Tactically, we believed
these advantaged raw materials could provide synthetic
benefits while simultaneously improving the environmental
footprint of production.
Scheme 3 1st generation synthesis of 3 from 3-hydroxypicolinic acid.
The chiral amine hydrochloride salt 4 was prepared in six
steps from optically pure (S)-ethyl lactate and N-Boc-L-alanine
(Scheme 4). (S)-Ethyl lactate was protected as the benzyl ether
(12) using benzyl trichloroacetimidate 11. Addition of two
equivalents of (4-FC6H4)MgBr to 12, gave 13 in 93% isolated
yield. Reduction of the tertiary alcohol to produce 14 was
accomplished in 92% yield using triethylsilane and trifluoroa-
cetic acid in dichloromethane.20 Debenzylation of 14 using Pd/
C under transfer hydrogenolysis conditions gave chiral alcohol
15. A 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-
mediated coupling of alcohol 15 and N-Boc-L-alanine afforded
16, which was subsequently deprotected with HCl in dioxane
to give amine hydrochloride salt 4.
Route to substituted picolinic acid 3
The development of an economical, scalable synthesis of the
substituted picolinic acid intermediate, 3, was a key challenge
for the commercial development of 2a. Although our 1st gene-
ration synthesis of 3 (Scheme 3) was sufficiently scalable for
structure–activity relationship studies, the cost and limited
availability of 3-hydroxypicolinic acid, combined with the need
for protecting groups, led us to evaluate alternative routes. We
envisioned an improved synthesis of 3 starting from the renew-
able raw material, furfural,22 in which the pyridine heterocycle
was constructed via an aza-Achmatowicz rearrangement,23 as
shown in Scheme 6. Strecker reaction of furfural gave aminoni-
trile 17, which was not isolated and underwent ring expansion
From a process and Green Chemistry perspective, this route
had high-yielding steps, and both stereocenters of the active
Scheme 4 1st generation synthesis of amine hydrochloride salt 4.
Scheme 5 Retrosynthetic analysis of 2a.
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such, process development research was focused on identify-
ing solutions to mitigate the risks and further improve the sus-
tainability profile of the 2nd generation route. For example, to
ensure the safe scale-up of the Strecker reaction to form 17,
the pH of the reaction and workup was continuously moni-
tored to minimize the possibility of forming HCN, and detec-
tors were used to identify the formation of HCN and protect
workers in the case of a process upset. Unfortunately, efforts to
identify an alternative to cyanide have not been successful to-
date. In the next step, the expense and hazards associated with
the use and shipping of elemental bromine on bulk scale were
avoided by utilizing HBr with aqueous H2O2 for the aza-
Achmatowicz-bromination sequence.26 Reaction of aminoni-
trile 17 with HBr/H2O2 to generate Br2 in situ gave an identical
yield of 18 with no evidence of oxidation of the pyridine nitro-
gen atom. For the subsequent step, benzonitrile was identified
as an alternative to DMSO, a reaction solvent that presents sig-
nificant hazards under the basic conditions used in the SNAr
reaction with NaOMe.27
Scheme 6 2nd generation synthesis of 3 from furfural.
directly upon reaction with Br2. The SNAr reaction of the result-
ing dibromide 18 with sodium methoxide (NaOMe) in
dimethyl sulfoxide (DMSO) occurred regioselectively at the
4-position without protection of the 3-hydroxyl group which
represented a significant improvement over the previous synth-
eses of 3. Hydrolysis of the nitrile functional group of 19 fol-
lowed by reductive debromination of 20 gave 3.
The overall efficiency of the 2nd generation route to 3 was
compared to the 1st generation route by calculating the process
mass intensity (PMI)24 for each synthesis (Fig. 2).25 Fig. 2a
shows the PMI for the 1st generation route starting from
3-hydroxypicolinic acid, and Fig. 2b shows the PMI for the 2nd
generation route starting from furfural. The 2nd generation
route has a greatly improved cumulative PMI compared to the
1st route (127 and 1543, respectively). The 1st generation route
to 3 was not optimized due to its identified shortcomings,
therefore the PMI of the synthesis could likely be significantly
reduced, if desired. However, commercial implementation of
the 1st generation route would ultimately require additional
synthetic steps to produce 3-hydroxypicolinic acid, which is
not available in bulk quantities, unlike furfural. Overall, the
efficiency of the 2nd generation route provides the potential for
a more sustainable manufacturing footprint than the 1st gene-
ration synthesis of 3.
Route to chiral alcohol, 15
A second critical challenge was to develop a more concise
route to produce chiral alcohol 15 with high enantiopurity.
The 1st generation, four-step synthetic sequence utilized an
O-benzyl protecting group strategy as shown in Scheme 4. To
streamline the route and minimize derivatization, we devel-
oped a protecting-group-free synthesis of 15 starting from (S,
Despite the improved efficiency of the 2nd generation route
to 3, several reagents used in the synthetic sequence pose
potential safety hazards (cyanide, bromine and DMSO). As
Scheme 7 Protecting-group-free synthesis of chiral alcohol 15 from (S,
S)-lactide.
Fig. 2 Process Mass Intensity (PMI) comparison of 1st (a) and 2nd (b) generation routes to substituted picolinic acid 3.
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S)-lactide, that we envisioned as a self-protected dimer of lactic
acid, a renewable raw material (Scheme 7).28 The addition of
(S,S)-lactide to four equivalents of (4-FC6H4)MgBr produced
two equivalents of diol 21.29 Reduction of 21 using the same
conditions as the 1st generation synthesis (triethylsilane and
trifluoroacetic acid) produced chiral alcohol 15 without any Scheme 9 Boc-deprotection of 16 with HCl in CPME.
loss of optical purity (>99 : 1 er). A similar yield and enantio-
purity were achieved by replacing triethylsilane with poly-
methylhydrosiloxane (PMHS) as the reductant. PMHS, which is
a by-product of the silicone industry, represents a more cost-
effective and sustainable alternative to the more commonly
used triethylsilane.30 Overall, the protecting group-free 2nd
generation synthesis produced 15 with high enantiomeric
purity (>99 : 1 er) while eliminating two derivatization steps
and the use of catalytic palladium.
Esterification and deprotection
The 1st generation conversion of 15 to amine hydrochloride
Fig. 3 Crystal structure of amine hydrochloride 4.
salt 4 had three notable shortcomings: (1) Boc-protection of
the amino acid, (2) use of EDC as a coupling reagent, and (3)
the use of undesirable reaction solvents (dichloromethane and
dioxane). Unfortunately, all efforts to couple stoichiometric
favored for its consistently high yields, mild reaction con-
ditions, and extensive functional group tolerance (Scheme 1).
However, PyBOP is not a preferred coupling reagent in manu-
facturing because it presents potential shock-sensitivity and
explosion hazards.35 Additionally, PyBOP is a relatively expen-
sive, high-molecular weight reagent that is not widely available
on bulk scale.36
Initial research efforts were focused on identifying mixed
anhydride coupling conditions similar to those that proved
effective for the esterification in Scheme 8. Interestingly,
when 3 was treated with a single equivalent of pivaloyl chloride
in the presence of stoichiometric base, a 1 : 1 mixture of start-
ing material and bis-pivalate 22 was formed (Scheme 10). As
expected, increasing the amount of pivaloyl chloride to two
equivalents resulted in full conversion to 22. Following treat-
ment of 22 with amine hydrochloride 4, picolinamide 23
bearing a pivaloyl ester was isolated in 82% yield (Scheme 11).
Unfortunately, attempted deprotection of pivalate ester 23 with
lithium hydroxide (LiOH) did not yield 2b and instead led to
undesired hydrolysis of the alanine ester bond.37
amounts of alcohol 15 and unprotected alanine failed. As
such, research efforts were primarily focused on identifying
improved coupling conditions using industrially-preferred sol-
vents.31 Mixed-anhydride chemistry was quickly identified as a
greener and more economical approach for the esterification
(Scheme 8).32 Specifically, alanine ester 16 was made in excel-
lent yield from the pivaloyl mixed anhydride of Boc-alanine
formed in situ from Boc-alanine, pivaloyl chloride and triethyl-
amine. Subsequent treatment of the mixed anhydride with
alcohol 15 and catalytic DMAP (4-dimethylaminopyridine) gave
16. Importantly, we found that dichloromethane could be suc-
cessfully replaced as the reaction solvent with less hazardous
options such as 2-methyltetrahydrofuran (MeTHF) or cyclopen-
tyl methyl ether (CPME).33
Substitution of the reaction solvent in the subsequent step
was also successful, as the HCl-mediated Boc-deprotection of
16 to give 4 was accomplished in CPME as opposed to dioxane
(Scheme 9). The relative and absolute stereochemical configur-
ation of 4 was confirmed by X-ray crystallography (Fig. 3).34
Eventually, it was found that the desired product 2b could
be synthesized in good yield by using ethyl chloroformate as
the coupling reagent and carrying out the deprotection of the
resulting carbonate as depicted in Scheme 11. Under con-
Amidation and acetylation
The 1st generation PyBOP-mediated amide coupling of 3 with
chiral amines enabled extensive SAR studies and was initially
Scheme 10 Treatment of 3 with one equivalent of pivaloyl chloride
Scheme 8 Synthesis of 16 via mixed-anhydride esterification.
and triethylamine.
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Scheme 11 Synthesis of 2b via mixed-anhydride amide coupling and hydrolysis.
Conclusions
Florylpicoxamid (2a) was designed by holistically utilizing the
principles of Green Chemistry (Scheme 13). Several principles
were incorporated into the molecular design of the active
ingredient leading to a highly efficacious structure with an
under-utilized mode of fungicidal action. To reduce the dose
rate of the product and avoid the risk of differential metab-
olism, the decision was made to develop florylpicoxamid as a
single enatiomer due to the lack of biological activity of its
other three stereoisomers (principle 4). The active ingredient
was strategically designed to degrade in the environment
(principle 10). Both design elements help to lower the environ-
mental impact of the active ingredient and improve its overall
sustainability profile.
Scheme 12 Synthesis of 2a via acetylation with acetic anhydride.
The synthesis of florylpicoxamid (2a) was also designed to
be more sustainable by systematically applying the principles
of Green Chemistry (Scheme 13). The novel synthetic sequence
developed to the trisubstituted pyridine from furfural, a renew-
able feedstock, increased the renewable carbon content of the
2nd generation route to 41% and minimized waste (principles
1 and 7). HCN detectors and continuous pH monitoring were
Fig. 4 Crystal structure of florylpicoxamid 2a.
ditions similar to the optimized procedure for the pivalate used during the Strecker reaction to provide data in real-time
mixed anhydride coupling to give 23, the use of two equiva- to help prevent the formation of HCN and protect workers in
lents of ethyl chloroformate produced 24 in 85% yield. the case of an unplanned release (principle 11). The key aza-
Chemoselective hydrolysis of the carbonate group was Achmatowicz-bromination sequence was made safer by gener-
achieved with LiOH to afford 2b in good yield (84%). Unlike in ating bromine in situ from HBr and hydrogen peroxide (prin-
the attempted deprotection of the pivalate ester 23, no hydro- ciples 3 and 12). The number of protecting groups in the syn-
lysis of the alanine ester bond of 24 was observed under these thetic sequence was reduced from three to one by employing
reaction conditions.
new chemistry from furfural and (S,S)-lactide which minimized
Improved reaction conditions were also developed for the derivitization and improved atom economy (principles 2 and
final step in the synthesis of 2a, as illustrated in Scheme 12. In 8). All the reactions in the 2nd generation synthesis were con-
the 1st generation route (Scheme 1), acetyl chloride and cata- ducted between 0–100 °C to avoid cryogenic conditions and
lytic DMAP were utilized to install the acetate ester, but over- maximize energy efficiency (principle 6). Lastly, safer solvents
acylation of 2a resulted in the formation of small amounts of were used whenever possible (principle 5). For example, the
25 (8% yield). However, by replacing acetyl chloride with acetic two-step synthesis to produce amine hydrochloride 4 from
anhydride and eliminating DMAP, the N-acetylated impurity alcohol 15 was conducted in CPME as opposed to dichloro-
(25) was minimized (<2%), and 2a was isolated in nearly quan- methane and dioxane. All of these improvements have estab-
titative yield. A crystal structure of the final active ingredient is lished a foundation for a sustainable manufacturing route to
depicted in Fig. 4.38
the active ingredient. Overall, the strategic application of
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Scheme 13 Holistic use of Green Chemistry principles in the design and synthesis of florylpicoxamid.
Green Chemistry principles during the design and synthesis of
florylpicoxamid will provide farmers with sustainable
product for the control of diseases of a variety of important
crops.
4 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, New York, 1998;
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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This paper is dedicated to the memory of Dr. Gary Roth, our
colleague, mentor and friend. The authors would like to thank
all the scientists at Corteva Agriscience who made contri-
butions to the design, synthesis, characterization and analysis
of picolinamide analogs leading to the discovery and develop-
ment of florylpicoxamid. The authors would especially like to
thank Mini Jan, Renzo Samame, and Grant Von Wald for
detailed analytical support.
a
New Picolinamide for Disease Control, in Recent
Highlights in the Discovery and Optimization of Crop
Protection Products, ed. P. Maienfisch and S. Mangelinckx,
Elsevier, in press.
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13 Both active ingredients inhibit mitochondrial electron
transport at the ubiquinone inside (Qi) site of the cyto-
chrome bc1 complex.
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When a second equivalent of lithium hydroxide was added,
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27 C. L. Øpstad, T.-B. Melø, H.-R. Sliwka and V. Partali,
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