Synthesis of the Intermediate of a Catalytic Reaction: An NHC-Stabilized, First-Row Transition Metal Complex

Meng Zhou, Lawrence Technological University

Location: Michigan


This advanced synthesis laboratory course engages students in synthesizing, purifying, and characterizing new diamagnetic organometallic complexes of a first-row transition metal. The complex is stabilized by an N-heterocyclic carbene (NHC) spectator ligand. It also bears an actor ligand and, therefore, is potentially a reactive intermediate of a catalytic reaction. In a catalytic reaction, a substrate binds to the metal to form a complex and the substrate or a derivative of the substrate becomes an actor ligand. The synthesis of reactive intermediates is the key to elucidate the mechanism of catalysis. An instructor may choose the first-row transition metal and the actor ligand based on their interests and expertise. The CURE starts from an NHC-ligated complex that does not bear this actor ligand but is otherwise similar. In our CURE, an anion ligand-replacement reaction was used to install the actor ligand by replacing a halide or hydroxide group, but an instructor may choose other approaches to install the actor ligand. The students evaluate their results by standard spectroscopic analyses using UV-vis, FT-IR, and proton NMR (60 MHz and above) analyses. Single-crystal X-ray diffraction may be performed if the instrument is available and the students may practice growing high-quality crystals for X-ray structural determination.

Student Goals

  1. Formulate testable hypotheses and state their predictions. Specifically, the students select an actor ligand to attach to the metal of an NHC-stabilized complex. This complex has never been synthesized and characterized and the actor ligand can potentially undergo metal-mediated bond formation as the key step in a catalytic cycle.
  2. Identify methodological problems and suggest how to troubleshoot them. Specifically, the students determine the reaction conditions in the synthesis, including the precursor to the actor ligand, reagent, temperature, solvent, reaction time, and the concentrations of the reagents.
  3. Analyze data related to the question or problem. Specifically, the students interpret the spectra obtained from UV-vis, FT-IR, and proton NMR (60 MHz and above) analyses. For example, d-d transitions and charge transfer band in UV-vis, strong CN, CO, and CH stretches in FT-IR, and all the NMR chemical shifts (including those of the impurities) should be assigned.

Research Goals

  1. Synthesize and purify a new, diamagnetic, and NHC-ligated complex that has an actor ligand (in contrast to a spectator ligand). The complex is potentially a reactive intermediate in a catalytic reaction. Common diamagnetic first-row transition metal cations include Co(III), Ni(II), and Cu(I), as examples.
  2. Characterize the new complex by proton NMR, UV-vis, and FT-IR analyses.


The CURE is designed for a small class size involving 4 to 10 upper-level students. The CURE spans four weeks with two 3-hour lab sessions and a one-hour lecture each week if the NHC ligand is available from the instructor. However, the author of this CURE instructed the students to perform the gram-scale and multi-step synthesis of the reported NHC ligand as the non-CURE part of the course. The synthesis of the NHC ligand had been tested by the instructor but purification and characterization are untested, thereby providing students an authentic research experience.

Target Audience:Major, Upper Division
CURE Duration:A few class periods

CURE Design

The goal of the CURE is to synthesize a reactive intermediate that enables the mechanistic studies of a catalytic reaction. Under proper guidance, the students design synthetic procedures by themselves without being provided a recipe to follow. However, the students are instructed to modify known and similar synthetic conditions rather than to design from scratch. For example, I instructed my students toemulate and modify the synthetic conditions of a reported procedure in the synthesis of the new but analogous metal complex. In addition, I explicitly stated on multiple occasions that I did not have the "right" answer, did not know what the result would likely be, and no one else had reported the results in the literature. I remind my students to pay attention to and interpret any unexpected results.

This CURE module does not include the synthesis of the reported, known NHC-stabilized metal complex that does not bear the novel actor ligand. In a catalytic reaction, a substrate binds to the metal to form a complex and the substrate or a derivative of the substrate becomes an actor ligand. An instructor may decide whether the students should synthesize the known complex before starting the CURE module or providing the students the known NHC-stabilized metal complex so the students can focus on making the new complex that bears the actor ligand. I instructed my students to perform a multi-step synthesis of the known NHC complex as a non-CURE component of the Advanced Synthesis Lab course. This approach benefited my students for the subsequent CURE module because they were able to learn the synthetic conditions to be implemented in the CURE component for the synthesis of a novel complex bearing an actor ligand.

In the initial trial, two groups proposed two slightly different procedures. They were different only in the concentration of the precursor to the actor ligand. One experiment had one equivalent of the reagent and the other experiment had ten equivalents of the same reagents. The students discussed the merits and drawbacks of each method. After the initial trial, two groups of students analyzed the results. They converged and followed up on the more promising synthetic conditions. Therefore, both groups succeeded in making the desired complex in the second attempt. Promising results may not be obtained in the second trial and, thus, it is important to remind students to focus on analyzing and reporting the results to pass them on to the next group of students. This practice demonstrated the iteration aspect of CURE, which is an essential component of the scientific method. The instructor may decide whether it is beneficial to follow up on the results instead of switching to synthesizing a different NHC-stabilized complex that bears an actor ligand.

Contextual information:

The department chair, tenure committee, and the HHMI CURE cohort at my university learned about CUREs from reviewing my work and internal presentations. The HHMI CURE cohort financially supports my CURE.

Collaboration: I have an external research collaborator who investigates the metal complex for their projects. The sample has been mailed to the collaborator and preliminary results have been obtained. I have also planned for single-crystal X-ray diffraction structural determination with the help of an external collaborator who manages the instrument.

The lab space is also used for sophomore organic labs. I recommend coordinating with colleagues for shared space, including planning for overnight experiments and removing all reagents and equipment by the time the lab is used for a different class. Communication with any other users of the space is the key to continue using the lab space beyond the scheduled class period.

Core Competencies:
Nature of Research:Basic Research, Wet Lab/Bench Research

Tasks that Align Student and Research Goals

Research Goals →
Student Goals ↓
Research Goal 1: Synthesize and purify a new, diamagnetic, and NHC-ligated complex that has an actor ligand (in contrast to a spectator ligand). The complex is potentially a reactive intermediate in a catalytic reaction.
Research Goal 2: Characterize the new complex by proton NMR, UV-vis, and FT-IR spectroscopy

Student Goal 1: Formulate testable hypotheses and state their predictions

1) Identify 3 synthetic methods available in the literature for the synthesis of NHC-ligated first-row transition metal complexes bearing the actor ligand

2) Summarize in a table the 3 synthetic procedures

3) List the structural differences between the reported complex and the new complex to be synthesized

4) Evaluate the chance of success of the 3 synthetic methods to make the new complex

5) Determine the method that is most likely to succeed

6) Briefly described to the class the advantage of the chosen method.

1) Describe regions (aromatic, olefins, alpha C-H, and aliphatic) of the NMR spectrum that you expect to see the signal

2) Describe the multiplicity of the NMR chemical shifts

3) Describe whether a d-d transition can occur

4) If yes, describe whether the transition is symmetry- or spin-allowed, based on the selection rules

5) Describe whether a HOMO-LUMO or ligand-to-metal charge transfer (LMCT) can occur

6) If yes, describe the region in the UV-vis spectrum where HOMO-LUMO or LMCT occurs.

7) Describe regions of the FT-IR spectrum that you expect to see intense stretches

Student Goal 2: Identify methodological problems and suggest how to troubleshoot them.

1) Identify the parts of the original synthetic conditions that require modifications, such as solvent, temperature, reagents, reaction time, and purification. State explicitly when no modification on the conditions is necessary

2) Summarize the modifications of the synthetic conditions

3) Write a paragraph to describe in detail how the reaction should be set up, including the modifications

4) Describe to the class the proposed synthesis and emphasize the modifications on the conditions.

5) Write a short paragraph to discuss an alternative synthetic method, if the original attempt is unsuccessful: no reaction, decomposition, or low yield

6) Describe to the class the possible advantage of this alternative synthetic method

1) Identify potential impurities such as solvent and unreacted starting materials that could be observed in the proton NMR spectrum

2) Assign the NMR chemical shifts that are due to the impurities

3) Identify any missing or unexpected absorptions in the UV-vis and FT-IR spectrum

4) If the results are unclear, describe the purification methods that can lead to a high-quality spectrum

5) Determine whether the planned complex has been successfully synthesized

Student Goal 3: Analyze data related to the question or problem

1) Draw the structure of the new complex that bears the actor ligand and write the molecular formula

2) Calculate the molecular weight of the new complex

3) Draw a balanced chemical equation for the formation of the new NHC-ligated complex.

1) Summarize the expected proton NMR chemical shifts in a table

2) Summarize the experimental proton NMR chemical shifts in the table

3) Summarize the expected FT-IR stretches in another table

4) Summarize the experimental FT-IR stretches in the table

5) Summarize the expected UV-vis stretches in another table

6) Summarize the experimental UV-vis stretches in the table

7) Describe the similarities and differences between the expected and experimental spectra

Instructional Materials

The tested and proven synthesis of the NHC ligands can be found here: Hintermann, L. Beilstein J. Org. Chem. 2007, 3, No. 22. doi:10.1186/1860-5397-3-22. As an example, the synthesis of Cu(I) complexes bearing a variety of actor ligands is available in the following paper. Fortman, G. C.; Slawin, A. M. Z.; Nolan S. P. Organometallics 2010, 29, 3966–3972. DOI: 10.1021/om100733n. The instructor may switch to a different metal, spectator ligand, or actor ligand. The spectator ligand and actor ligand may be a derivative of the ligands reported in this work by Nolan and others. For the relevant work on C-H carboxylation catalysis involving the synthesis of a complex bearing an actor ligand, see the following. Boogaerts, I.I.F., Fortman, G.C., Furst, M.R.L., Cazin, C.S.J. and Nolan, S.P. ACIE 2010, 49, 8674-8677.

The suggested schedule is shown below. To make the course inclusive, the discussion and problem solving on the concepts of organometallic chemistry should be kept at a minimum so that students may focus on understanding the experimental procedures. The instructor may choose to discuss the metal-ligand bonding in NHC complexes regarding coordinate covalent bond and backbonding. The students should be able to distinguish between coordination complexes that have no metal-carbon bonds and organometallic complexes that have metal-carbon bonds. I provide the background on organometallic chemistry involving NHC complexes using the olefin metathesis studies as examples.

Week 1

Lab 1: Discussions on the planning of the experiments
Lecture: Lecture on research and introduction to CURE

Week 2
Lab 1: Synthesis of the proposed NHC-stabilized metal complex bearing an actor ligand. 
Lab 2: Characterizations
Lecture: Two 20-minute group presentations (2 students in a group) and discussions on the relevant progress, concepts, and trouble-shooting

Week 3
Lab 1: Synthesis - 2nd iteration. Optimization or modification of the synthesis is performed.
Lab 2: Characterizations - 2nd iteration. Modification on the conditions or methods for characterizations is performed.
Lecture: Discussions on the relevant progress and concepts

Week 4
Lab 1, Lab 2, and Lecture: additional time for potentially repeating the experiments and working on unexpected results, purification, or follow-up studies.


I have two main forms of assessment for this CURE.

1. A presentation as a formative assessment after the first experiment at the end of week 2.

2. Two lab reports, one for each week. The first report is used as the formative assessment and the second one as the summative assessment. The first lab report is focused on the initial attempt at the synthesis of the proposed intermediate and the second lab report is focused on the optimization or modification of the experiment performed previously. Instructors may include problems based on the synthesis of the NHC-stabilized metal complex in the results and discussion section of the lab report. Instead, students may design their original questions to be solved as part of the lab report.

Instructional Staffing

A professor prepared the reagents and equipment and taught the class. No additional staffing is required.

Author Experience

Meng Zhou, Lawrence Technological University

Elucidating the mechanisms of catalytic reactions is challenging. The synthesis and characterizations of reactive intermediates enable organometallic chemists to directly study the individual reactions in a catalytic cycle. Therefore, the synthesis of reactive intermediates is essential for investigating the catalysis mechanism. This CURE introduces undergraduate students to this established approach for mechanistic studies. Also, the CURE focused on the first-row transition metal complexes that are abundant, inexpensive, and novel.

Advice for Implementation

For a large class, presentations over 5-10 minutes can be used instead of 20 minutes. Presentations could be eliminated entirely as long as the instructor discusses the progress and future directions with the students. Students may choose to work on different actor ligands if the class size is greater than 20 students.

Our group studied an air-stable NHC-ligated complex that was easy to store and handle, though it was synthesized under a nitrogen atmosphere. An instructor may choose to study an air-sensitive complex to teach students air-free techniques.

The instructor should plan extra time for characterizations if only one set of instruments is available. Discussing the spectra with the students takes additional time but is highly recommended since the characterization of a novel complex is the most difficult part of the CURE. The instructor should gauge the progress of the students and adjust the pace when necessary.

It is essential to make available extra reaction vessels and equipment so that the students don't waste their time during class on cleaning glassware or waiting for the instructor to bring in items from the stockroom.


For the synthesis of the new complex, two groups of students tested two sets of reaction conditions that differ from one another only in one variable (one equivalent vs. an excess amount of reagent). The reaction with a 10-fold excess amount of a reagent led to selective product formation. In contrast, the reaction with one equivalent of a reagent led to the decomposition of the starting material (the NHC metal complex without an actor ligand). This initial synthesis was performed on a 100-mg scale. Characterizations of the decomposed material ruled out one possibility (formation of a common mineral) but were insufficient to establish the structure of the decomposed material.

The lesson learned was that one could not easily predict the outcome of the synthesis so it is important for the students to rationalize the potential merits and drawbacks of both conditions. Students should be taught that trial-and-error over several iterations is necessary for discovery. Also, to make rigorous comparisons between two reaction conditions, it is vital to make only one adjustment at a time as opposed to several adjustments at once.

After an initial screening of the reaction conditions, both groups of students used the reaction with a 10-fold excess amount of reagent to reproduce the promising preliminary result and to scale up the synthesis from 300 to 500 mg. Both groups successfully reproduced the synthesis. The next step is single-crystal X-ray diffraction structure determination with the help of an external collaborator who manages the instrument.

A separate 3-hour lab session and a 50-minute lecture session were used exclusively to plan the experiments. I used a list of topics to discuss the synthetic conditions and their merits. 

Many iterations or thought experiments were carried out before a single trial to ensure that the solvent, temperature, scale, amount of reagents, and reaction time were properly chosen. Students "failed" several times in the planning stage by choosing a temperature that was too high, a scale that was too large for an initial trial, a solvent that is not inert or does not dissolve the starting material, a reaction time that is not sufficient, and etc. By "failing" students learned that luck plays a role in research, but the key is to invest time in designing and planning the experiments based on prior attempts in order to succeed in the next iteration.

Using CURE Data

The research data from the CURE module are gathered from the students by the following documents.

1. PowerPoint Slides from the group presentations after the initial attempt on the synthesis to discuss the research findings and a plan to move forward (presentation for 15-20 minutes and Q&A for 5 minutes). Each group consists of 2 students.

2. Lab reports on the progress each week for two weeks (2 lab reports in total), including all the standard sections of a report: introduction, background, data analyses, and conclusions.

The data are then used for the following research activities.

1. The experimental procedure that produced the desired NHC complex bearing the actor ligand is reproduced by the next group of CURE students or undergraduate researchers who are not involved in the CURE course.

2. A CURE module or research project is designed to recrystallize the NHC complex bearing the actor ligand for X-ray structural determination by a collaborator.

3. A research project is planned for studying the reactivity of the NHC complex bearing the actor ligand and the role that the complex plays in a catalytic cycle.

4. A potential publication is envisioned to report the synthesis, characterizations, and reactivity study of this metal complex that could be part of a catalytic cycle.


(1) Hintermann, L. Beilstein J. Org. Chem. 2007, 3, No. 22. doi:10.1186/1860-5397-3-22

(2) Fortman, G. C., Slawin, A. M. Z., Nolan S. P. Organometallics 2010, 29, 3966–3972. DOI: 10.1021/om100733n

(3) Boogaerts, I.I.F., Fortman, G.C., Furst, M.R.L., Cazin, C.S.J. and Nolan, S.P. ACIE 2010, 49, 8674-8677.