Compliance for Intermediates - Solutions - Chemicals

Compliance for Intermediates - Solutions - Chemicals

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Chemical intermediates are widely used during the synthesis process of products such as pesticides, pharmaceuticals, veterinary medicine and more. Recently, increased scrutiny has been placed on compliance and the regulations surrounding these intermediates. Notably, the importance of adhering to regulatory standards in regions like the EU, China, and Korea cannot be overstated. This article introduces the registration requirements for intermediates in these regions.

Intermediates under EU REACH

Definition of Intermediate

According to the REACH regulation, a chemical intermediate is defined as a substance that is manufactured for and consumed in or used for chemical processing to be transformed into another substance. This means that the intermediate is not present in the final product.

Categories of Intermediate under EU REACH

Under REACH, three types of intermediates are defined:

Type

Definition

Non-Isolated Intermediate

A substance that is manufactured solely for transformation into another substance and is used up within this reaction. It is not intentionally removed from the synthesizing equipment.

On-site Isolated Intermediate

A substance manufactured or used for chemical processing to be transformed into another substance, synthesized on the same site operated by one or more legal entities.

Transported Isolated Intermediate

A substance manufactured for or used for chemical processing to be transformed into another substance, transported between or supplied to other sites.

Data Requirements under EU REACH:

Type

Tonnage

Data Requirement

Note

Non-isolated intermediates

Exempt from registration

Transported intermediates manufactured under strictly controlled conditions (SCC*)

<1t/y

Exempted

Data requirements are reduced under SCC. Manufacturer or downstream user needs to provide SCC confirmation letter.

1-1000t/y

Provide available data (e.g., information the registrant holds or can obtain from other sources)

>1000t/y

Provide standard EU REACH 1-10t/y registration data.

Isolated intermediates not manufactured under SCC*

<1t/y

Exempted

Data requirements increase with tonnage level.

>1t/y

Standard REACH registration data requirement

Note: For on-site isolated intermediate under SCC, any available existing information on physicochemical, human health, or environmental properties of the intermediate shall be provided.

Besides the available data on the substance's intrinsic properties, the registrant still has to provide the following information:

• A brief general description of the use;
• Details of the risk management measures applied and recommended for the use;
• The identity of the manufacturer or importer;
• The identity of the intermediate;
• The classification of the intermediate;

To assess if the intermediate is manufactured and used under strictly controlled conditions (SCC) during its whole lifecycle, the registrant should ensure all the following conditions apply:

1. The substance is rigorously contained by technical means during its whole lifecycle including manufacture, purification, cleaning and maintenance of equipment, sampling, analysis, loading and unloading of equipment or vessels, waste disposal or purification, and storage;
2. Procedural and control technologies minimize emission and resulting exposure;
3. Only properly trained and authorized personnel handle the substance;
4. Special procedures such as purging and washing are applied before the system is opened and entered for cleaning and maintenance works;
5. Procedural and/or control technologies minimize emissions and resulting exposure during purification or cleaning and maintenance procedures in cases of accident and where waste is generated;
6. Substance-handling procedures are well-documented and strictly supervised by the site operator.

Intermediates under MEE Order No.12 (China REACH)

Definition of Intermediate

Under China MEE Order No.12, intermediates refer to the chemical substances produced by the previous chemical reaction in the entire chemical reaction process, consumed in the next chemical reaction process to produce other chemical substances or products. Intermediates shall not appear in the produced substances or products, except as impurities.

Categories of Intermediate under MEE Order 12

Intermediates are divided into two categories:

Type

Definition

Non-Isolated Intermediate

Intermediates that do not leave a reaction vessel or device, including those placed in the vessel for temporary storage and used for the next chemical reaction in the same plant area

Others

Intermediates other than Non-isolated intermediates

Data Requirements under China REACH

Type

Tonnage

Data Requirement

Note

Non-isolated intermediate

Exempt from MEE Order 12

Intermediates other than Non-isolated intermediates

<1t/y

Record, no testing requirement

For chemical substances only used as pesticide intermediates, pharmaceutical intermediates, or veterinary drug intermediates, basic data shall be submitted for new chemical registration under MEE Order 12.

1-10t/y

Simplified registration

>10t/y

Regular registration

K-REACH

Under K-REACH, non-isolated intermediates or on-site isolated intermediates which can be technically blocked from leakage or exposure are exempted from registration.

Data Requirements under K-REACH

Type

Registration Requirement

Note

Non-Isolated Intermediate

Need to apply for exemption

Process diagram should be provided

On-site Isolated Intermediate

Need to apply for exemption

If the outflow or leakage can be technically blocked

Transported Isolated Intermediate

Shall be registered

Register with reduced data requirements, equivalent to one-tier down level from normal substance registration, with additional data endpoints.

Note: Imported chemical substances are not considered as intermediates;

Monomers/reactants of polymers cannot be regarded as intermediates;

Authorities may conduct inspections on intermediate exemptions and registrations.

If you have any needs or questions, please contact us at service@cirs-group.com.

3.1: Intermediates - Chemistry LibreTexts

By now you are familiar with a range of reaction types in organic, inorganic, and biochemistry. The purpose of this chapter is to review some tools we use to communicate how reactions happen.

First and foremost, a mechanism is a sequence of intermediates. What happens to the structure of the compound as it undergoes chemical change? Does that change happen all at once, or in stages? If it happens in stages, what kinds of intermediates are involved?

Let’s review different kinds of reactive intermediates that may occur along a reaction pathway. These intermediates are not particularly stable, and so they react further until they form more stable products.

Cations

Cations and anions can be unstable because charge separation costs energy. There are a few cases in which these ions are quite stable -- alkali cations such as Na+ and halide anions such as Cl- come to mind -- but we are interested in exploring the less stable, more temporary ions.

Unlike sodium ions, cations of carbon, nitrogen, or oxygen are reactive. These relatively electronegative atoms are not very stable with a positive charge.

Carbocations, or carbenium ions, with a positive charge on a carbon atom, are generally unstable. Carbon is in the upper right part of the periodic table, so it is not electropositive like sodium. A positive charge on carbon frequently makes a molecule reactive. Nevertheless, this intermediate is frequently encountered during organic reactions.

Are all carbocations equally unstable? No. In general, there are two main factors that stabilize carbocations. The first, and most important, is the degree of substitution. Tertiary carbocations, with positive carbon attached to three other carbons, are fairly stable. Primary carbocations, with positive carbon attached to only one carbon and two hydrogen atoms, are less stable. Secondary carbocations, with positive carbon attached to two carbons and a hydrogen atom, are intermediate in stability. A methyl cation, with positive carbon attached to three hydrogen atoms, is not stable at all.

The reasons for these differences are sometimes explained in terms of hyperconjugation. According to this idea, weak interactions between the unoccupied p orbital on the positive carbon and the occupied sigma bonds on the neighboring carbons stabilize the cation. Imagine these bonds, which are pairs of electrons, overlap a bit with the cation, lowering its overall positive charge. The empty p orbital interacts with the sigma bonds to produce two molecular orbital combinations; one in-phase and lower in energy, and one out-of-phase and higher in energy. Because only two electrons are involved, both drop into the lower energy combination, stabilizing the cation.

The second factor stabilizing positive charge is resonance delocalization. If a double bond is adjacent to a cation, conjugation between filled and empty p orbitals distributes the positive charge across multiple carbons, lowering its effect. Allylic (CH2=CH-CH2+) and benzylic cations (C6H5CH2+) are particularly stable due to this effect.

Other atoms can also be cations. Oxygen and nitrogen cations are common because they donate electrons to neighboring atoms.

Exercise \(\PageIndex{1}\)

Identify the positive atom in each of the following molecules.

Answer

Exercise \(\PageIndex{2}\)

Rank the cations within each group from most stable to least stable.

Answer

Exercise \(\PageIndex{3}\)

Remote groups can provide additional stabilization for a cation. Indicate whether each of the following cations would be more stable or less stable than a benzyl cation, and explain why.

Answer

Other, more subtle factors can influence cation stability. The structure further from the charged atom also affects it. For example, triethylammonium cation is less stable than trimethylammonium cation.

The difference is due to molecule size. Reactions typically occur in a solvent, which helps stabilize the charge by arranging in a favorable way around the cation. The larger the cation, the more solvent molecules are needed for stabilization.

Anions

Negatively charged ions are also common intermediates. They are frequently unstable and are stabilized by a few key factors.

Carbanions, amide ions, and alkoxide ions are examples of anionic intermediates.

Remember, a few factors explain much about anion stability.

Within a periodic table column, anion stability depends on atom polarizability -- the larger and more polarizable the atom, the more stable the anion.

Within a row, more electronegative atoms are more stable as anions.

Exercise \(\PageIndex{4}\)

Rank the anions within each group from most stable to least stable.

Answer

Exercise \(\PageIndex{5}\)

Remote groups can provide additional stabilization for an anion. Indicate whether each of the following anions would be more stable or less stable than a phenoxide anion, and explain why.

Answer

Radicals

Radicals are species with an unpaired electron, making them reactive due to a lack of an octet. Radicals react differently from typical electrophiles. Carbon, nitrogen, and oxygen radicals are common examples.

These radicals do not necessarily have charges because they retain one of the electrons from a missing bond. Radicals often form by bond homolysis, splitting the bond evenly between the atoms. In contrast, bond heterolysis splits it unevenly, with one atom taking both electrons.

Exercise \(\PageIndex{6}\)

Confirm that there is no formal charge in each of the species shown above.

Answer a

Answer b

Answer c

Radical ions are also possible. Radical anions can result from adding an extra electron to a closed-shell compound. Radical cations result from removing an electron from a closed-shell compound.

Radicals are stabilized by the same factors that stabilize a cation, such as resonance delocalization. Carbon radicals are more stable on more-substituted carbons, like cations, but are generally less sensitive to these factors.

Exercise \(\PageIndex{7}\)

Rank the radicals within each group from most stable to least stable.

Answer

Carbenes and Nitrenes

Carbenes and related nitrenes are intermediates in synthetic processes involving electrophilic addition to alkenes. They are two electrons short of an octet but do not have formal charges.

Carbenes can act as both electrophiles and nucleophiles. They have lone pairs for nucleophilicity and an empty orbital for electrophilicity.

Due to their lack of an octet, carbenes and nitrenes can be stabilized through pi-donation.

Exercise \(\PageIndex{8}\)

Arrange the following carbenes in order from most stable to least stable.

Answer

Coordination Complexes

Exercise \(\PageIndex{8}\)

In the following pictures, decide whether the ligand is an anionic or neutral donor. Use the correct symbol (a line or an arrow) to represent the ligand-metal bond. Assign the oxidation state to the metal to satisfy the