Cyclohexylboronic Acid MIDA Ester: Handling & Use Guide

Cyclohexylboronic acid MIDA ester is a bench-stable, crystalline N-methyliminodiacetic acid (MIDA)-protected boronate building block that enables controlled release of a cyclohexylboronic acid equivalent for iterative cross-coupling and complex molecule synthesis.

CAS / SKU

1220699-87-5 (tentative) — SKU C302193; verify CAS in SDS

Molecular Formula

C₁₁H₁₈BNO₄

Molecular Weight

~239.08 g/mol (review_flag: confirm exact MW from CoA)

Physical Form

White to off-white crystalline solid

Key Stability Feature

Air- and moisture-stable solid; MIDA group protects boron from protodeboronation

Deprotection Conditions

Mild aqueous base (e.g., NaOH or NaHCO₃/H₂O) or hydrolysis under physiological-like aqueous conditions releases free boronic acid

Primary Application

Iterative cross-coupling, Suzuki–Miyaura coupling after deprotection, sp³-boron fragment coupling

What Is Cyclohexylboronic Acid MIDA Ester?

Cyclohexylboronic acid MIDA ester (Aladdin SKU C302193) belongs to the family of MIDA (N-methyliminodiacetic acid) boronate esters pioneered in the Burke laboratory as a practical protecting-group strategy for boronic acids. In this compound, the boron atom of cyclohexylboronic acid is covalently sequestered within the tridentate MIDA ligand, forming a stable tetracoordinate boron species. This coordination renders the boron electrophilically attenuated, preventing uncontrolled protodeboronation and enabling the reagent to be stored and manipulated under ordinary benchtop conditions without an inert atmosphere.

The cyclohexyl group provides an unactivated, fully saturated sp³ carbon centre attached directly to boron, making this building block especially valuable when aliphatic boron fragments — which are inherently more sensitive than aryl or vinyl boronate esters — must be incorporated into complex molecular architectures using a sequential, controlled coupling strategy.

Storage and Handling Guidelines

Storage: Store cyclohexylboronic acid MIDA ester as a solid at 2–8 °C in a tightly sealed container, away from moisture and direct light. Although the MIDA ester is significantly more air- and moisture-stable than the parent free boronic acid, prolonged exposure to humidity can lead to slow hydrolysis of the MIDA ester bond. Confirm recommended storage temperature on the product label and CoA upon receipt.

Handling: Standard laboratory PPE (lab coat, nitrile gloves, safety glasses) is sufficient for routine handling. Weighing operations should be performed in a well-ventilated area or a laminar-flow hood to minimise dust inhalation. The compound is not classified as acutely hazardous under typical research quantities; however, always consult the current Safety Data Sheet (SDS) before use.

Dissolution: The compound dissolves readily in polar aprotic solvents such as DMF, DMSO, and THF, and in chlorinated solvents such as DCM. Aqueous solubility is limited under neutral conditions but increases significantly under basic aqueous conditions as MIDA hydrolysis proceeds. Prepare stock solutions fresh where possible to maximise reproducibility.

Deprotection Protocol: Releasing Free Cyclohexylboronic Acid

The MIDA ester protecting group is removed by hydrolysis under mildly basic aqueous conditions. Two commonly employed approaches are described below. Verify these conditions against primary literature before adoption in a new substrate context.

1. Aqueous base deprotection: Dissolve cyclohexylboronic acid MIDA ester in a minimal volume of THF or acetone, then add an aqueous solution of NaOH (typically 1 M, 3–5 equivalents) or saturated aqueous NaHCO₃. Stir at room temperature for 1–4 hours and monitor by TLC or ¹¹B NMR. Upon complete hydrolysis, acidify carefully to near-neutral pH, then extract or use the aqueous phase directly in coupling reactions.
2. In situ two-phase deprotection/coupling: When the liberated boronic acid is to be used immediately in a Suzuki–Miyaura coupling, the MIDA ester can be hydrolysed in situ under the aqueous basic conditions of the coupling reaction itself. This approach simplifies the workflow by avoiding isolation of the free boronic acid, which can undergo protodeboronation if left in solution for extended periods.

Note: Sp³-alkylboronic acids are more prone to protodeboronation than their aryl counterparts. Minimise the time between deprotection and use, and keep the pH controlled.

Applications in Iterative Cross-Coupling and Synthesis

The principal utility of cyclohexylboronic acid MIDA ester lies in its role as a stable, shelf-storable sp³-boron building block for controlled release during iterative cross-coupling strategies. Key application areas include:

• Iterative Suzuki–Miyaura coupling: MIDA boronates participate in iterative cross-coupling sequences where multiple C–C bond-forming steps can be executed in a defined order by selective deprotection and coupling. The cyclohexyl unit introduces a saturated, conformationally constrained carbocyclic motif into target molecules — a structural feature prevalent in bioactive natural products and drug candidates.
• Medicinal chemistry fragment coupling: Cyclohexyl-containing pharmacophores are ubiquitous in drug discovery. Using the MIDA ester format avoids the handling difficulties of free alkylboronic acids and enables efficient library synthesis.
• Total synthesis: Complex natural product synthesis programmes that require sequential installation of multiple boron-containing fragments benefit from the orthogonal stability profile of MIDA boronates relative to other protecting groups.
• Automated synthesis platforms: The air- and moisture-stability of MIDA boronates makes them compatible with automated liquid-handling and solid-phase synthesis workflows, supporting high-throughput chemistry efforts.

Quality, Purity and Ordering Information

Aladdin Scientific supplies cyclohexylboronic acid MIDA ester under SKU C302193. Each lot is accompanied by a Certificate of Analysis (CoA) confirming identity (typically by ¹H NMR and/or HPLC) and purity. Researchers should request the CoA for the specific lot received and verify that purity meets the requirements of their application before use. For sensitive coupling reactions, HPLC purity ≥95% is generally recommended; contact Aladdin technical support if higher-purity material is required.

When placing an order, note the available pack sizes and confirm that quantities are suitable for your planned experiments. Bulk or custom quantities may be available upon request through Aladdin's procurement team. For regulatory or export compliance questions, consult the product SDS and your institutional compliance office.

Frequently asked questions

Can cyclohexylboronic acid MIDA ester be used directly in Suzuki–Miyaura coupling without prior deprotection?

In most cases, deprotection is required first because the MIDA ligand strongly attenuates boron reactivity and prevents transmetalation under typical coupling conditions. However, under aqueous basic conditions used in Suzuki coupling, in situ hydrolysis of the MIDA ester can occur, effectively releasing the active boronic acid during the reaction. This behaviour can be exploited in two-phase or one-pot protocols, but reaction optimisation is recommended to ensure complete conversion.

How should I monitor the deprotection of cyclohexylboronic acid MIDA ester?

¹¹B NMR spectroscopy is the most direct method: the MIDA boronate typically shows a ¹¹B signal in the range of approximately 10–12 ppm (tetracoordinate boron), which shifts downfield to around 28–33 ppm for a tricoordinate free boronic acid upon deprotection. TLC can also be used if appropriate staining conditions (e.g., KMnO₄) are employed, although ¹¹B NMR provides unambiguous structural confirmation. HPLC monitoring is useful for quantitative assessment.

What solvents are recommended for dissolving cyclohexylboronic acid MIDA ester for coupling reactions?

THF, DMF, and DMSO are suitable solvents for dissolving the MIDA ester prior to or during coupling reactions. Acetone/water mixtures are often employed for in situ deprotection steps. Avoid prolonged storage of solutions in protic solvents or in the presence of base, as this promotes hydrolysis and potential protodeboronation of the released boronic acid. Always prepare fresh solutions when possible.

Is cyclohexylboronic acid MIDA ester air-stable enough for routine benchtop use?

Yes. Unlike free alkylboronic acids, which can be sensitive to air and moisture and prone to oxidation or protodeboronation, the MIDA ester form is appreciably more stable and can be weighed and handled briefly on the benchtop without a glovebox. For long-term storage, however, keeping the material tightly sealed at 2–8 °C under dry conditions is recommended to maintain full purity over time.

References

1. Gillis, E. P.; Burke, M. D. A simple and modular strategy for small molecule synthesis: iterative Suzuki–Miyaura coupling of B-protected haloboronic acid building blocks. J. Am. Chem. Soc. 2007, 129, 6716–6717. doi:10.1021/ja0716204
2. Knapp, D. M.; Gillis, E. P.; Burke, M. D. A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates. J. Am. Chem. Soc. 2009, 131, 6961–6963. doi:10.1021/ja901416p
3. Aladdin Scientific Product Page: Cyclohexylboronic acid MIDA ester, SKU C302193. Aladdin Scientific, Shanghai.

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