Sustainable Chemistry and Pharmacy 10 (2018) 79–83

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Sustainable Chemistry and Pharmacy

journal homepage: www.elsevier.com/locate/scp

Introducing new reactions and technologies in industrial synthesis: T

Challenges, hurdles and opportunities for start-up initiatives for sustainable
chemistry
Irene Erdelmeier
INNOVERDA, 38 Rue Dunois, 75013 Paris, France

ABSTRACT

Following up on the UNEP/UNIDO/ISC3-workshop in Berlin in September 2017, the context of the French start-up initiative INNOVERDA is presented, and its
anticipated contribution to mainstreaming the practice of green and sustainable chemistry highlighted. INNOVERDA is dedicated to implement electrochemical flow
methods for sustainable production processes in the chemical and pharmaceutical industry. Challenges and hurdles encountered during the first phase of this start-up
as also experiences from a previous one, TETRAHEDRON, are summarized, and potential solutions proposed.

1. Introduction: The ideas behind the start-up
The recent creation of INNOVERDA, a French start-up dedicated to
implement green and sustainable chemistry solutions in industry, was
inspired by key experiences and insights which we gained with our first
start-up in the chemical sector, TETRAHEDRON (www.tetrahedron.fr),
created in 2003 together with J. C. Yadan and M. Moutet. TETRAHE-
DRON set up to develop safe and natural or nature-derived novel an-
tioxidants for nutrition, cosmetics and pharmaceutical applications. In
several years of research and development, we succeeded to bring
Ergothioneine, a fascinating amino acid, (Cheah and Halliwell, 2012)
from the lab to the market.1 (Fig. 1).
Essential steps on the long way to the market were (i) the devel-
opment of an industrial production process, for which we invented a
new green and biomimetic synthesis in water (Erdelmeier et al., 2012)
and (ii) obtaining a regulatory status for our product as Novel Food,
(Statement on the safety of synthetic l-ergothioneine as a novel food,
2017) thus overcoming the final barrier to broad commercialisation.
During the process development phase, we faced technical chal-
lenges of purification and separation from salts, due to the extremely
high polarity and water solubility of this unusual zwitterionic amino
acid. While others circumvent this by using protecting group chemistry
to gain on lipophilicity with the goal to work in organic solvents,
playing the high price of adding several steps, (Xu and Yadan, 1995;
Trampota) we searched an appropriate purification technology. The
solution was the implementation of a desalination-purification method
based on electrochemical principles, called electrodialysis.
The simplicity and efficacy of this method is striking, contrasting
with the fact that it is only rarely used in organic synthesis in the la-
boratory, and even less in industrial productions.
This observation led us to take a broader look in the current use of
electrochemical methods such as electrodialysis (ED) and electro-
synthesis in chemical research, development and production. Quite
surprisingly, the results showed that there seems to be a huge unused
potential for such a potentially sustainable production technology,
particularly in organic synthesis. This is perhaps simply due to the
historical separation in the chemistry curriculum assigning electro-
chemistry to the physical chemistry, not being specifically addressed in
the training of organic synthetic chemists. Another explanation could
be the lack of convenient equipment for the synthetic organic chemist,
as highlighted recently by Baran et al. (Yan et al., 2018).2,3
Therefore, at the time when TETRAHEDRON concentrated on
marketing and sales of its key product ergothioneine (under the brand
name Ergoneine®), I decided to launch a new company in 2017. The
goal of this start-up initiative, INNOVERDA, is to focus on the im-
plementation of electrochemical methods and in particular flow

1
Under the trade name Ergoneine®.
2
Interestingly, some equipment suppliers start to supply convenient lab equipments: see for example: https://www.ika.com/laboratory-equipment/products/
electrochemistry-kit/ and http://www.pccell.de/.
3
See for example the following statement: Electrochemistry and photochemistry are not really new technologies, but they are certainly technologies that have been
largely viewed as curiosities by most of the fine chemical and pharmaceutical community. Some companies are looking at or even using both these techniques, but
the two reasons listed for having low interest in this area is a lack of in house expertise and perhaps more importantly a lack of suppliers/vendors with expertise and/
or equipment in this area. in Watson W. J. W., “How do the fine chemical, pharmaceutical, and related industries approach green chemistry and sustainability?”
Green Chem., 2012,14, 251–259, DOI:10.1039/c1gc15904f.

https://doi.org/10.1016/j.scp.2018.09.006
Received 31 May 2018; Received in revised form 23 September 2018; Accepted 27 September 2018
Available online 05 October 2018
2352-5541/ © 2018 Elsevier B.V. All rights reserved.
I. Erdelmeier
Fig. 1. TETRAHEDRON's key product L-Ergothioneine, commercialised under the trade name Ergoneine®.
electrosynthesis in organic synthesis from the research lab to industrial
productions.
2. Anticipated contribution to green and sustainable chemistry
While we should be very careful and selective to introduce further
new chemicals into the environment, we nevertheless need new sus-
tainable materials, and sustainable production processes to provide
essential chemical intermediates, final products and drugs.
At INNOVERDA, we design and develop continuous flow electro-
chemistry and biomimetic processes. This technology will contribute to
green and sustainable chemistry by two means:
Firstly, by significantly changing and/or improving industrial pro-
duction processes by not only replacing corrosive and/or toxic agents,
but also by increasing selectivity, efficiency and safety, using electrical
energy (i.e. renewable energy), thereby offering ecological and eco-
nomic advantages.
Obviously, oxidative and reductive transformations, which are de-
fined by adding or removing electrons (and protons) are excellent
candidate reactions for electrosynthesis, using electrons (and occa-
sionally water to deliver protons) as sole reagent. In traditional che-
mical oxidoreductions, stoichiometric quantities of oxidants or re-
ductants are required to deliver or remove electrons, with the
concomitant generation of at least (molar) equivalent quantities of
waste. In electrosynthesis, electrons are added at the cathode and re-
moved at the anode, if appropriate reaction conditions are identified.
By choosing the appropriate parameters for electrode materials, dis-
tance between electrodes, solvents, pH, temperature and flow rates,
these synthetic transformations are reduced to its essential feature.
Impressive examples are the industrial production of Erythritol (vide
infra), but also innovative electrochemical oxidations of non-activated
C-H-bonds, (Kawamata et al., 2017) or NH-bonds, as illustrated recently
by the group of Baran in the synthesis of Dixiamycin (Rosen et al.,
2014). Electrochemical reduction can also be used to afford smooth
dehalogenation without the need for chemical reagents, as illustrated
by the group of Waldvogel in the synthesis of a Cyclosporin analogue
(Gutz et al., 2015a; 2015b). A broad diversity of other chemical
transformations may be improved or enabled by electrochemical acti-
vation or mediation (Atobe et al., 2018; Möhle et al., 2018). Interest-
ingly, some of those new electrosynthetically feasible transformations
had been highlighted a decade before as “key green chemistry research
areas from the Pharmaceutical Manufacturers perspective”, for which
“greener” solutions were needed (Constable et al., 2007).
Most recently developed electrochemical reactions respect several
principles of Green Chemistry, such as prevention of waste, less ha-
zardous processes, higher energy efficiency, reduction of derivatives,
catalysis (often plays the electrode material also a catalytic role or
catalytic mediators are involved), and inherently safer chemistry.
Electrochemical processes can move chemical production to more sus-
tainability, if additional aspects are considered such as (i) sourcing of
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Sustainable Chemistry and Pharmacy 10 (2018) 79–83
renewable energy for electricity, (ii) sustainable electrode materials, as
for example stainless steel or graphite, avoiding further depletion of
rare elements, and (iii) use of renewable raw materials.
INNOVERDA wants to contribute with its second business focus to
this movement to more sustainable chemistry, by developing new
processes for the transformation and valorisation of biomass (in pre-
ference waste) to supply in an economic and ecological way starting
materials for the chemical industry, replacing petrochemical feed stocks
by biomass. In this context electrosynthesis is a particularly powerful
and promising tool for the biorefinery concept, as bioderived feedstocks
are inherently highly oxygenated and functionalised. To obtain plat-
form molecules or fine chemicals and ingredients from biomass, re-
ductive transformations are essential. Therefore, a broader application
of electrosynthesis using “electrons as sole reagents” wherever possible
is a promising goal and economically feasible, as exemplified with the
industrial scale production of erythritol by an American Company
(Dynamic Food Ingredient, http://dficorp.com/). In this process, C6-
sugars are first electrochemically oxidized and decarboxylated at an
anode, followed by electrochemical reduction at the cathode to ery-
thritol (see Scheme 1) (Stapley et al.).
Key features of flow electrochemical methods are the possibility to
use water but also organic solvents if required, modularity, efficiency
and selectivity. Moreover, they can be conveniently upscaled and easily
replicated in other regions, as flow processes can be implemented with
mobile units. These aspects are important, not only to avoid the
transportation of dangerous goods (as shown for example in the “on
demand” generation of ammonium persulfate (Zhu et al., 2016)), but
also in the perspective of waste transformation.
Besides working with flow electrosynthesis, INNOVERDA thrives to
explore also the potential of electrodialysis as sustainable process
technology for treatment and purifications. ED is a high-throughput
membrane-based technique which is easily adaptable on an industrial
scale, and commonly used in water treatment for (solar-driven) desa-
lination of seawater, (Wright and Winter, 2014; Strathmann, 2010) or
removal of inorganic trace contaminants from bore water sources
(Banasiak and Schäfer, 2009). Its sustainability depends on membrane
material, efficiency and water consumption, but also on the source of
energy. Contrary to ion-exchange column chromatography, where the
ions are absorbed on a resin, ions are migrating in ED through the
membranes and collected in a “concentrate”. The membranes can be
Scheme 1. Industrial electrosynthesis of erythritol (Ref. Stapley et al.).
I. Erdelmeier
Fig. 2. Example for raw material savings using an electrochemical flow method (see Ref. Erdelmeier).
used indefinitely in theory without saturation, but process impurities
may induce scaling and occluding. The process density of exchange via
electrodialysis and its material efficiency is higher by orders of mag-
nitude, combined with lower processing costs, compared to classical ion
exchange resin chromatography. Despite these powerful advantages, it
has been only scarcely applied in organic chemical productions.
One example for the real impact on cost savings and waste reduction
is the successful substitution of ion-exchange resin chromatography by
flow electrodialysis in the synthesis of Hercynine, a natural amino acid.
We developed the process first at the gram scale before upscaling
straightforward to industrial production, saving 67 t of solvents and 14 t
of resins per ton of product compared to the traditional synthesis (see
Fig. 2) (Erdelmeier).
3. Individual approaches
Before launching the start-up INNOVERDA, we planned to proceed
through a series of feasibility tests and proof of concept for redesigning
the production process of three different product families, but we met
two major difficulties, typical in the early phase of a chemistry-start-up,
which are
1. To find an appropriate lab space and
2. To obtain the legal possibility to order chemicals.
We could overcome these hurdles by joining an open science/open
laboratory initiative in Paris, “La Paillasse”. In this association it is
possible to rent a work space in the required infrastructure to affordable
costs or alternatively get access for free in the context of the “Open
Residence Program” (http://lapaillasse.org/en/incubation). Interest-
ingly, our project was accepted in residence due to the fact that it is
dedicated to sustainable chemistry and chemistry in water and fosters
the use of renewable energy.
During 9 months we explored the potential of our business idea,
established first contacts with potential clients and prepared the busi-
ness plan before eventually creating and officially registering the
company in October 2017. During this evaluation phase, it was ex-
tremely helpful and inspiring to be surrounded by other entrepreneurs
in various disciplines, and to confront our ideas with others – and in
particular also non-scientists. Another useful “brick stone” in the pre-
paration phase was the participation in a contest for “women en-
trepreneurs” start-up initiatives, (http://www.cnam-incubateur.fr/)
which required to propose a clear business concept including financial
details.
Our approach to develop the start-up is to offer a service to in-
troduce electrosynthesis, from the lab scale to development and pro-
duction. This includes a sequential quick pre-screening offer to evaluate
with the customer the potential benefits of re-designing an existing
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Sustainable Chemistry and Pharmacy 10 (2018) 79–83
process to electrosynthesis or designing an entirely new pathway based
on electrosynthesis. This first step may be followed by a detailed
screening and (co)development phase, including identification of key
parameters, and selection of appropriate equipment, with the potential
for straightforward upscaling.
The basic concept is to initiate and facilitate change (to more sus-
tainable processes) by lowering the “entry-barrier”. From our own re-
search and development experience we know that the up-front invest-
ments for new equipment may be the first and major hurdle to evaluate
a new technology. That is why we propose quick screenings and mobile
platforms, which allow to get quickly in touch with the key features of
electrosynthesis, and to identify the “low-hanging” fruits, i.e. those
process improvements with the most significant benefits.
4. Factors of success and hurdles
From both start-up experiences, TETRAHEDRON and INNOVERDA,
some insights can be extracted:
Key factors of success have been:
1. Innovations which are solutions for concrete problems, either filling
unmet market needs for a specific product or material, or solving
issues in synthesis, processing and purification technologies in-
cluding transversal technology transfer. Key for success is to si-
multaneously offer ecological AND economic advantages which can
be concretely quantified.
2. For INNOVERDA, the possibility to join an Open Lab Initiative in
Paris (“La Paillasse”, www.lapaillasse.org). TETRAHEDRON could
be launched in 2003 in an academic environment (ENSCP, Paris) at
not too high costs for infrastructure and access to scientific litera-
ture, databases andcongresses.
3. A small but passionate team with complementary competences.
4. Considering the up-scaling from the beginning on, with a holistic
view on the process/product. This requires building strong re-
lationships with equipment suppliers (in the optimal case with an
option to rent equipment for validation of new processes before
investing in an acquisition).
5. Highlighting and quantification of ecological and economic im-
provements thanks to the introduction of the respective technology/
product (i.e. continuously evaluating the efforts towards more sus-
tainability).
There are several phases in the start and development of initiatives
dedicated to Sustainable Chemistry, with specific challenges and hur-
dles (i.e. the start-up itself; a first consolidation phase, protoptype
production/pre-launch; industrial production with authorization to
market). Each phase requires a wide diversity of competences, which
are not obvious for the founders/entrepreneurs. Therefore, the Start-up
I. Erdelmeier
itself but also the transition between these different development
phases may constitute critical moments.
Critical issues and challenges we faced initially and during devel-
opment:
1. Before we heard about the open lab initiative “La Paillasse”, it was a
challenge for INNOVERDA and also initially for TETRAHEDRON to
find an appropriate infrastructure to start and validate the key idea -
Proof of Concept (lab space with at least one chemical fume hood
and a minimum of appropriate equipment/material).
2. Dealing with all the administrative un-knowns before, during and
following the creation of a start-up, such as
● identifying the most appropriate legal structure,
● finding competent and affordable offers for accounting and
human resources services,
● establishing contacts and customer accounts with all required
suppliers, including the negotiation of acceptable payment con-
ditions,
● identifying required assurances and finding assurance companies
which accept to deal with start-ups.
3. Identifying which funding is possible and appropriate at which
moment of the first years of the start-up (and knowing the corre-
sponding deadlines).
4. High upfront investments (time and money) required with late re-
turn on investment. This is mainly an issue when the goal is to
launch a new product on the market, in particular when introducing
new technologies in the production with Contract Manufacturing
Organizations.
In the context of limited financial resources compared to the ne-
cessary high up-front investment, we chose with the TETRAHED-
RON team to offer during the first years in parallel research ser-
vices4 with the goal to finance our own projects, like most start-ups
do. Fortunately, this plan worked for us, but it is a real challenge to
keep the focus on the initial goal and vision, without falling in the
“service-trap”, losing the real goal out of sight.
5. Regulatory procedures may be far longer than announced and ex-
pected, delaying the market launch and commercialisation,5 and
extending the so called “valley of death” (the expensive phase be-
tween R&D to first incomes till complete autofinancing).
6. Communication and marketing efforts and budgets are difficult to
estimate for scientists (often by far underestimated), as also “finding
the right words” to highlight the value of the offer in the commu-
nication with non-scientists.
7. Facing the fact that potential clients are rarely willing to pay a
premium price for a more sustainable process or product, regardless
of the fact that it is difficult to offer a competitive pricing structure
in the early phases.
5. Possible solutions and improvements
Actions to overcome potential barriers:
• Build dedicated platforms or collaborative centres (for example in
academic institutions) for academic but also non-academi-
c”outsider” start-ups initiatives with lab space/fume hoods and a
minimum of appropriate equipment, including access to scientific
databases, for a minimum residence time of 3–6 months which may
be extended up to three years. A contribution of the residents could
be to participate in green and sustainable chemistry training for
4 amino acids: biomimetic synthesis of L-ergothioneine in water. Green Chem. 14,
With a distinct company, Expertise & Consulting.
5 2256–2265. https://doi.org/10.1039/C2GC35367A.
In the case of Ergoneine, the regulatory process took 4 years from the na-
tional registration till final decision by EFSA and granting of the Novel Food
status.
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Sustainable Chemistry and Pharmacy 10 (2018) 79–83
students or professionals, or in open science/citizen science projects
(e.g. 1 day/week),
• Create a support structure to facilitate administrative proceedings,
such as identifying the best legal structure, advice in regard to re-
quired assurances (in regard to its scope and at which stage of de-
velopment), indicate basic rules and typical figures for licencing
negotiations, etc.,
• Advocate for public procurement policies introducing a quota for
more sustainable products,
• Build a network of experts to accompany start-up initiatives in the
transitions from initial start-up to later stages, helping to face the
nonchemical challenges (i.e. market study, identification and vali-
dation of market needs, regulatory frameworks) and to select the
required competences to join the growing start-up team,
• Help start-up initiatives in measuring their efforts towards more
sustainability in a gradually more complex way, from simple metrics
such as mass and energy balances to more complex indicators (e.g.
LCA as proposed in the World Business Council for Sustainable
Development, see the EU-Project SPIRE, GC3 roundtable Green
Chemistry metrics).
6. Conclusion
Facing the competition with low-cost productions due to long-es-
tablished and depreciated installations and “grandfathered” products,
innovations in sustainable chemistry can reach the market, become
mainstream and offer safer products and processes, if actions are taken
to influence public procurements policies and to accompany start-ups in
the critical transitions from early lab phase to industrial production.
One step in this direction is the gathering of experiences from start-
up initiatives about key factors of success and failures, started at the co-
organised UNEP/UNIDO/ISC3 workshop in Berlin, September 2017
(http://www.suschem.org/newsroom/advancing-entrepreneurship-
and-start-up-initiatives-for-sustainable-chemistry). Sustainable chem-
istry can contribute in various ways to help reach the UN-defined
Sustainable Development Goal (https://www.un.org/sustaina-
bledevelopment/sustainable-development-goals/). Our hope is that
INNOVERDA contributes to the implementation of sustainable chem-
istry by developing electrochemical flow methods for sustainable che-
mical productions and the transformation of waste for biorefinery,
overcoming the existing technical and scientific challenges to main-
stream this promising approach.
Acknowledgements
Many thanks to Jean-Claude Yadan and Marc Moutet, the co-foun-
ders of TETRAHEDRON, which was and is such a fascinating en-
deavour, and to Sylvain Daunay, on the way with INNOVERDA to ad-
vance towards green and sustainable chemistry.
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