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Methanol vs. Acetonitrile: Which Solvent is Better for Chromatography?

Introduction: When it comes to chromatography, one common dilemma that scientists face is choosing between two popular organic solvents: methanol and acetonitrile. While availability often dictates the choice, is there a difference in chromatographic characteristics between these solvents? In this article, we'll explore the unique properties of methanol and acetonitrile and discuss when and why you might prefer one over the other for liquid chromatography.

Understanding Methanol and Acetonitrile: Methanol is known as a polar protic solvent. Its polarity arises from the presence of highly electron-withdrawing atoms, such as oxygen, which creates a slightly negative charge on oxygen and a slightly positive charge on hydrogen. Being a protic solvent, methanol can form hydrogen bonds with other compounds due to the presence of hydrogen directly connected to the electron-withdrawing oxygen atom.

Acetonitrile, on the other hand, is a polar aprotic solvent. Its polarity is attributed to the presence of an electronegative nitrogen atom, creating a slight positive charge on carbon and a slight negative charge on nitrogen. However, it is called aprotic because it lacks hydrogen atoms directly connected to the electronegative atoms, which means it cannot form hydrogen bonds with other compounds.

Five Reasons to Prefer Acetonitrile Over Methanol:

ELS Detection:

Acetonitrile is preferred for ELSD (evaporative light scattering detection) due to its ability to provide a better signal

Low UV Cutoff:

Acetonitrile has a lower UV cutoff than methanol, making it ideal for minimizing noise and increasing sensitivity, especially when detecting compounds at low UV wavelengths like 200 or 210 nanometres.

Back Pressure:

Methanol can increase back pressure when mixed with water, while acetonitrile generates less back pressure, making it suitable for high-flow rate analyses or columns with small diameters.

Dipole-Dipole Interaction:

Acetonitrile's dipole-dipole interactions can result in different selectivity compared to methanol, impacting separation.

Greater Elution Strength:

Acetonitrile has greater elution strength than methanol, which can help reduce runtime.

Advantages of Methanol Over Acetonitrile:


Methanol has a lower elution strength than acetonitrile, which can improve resolution, making it a better choice when resolution is a priority.

Pi-Pi Interaction:

For phenyl columns, using methanol as the mobile phase allows pi-π interactions, enhancing separation.


Methanol has higher solubility than acetonitrile for ionic compounds like acids and bases, which can be advantageous when using high-salt mobile phases.

Hydrogen Bonding:

Methanol, as a protic solvent, can form hydrogen bonds, influencing selectivity differently from acetonitrile.

Environmental Friendliness:

Methanol is considered more environmentally friendly and less toxic than acetonitrile.


Methanol and acetonitrile each offer distinct advantages and disadvantages. Their different interactions with analytes can lead to substantially different selectivities. It is advisable to investigate both solvents separately and, if necessary, use a combination of both in your mobile phase. The choice between methanol and acetonitrile should be guided by the specific requirements of your chromatographic analysis.

In conclusion, there is no one-size-fits-all answer to the question of which solvent is better for chromatography. It's a matter of understanding the unique characteristics of each solvent and choosing the one that best suits your analytical needs. Thank you for reading, and we'd love to hear your thoughts on this topic in the comments below.


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