The
Helping you react with chemical reactions

Issue12June2023

The many
combinations ofcomputationalchemistry

The many combinations of computational chemistry
Molecules are collections of atoms connected in different arrangements by chemical bonds, and chemical reactions combine different molecules and change how they are connected.
The process of combining ingredients and adding energy through heat or light is very similar to the process of cooking. In the laboratory, computers are used to predict chemical
reactions through calculations. However, if there are many combinations of ingredients and reaction conditions to explore, the prediction takes an extremely long time. In that case, it
is important pick out only the realistic combinations from the massive number of possibilities in order to reduce the calculation time.

SaltPe ppe r

Eggs

Crack

Crack

Boil
Mix

Carrots

Soybeans

Separate

Egg white

Egg yolk

Whitekidney beans
Konyaku

Boiled egg

Mix

Soy milk
Mix

Meringue

VEGAN
EGG

Mix

Egg mixture

Oil・Flour・Sugar

Supercomputer

FLOUR

Vinegar
V・Oil

Sugar
Mayonnaise

MixgentlyStockMix

Chiffon cake

Bake ina mold

Retrosyntheticanalysis

CookBreadMix andCookSteam
Cook

Scrambled eggs

Egg salad sandwich
Egg salad

Steamed egg custard
Japanese omeletteOmelette

1. Recipe Variations
So it’s about time to make dinner, butwhen you open your refrigerator, there
are only eggs inside. Hmm…what canbe made with that? A fried egg? Aboiled egg? An omelette? Although
there is only one ingredient, there aremany cooking methods including
frying, boiling, and steaming, andthere are many seasonings that can beadded, such as salt, pepper, or soysauce. For example, if you could use
four cooking methods and threeseasonings, there would be 24 possiblecombinations. However, if instead you
had 15 seasonings in your kitchen,
there would be over 100,000 possiblecombinations! If you tried every recipe,
you might discover new dishes that are
more delicious (or disgusting!) thananything you’ve eaten before.

3. Narrowing it down
In order to prevent an explosion in thenumber of combinations that must be
simulated, ICReDD developed amethod for evaluating reaction paths
after calculating each step anddiscarding paths that are notpromising. When performing acalculation, a computer simply tries
all possible combinations, without
asking whether they are realistic.
This leads to unrealistic reaction
paths where, for example, thereaction temperature is bizarrely high(i.e., higher than lab equipment capabilities). By not including paths that are unrealistic in
the next step of the simulation, unnecessary calculation time can be avoided. Using
this method, the number of reaction paths that need to be explored can be reduced
by a factor of 1000, which makes it possible for computational chemists to simulate
multi-step reactions and other complex systems.

2. Too many options…
Similarly, when predicting chemicalreactions, as the number of atoms
and molecules or the number of steps
in the reaction increases, thecomplexity of the calculation sharply
increases. At ICReDD, we use theArtificial Force Induced Reaction(AFIR) method to calculate every
possible reaction path. In thismethod, different strength forces areapplied to push or pull atoms andmolecules at different locations andin different directions to simulate thenext step in a reaction. This process iscarried out for each step in thereaction, and if there are many steps,
and many atoms and molecules
involved, even a supercomputer may
not be able to explore every reaction
path in a reasonable amount of time.

4. Going in reverse
One such complex system is retrosynthetic analysis,
in which the reaction is predicted in the reverse
direction using only information about the final
product molecule. Instead of going fromstarting materials to the product, thecomputer begins with the product moleculeand searches for paths backwards to starting
materials. For example, rather than thinking“what can I make with an egg?” , it’s likethinking, “what are these scrambled eggs
made from?” Of course, “eggs” is the only
answer, right? Actually, if we searchbackward from the finished dish to find all
possible ingredients, we realize there are alsovegan egg substitutes, which we hadn’t predicted.
For reaction path exploration, there are near limitless starting material possibilities, so it isimportant to discard unrealistic paths along the way. ICReDD is working to improve
retrosynthetic analysis, so that in the future chemists can think of a new molecule they wantto make, and then simply press the “rewind button” in a computer program to find out how
to make that molecule!

on!
itav
itAc
Quiz
The number ofcombinations to compute_as molecules becomelarger and reactions havemore steps.
Send us your answer!

A decreases sharply
B stays the same
C increases slightly
D increases sharply
Check ourInstagram
highlights forthe answer
to the quiz!
#ReactWithUs@ICReDDconnectNew Researchers

ICReDDN e wsSuvankar Debbarma

J u n e 2023

Zannatul Ferdous

Organocatalysis,photocatalysis

Milena Lama

Cancer stem cellcharacterization

Materials science,hydrogels

Dmitry Zankov

Chemoinformatics,
retrosynthetic analysis

Selected Publications (from March 2023 to May 2023)
Healing the brain: hydrogels
enable neuronal tissue growth

Customizing catalysts forsolid-state reactions(K. Kubota, H. Ito)

Synthesis of bicyclo[1.1.1]pentane-based, straight-shaped
diphosphine ligands

Birch reduction simplified to a
one-minute mechanochemicalprocess(M. Imajo, M. Tsuda, J.P. Gong, S. Tanaka)
https://www.icredd.hokudai.ac.jp/research/8753

https://www.icredd.hokudai.ac.jp/re-(H. Hayashi, T. Mita, S. Maeda, Y. Hasegawa)(K. Kubota, H.Ito)search/8776

https://www.icredd.hokudai.ac.jp/re-

https://www.icredd.hokudai.ac.jp/re-search/8935

search/8947

Real-time, macro-scale visualization of molecular-scale mechanochemical damage in double-network hydrogels( Y. Zheng, M. Jin, K. Kubota, T. Nakajima,
S. Maeda, H. Ito, J.P. Gong)
https://www.icredd.hokudai.ac.jp/research/9194

Outreach・Promotional video
featuring ICReDD’s newbuilding
・Monthly Research
Postcard
・The CATALYST 11th Issue

Promotionalvideo
Watch here!

Monthly Research
Postcard

The CATALYST
11th Issue

Symposia

Awards・Joint Symposium ofWPI-ICReDD and theResearch Faculty of Agriculture in Hokkaido University・American Physical Society
Polymer Physics Prize( J.P. Gong )・The Japanese Society ofPathology Japan Pathology
Award ( S. Tanaka )Researcher Profile

vol.12

Yu Harabuchi
Specially Appointed Associate Professor Harabuchi uses quantum chemistry
to develop computational tools inorder to fully understand how molecules respond to light. He uses computers to analyze phosphorescence,
photoswitching and the mechanism ofphotosensitization. Recently, he has
been using these methods combinedwith reaction path networks to understand radical-based reactions that use
photoelectron transfer catalysts.
Representative Papers:
Phys. Chem. Chem. Phys., 17, 22561 (2015)
Nat. Comm., 11, 3909 (2020).
Angew. Chem. Int. Ed., 62, e202211936 (2023).

Short Biography
Assistant to the Center Director, Fusion Research
Coordinator and Specially Appointed Associate
Professor. In 2013, Prof. Harabuchi received his PhDfrom the Hokkaido University Graduate School ofChemical Sciences and Engineering. After this heworked as postdoctoral researcher at Hokkaido
University and Iowa State University and as aJST-PRESTO researcher. He then became anAssistant Professor in the Department of Chemistry, Faculty of Science at Hokkaido University
before starting his current position in April 2023.

About ICReDD
The development of new chemical reactions is intrinsically entangled with the prosperity ofhumanity and the preservation of the environment. A recent example of such transformative chemical reactions with profound impact is cross-coupling reactions, the discovery of which was awarded
with the 2010 Nobel Prize in Chemistry. These reactions are used to produce approximately 20% ofall medicinal reagents, and almost all liquid crystalline and organic electroluminescent materials.
The industrial use of these chemical reactions contributes ~60 trillion yen per annum to the global
economy. The development of new chemical reactions thus significantly affects the evolution ofsociety.
ICReDD is the Institute for Chemical Reaction Design and Discovery, a WPI center at Hokkaido
University where researchers from different disciplines combine their strengths to take full control
over chemical reactions. The institute was born out of the realization that the purposeful design ofchemical reactions requires cross-sectional collaborations at every step. Working on such a fundamental natural process, quantum-chemical computations, information technology, modern experimental techniques, and the development of advanced materials can no longer be separate fields if
we want to achieve significant breakthroughs. Rather, they have to become part of a diverse
toolbox for truly integrated research.

The Catalyst is inspired by catalysts used inchemistry to bring molecules together, to reduce
reaction barriers, and to activate molecules—to makereactions happen faster. In this spirit, this poster series
should enable its readers to make the connection
between chemical reactions and the wellbeing of oursociety, and to look at the world in a new way, seeing
how chemical reactions and chemistry shape the world
around them. And if we can take this opportunity tointroduce ourselves, too, this may also catalyze newfriendships and opportunities. #ReactWithUs

React With Us!
To stay up to datewith what’s happening at ICReDD,
follow us on our social media channels:@ICReDDconnect
ICReDD moved into its newly constructed building in March 2023. The spacious Fusion Research
Office (top) spans two floors and accommodates 100 researchers and our new server room (bottom) is
equipped with supercomputers used for predicting chemical reactions.

Published in June 2023
Published by theInstitute for Chemical Reaction Design and Discovery (WPI-ICReDD)
Hokkaido University
North 21, West 10, Kita Ward, Sapporo, Hokkaido, 001-0021 Japan
Telephone: + 81-11-706 -9646 (Public Relations)
Email address: public_relations@icredd.hokudai.ac.jp

https://www.icredd.hokudai.ac.jp/