Chemistry with glasses on

I’m going to take you back in time. Forget all the chemistry you know for the next few seconds – say three. Can you wonder how it must have been to think, ‘Hey, this material must have some structure.’? Sounds bizarre. As bizarre as Newton asking himself, “Why does anything fall?’

These three scientists wondered about chemical structures in the same bizarre way and are the founders of the theory of chemical structure.

  1. Alexander Mikhaylovich Butlerov, a Russian chemist, one of the principal creators of the theory of chemical structure.
  2. Archibald Scott Couper, a Scottish chemist who proposed an early theory of chemical structure and bonding.
  3. August Kekulé, German organic chemistHe was the principal founder of the theory of chemical structure.

First glass

In 1951, physicist Erwin Wilhelm Müller,  a German physicist, was the first to see atoms. He did this using his own invention: the field ion microscope. Literature doesn’t have the photograph of what he saw but the following photograph is similar to what he observed: each dot is the image of an individual platinum atom.

(Image: ACS)

Second glass

In 1931, Max Knoll and Ernst Ruska built the first TEM. In 2013, researchers put this to use by observing what happens inside a battery. The following image is a TEM image of the polio virus.

(Image: Wikipedia)

Third glass

The third glass quickly replaced the second in the year 1952 when the following photo was captured. But it was rather an indirect picture – Photo 51. Photo 51 is the nickname given to an X-ray diffraction image of DNA taken by Raymond Gosling  in the lab of Rosalind Franklin, as her PhD student.

(Image: Wikimedia)

Fourth glass

The fourth glass was put on with the advent of scanning tunneling microscope. This gave rise to a technique called as scanning probe microscopy. Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very high-resolution type of scanning probe microscopy. In 2009, a single molecule was imaged for the very first time by IBM researchers. This was done by using a AFM. It is with AFM that for the very first time (2013) that scientists saw how hydrogen bonds looks like. The following is its picture.

(Image: RSC)

Fifth glass

The fifth glass is our very own digital camera.

“A great deal of time is spent within synthetic chemistry laboratories on non-value-adding activities such as sample preparation and work-up operations, and labor intensive activities such as extended periods of continued data collection. Using digital cameras connected to computer vision algorithms, camera-enabled apparatus can perform some of these processes in an automated fashion, allowing skilled chemists to spend their time more productively. In this review we describe recent advances in this field of chemical synthesis and discuss how they will lead to advanced synthesis laboratories of the future.” – Abstract from an open-access paper ‘Camera-enabled techniques for organic synthesis‘ (Beilstein J. Org. Chem. 2013, 9, 1051–1072.)

Researchers from UCLA have developed a smartphone microscope to see single virus and synthetic nanoparticles. It produces images almost as good as a SEM.

(Image: geek.com)

Sixth glass

Last week, I attended a lecture by Prof. Prashant Jain (nanogold.org) from the University of Illinois, at ICT, Mumbai. It was called ‘Elucidating chemical reactions on the nanoscale’. He described how we can observe individual nanoparticles instead of observing the reaction in bulk. His research involves ‘Imaging Phase Transitions in Single Nanocrystals’. The following is a section from his profile describing this research work.

Phase transitions in solid-state materials often involve interesting dynamics. Since macroscopic solids are typically polycrystalline, such dynamics is smeared out in studies on bulk solids, due to ensemble averaging over different crystalline domains. By acquiring snapshots of a single nanocrystalline domain undergoing a phase transition, our lab is attempting to uncover the dynamic trajectory involved in the nucleation of a new phase. We are developing new optical and spectroscopic methods to acquire snapshots of model phase transitions and also using these techniques to learn new facts about fundamental phenomena such as crystal growth, impurity doping, and correlated electron systems.

We’ve come a long way observing chemistry, haven’t we? The more we see, we find how less we know.

Acknowledgment: Thanks to Dirk Schweitzer for introducing me to the paper – ‘Camera-enabled techniques for organic synthesis‘. You can find him on Google+.

New in Green Chemistry: The Zipper approach

Many chemical products can be produced via different routes. One of these routes may be industrialized depending upon its cost-effectiveness, satisfaction of environmental constraints and ease of scale-up. As you may be aware, environmental constraints have become stringent due to the effects the chemical and allied industries have on our environment. Green Chemistry, with its 12 guiding principles has made the world look at conventional chemistry and its subsequent scale up with a fresh approach that is environmentally benign.

In 1990, Elias James “E.J.” Corey, an American organic chemist won the Nobel Prize in Chemistry for his development of the theory and methodology of organic synthesis, specifically retrosynthetic analysis. The most famous of all the restrosynthesis processes is the production of Ibuprofen, wherein 6 steps were reduced to just 3. This achieved one of the 12 principles of Green Chemistry that says, “Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.”

Synthesis Explorer by the Royal Society of Chemistry (RSC) helps students and teachers plan synthetic routes by choosing a starting compound, reacting it and viewing details of the reaction.

According to Warner, only 10 percent of current technologies are environmentally benign and 35 percent could be made benign relatively easy. The remaining 65 percent will need to be reinvented in more environmentally benign ways. A report by Lisa Lilleland, a sustainability advisor and environmental advocate.

Retrosynthesis is design of organic synthesis to find newer, simpler and benign ways to produce a compound. Technion Scientists have now developed a new method for selective synthesis of complex molecules. They call it the “Zipper Approach”. It is a one-of-a-kind stereochemistry for difficult transformations: allylic C-H (H=Hydrogen) and selective C-C bond activations. The paper is published in the journal Nature.

More and more companies are now offering services in upscaling and route scouting. Route scouting is the creation of sustainable synthesis routes. Some of the companies that provide such services are:

Accepting reality

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Volunteer image author Tigerlily713

Are green chemistry principles feasible? Can they be scaled to plants? Can the industries helps the environment and at the same time profit from it?

First, let’s look at the ideal process parameters. An ideal process should be green, because it not only is safe to the environment but at the same time saves a lot of money. Following are the ideal process parameters, not in an order of preference:

  1. Room temperature
  2. Atmospheric pressure
  3. No solvent use
  4. No flammability
  5. Not a viscous fluid (Why? Because if it is viscous we have to spend energy in agitating it or mixing it)
  6. Benign like water

Are there any such ideal processes? No. So how are the real processes? This is what happens in the industry:

  1. Machines are needed (Motion free process is not conceivable)
  2. Driven by electricity or some other form of energy
  3. Skilled or semi-skilled or unskilled workers (Automation may not be a complete solution)
  4. Ill-informed operators work on real processes because they are not allowed to know the intricacies of the process. For example, no worker in the Coca-Cola company knows the recipe of its cold-drink.
  5. Fierce competition for survival and growth exists
  6. “Risk is better than starvation” attitude
  7. NIMBY (Not-in-my-back-yard) attitude of manufacturers
  8. Hazard exists (Risk is part and parcel of all activities)

Now, what can we do?

  • Can all chemicals be replaced by safer chemicals?
  • Can we live without gases to avoid leaks which cannot be contained?
  • Can we avoid volatile liquids altogether?
  • Can we stop designing and operating plants irrespective of the inherent characteristic of the chemicals?

Can you live like a caveman, a nice hut, a little vegetable garden, livestock in the backyard? Will everyone do it? No. So what now? We now should accept things and adapt to them. Adapt in a way that will keep this planet sustainable, for us and other species.

What green chemistry will do for us is to deal with the existing problems and helps us create a sustainable environment, at the same time cleaning up the mess that our creations have caused. We don’t know if we are late but it is worth the try. Act in a way that also takes care of the economy because if economies fail, the nation fails, it will lead to chaos, we don’t want that.

Reading more: Principles of Green Engineering

Last edited: December 19th 2017

Isosteres

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Volunteer image author Kangheungbo

Isosteres are substances with similar molecular and electronic characteristics. They may not be structurally related, but they often have similar physical properties. They are chemical substances, atoms or substituents that possess nearly equal or similar molecular shape and volume, approximately the same distribution of electrons and which exhibit similar chemical properties. Benzene and pyridine are classical examples of isosteres.

Can a carcinogenic molecule be made safe by knowing its isostere ? Yes. Look at this for example.

Isosteres

Does it mean all F isosteric substitutions are safe?

Isosteres -2

Does it depend on the position?

Isosteres -3

Silicon as an isostere for Carbon:

Si is the 2nd most abundant element on the planet. Naturally occurring Si-C bonds are unknown. Even if they were, such bonds must have immediately formed some other bond.

Silicon substitution in acetylcholine analogs:

Isosteres -4

Acetylcholine is a neurotransmitter. A muscarinic receptor agonist is an agent that enhances the activity of muscarinic acetylcholine receptor.

Silane analogue of Polyethylene, Air stable:

Isosteres - 5

In the presence of water and/or soil, siloxanes hydrolyze to smaller oligomers and monomeric 1,1-dimethylsilanediol.

Isosteres-6

Mammals also rapidly oxidize silicon-hydrogen bond, whereas the carbons attached to silicon are metabolized much like simple hydrocarbons.

Isosteres-7

DDT, DDD & Silicon isosteres:

Isosteres-8

DDT  = dichlorodiphenyltrichloroethane

DDD = dichlorodiphenyldichloroethane

Why is DDT good? Millions of lives were saved against mosquitoes with the help of it. Why is DDT bad? It turned out to be an endocrine disruptor, genetoxic, persistent and exteremely hydrophobic chemical.

Insecticide MTI-800:

Isosteres-9

If you replace C with Si, no mortality of fish is observed at 50 mg/l. While with C in it, Fish LD50 is 3 mg/l.

Further reading:

Last edited: December 19th 2017

Toxicity generating mechanisms

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Volunteer image author Miniformat65

This post assumes you are well-versed with electrophiles and nucleophiles along with basics of Biology. If not, here are some links for you that can help.

Toxicity generating mechanisms involving electrophiles:

Electrophilic substitution or those metabolized to electrophilic species are capable of reacting covalently with nucleophilic substituents of cellular macromolecules such as DNA, RNA, enzymes, proteins and others.

Nucleophilic toxic substituents

  • Thiol groups of cysteinyl residue in protein
  • S atoms of methionyl residue in protein
  • Primary amino groups of argimine and lysine residues
  • Secondary groups (histidine) in protein
  • Amino groups of purine bases in DNA or RNA
  • O atoms of purines and pyrimidines
  • P=O of RNA and DNA

Refer to this table: Nucleophilic toxic substituents. Keep the table opened in one of your tabs and read further.

These are the groups highly likely to cause such effects but the effects can be reduced or eliminated by replacing the functional group or by changing its position in the molecule. Hence, the presence of any of these substituents does not automatically mean that the substance is or will be toxic.

Example 1:

Ethyl Acrylate (Carcinogenic)

IMG-1463.jpg

Acrylates contain alpha, beta unsaturated C=O system and undergo Michael addition. This is the reason for carcinogenic properties of acrylates. Methacrylates are better than acrylates. Incorporation of a CH3 group on to the alpha C to give ethacrylates decreases the electrophilicity (i.e. reactivity) of the beta C. Hence, methacrylates do not undergo 1,4-michael addition easily. Methacrylates have some commercial efficacy.

Example 2:

Isocyanates are used in adhesives and intermediates. The endogeneous nucleophiles in isocyanates are responsible for their toxicity. During coating, the ketoxime moiety is removed thermally thereby regenerating the isocyanate.

Example 3:

Vinyl sulfolane are:

  • highly electrophilic
  • used in textile fibre industry
  • reacts covalently with hydroxy groups of cellulose fibres
  • is made safe by converting into a sulfate ester which is not electrophilic during storage and handling. It can be regenerated again by neutralizing.

Example 4:

Structural requirements for high teratogenic potency of carboxylic acids? *

IMG-1463 (1).jpg

What aspects of this molecule can lead to teratogenic potency?

  • a free carbonyl group
  • only one hydrogen atom at C(2)
  • an alkyl substituent larger than methyl at C(2)
  • no double bonds between C(2) and C(3) or C(3) and C(4)

*Teratogenic potency is based on in vivo data.

In general we can say:

  • Ortho or meta substituents are better.
  • Reduce alkyl chain carbons.
  • Methyl is better than ethyl.

Last edited: December 19th 2017

Designing a safer chemical

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Volunteer image author Eswamy

Here are some strategies for safer chemical design:

  1. Reduce absorption
  2. Use of toxicity generating mechanism
  3. Use of structure activity (toxicity) relationships
  4. Use of isosteric replacements
  5. Use of retrometabolic (‘soft’ chemical) design
  6. Identification of equally efficacious less toxic chemical substitutes of another class
  7. Elimination for the need for associated toxic substances

While considering these aspects, it is best to dividethem into two categories, namely external considerations and internal considerations.

External considerations:

Reduction of exposure or accesiblity:

Properties related to environmental distribution/dispersion:

  • Volatility, density, melting point. For example, Carbon disulphide is stored in pool of water because it is denser than water. Also, petrol/diesel are stored underground to keep the temperature low.
  • Water solubility.
  • Persistence/Biodegradation: Oxisdation, hydrolysis, photolysis, microbial degradation. These are all related to structural stability.
  • Conversion to biologically active substances.
  • Conversion to biologically inactive substances.

Properties related to uptake by organisms:

  • Volatility
  • Lipophilicity
  • Molecular size
  • Degradation: Hydrolysis, effect of pH, susceptibility to digestive enzymes.

Consideration of routes of absorption by mass, animals or aquatic life:

  • Skin/eyes
  • Lungs
  • GI tract
  • Gills or other species-specific routes

Reduction/elimination of impurities:

  • Generation of impurities of different classes
  • Presence of toxic homologues
  • Presence of toxic, geometric, conformational or stereoisomers.

Internal considerations:

Facilitation of detoxication:

  • Facilitation of excretion: Selection of hydrophilic compounds, facilitation of conjugation/acetylation
  • Facilitation of biodegradation: Oxidation, reduction, hydrolysis.

Avoidance of Direct Toxication:

  • Selection of chemical class or parent compound
  • Selection of functional groups: Avoidance of toxic groups, planned biochemical elimination of toxic structure.
  • Structural blocking of toxic grouos
  • Alternative molecular sites for toxic groups

Avoidance of Indirect Biotoxication (Bioactivation):

  • Addressing Bioactivation: Avoiding chemicals with known activation routes – (1) highly electrophilic or nucleophilic groups (2) unsaturated bonds (3) other structural features
  • Structural blocking of bioactivation

You must already be familiar with isosteres by now. Here are some other ways to deal with toxic substances.

Use of Retrometabolic (Soft Chemical) Design:

A ‘soft’ chemical can be defined like soft drugs. A substance deliberatly designed such that it contains the structural features necessary to fulfill its commercial purpose but if absorbed into exposed individuals, it will break down quickly and non-oxidatively to non-toxic readily excretable substances. For example, safer alkylating agents and safer analog of DDT.

Equally efficacious, less toxic substitutes of another class:

Focus on commercial application and depends on the successful identification of a less toxic substance of a different chemical class.

Examples:

  1. Acetoacetate as substitutes for isocyanates in sealants and adhesives
  2. Isothiazoles as substitutes for organotin anti-foulants
  3. Sulfonated diaminobenzanilides for benzalidines in dyes

Elimination of associated toxic substances:

The subtance per se is not toxic but its storage, transportation or use may require an associated substance which is toxic. For example, solvent replacement.

Examples:

  1. Water based paints instead of oil based paints
  2. Supercritical CO2 for organic solvents
  3. Dibasic esters (e.g. methyl esters of adipic, succinic acid and glutaric acids) to replace glycol ethers, cyclohexanone, isophorone, cresylic acid, methylene chloride and others)

Cetylpyridinium chloride and its soft analog:

Cetylpyridinium chloride (CPC) is a cationic quaternary ammonium compound in some types of mouthwashes, toothpastes, lozenges, throat sprays, breath sprays, and nasal sprays. Cetylpyridinium chloride is present in commercial products listed in this Wikipedia article.

IMG-1461 (1)

Acetoacetate based sealants and adhesives:

img-1461-2.jpg

Carcinogenicity of Aromatic Amines:

Simplest of these systems is Aniline. The unattached bonds on these ring systems indicate the positions where attachment of amines or amine generating group(s) gives rise to carcinogenic compounds.

Let’s look at the molecular design of aromatic amine dyes with lower carcinogenic potential. Find it here: OncoLogic™ – The Cancer Expert System – An Overview

Last edited: December 19th 2017