Logic Puzzle #8: Strong Coupling or Peak Overlap? … Solution

There are two approaches to deciding which scenario best fits the NMR data in the puzzle. A structure elucidator can provide evidence that one scenario is more probable than an other and/or eliminate one scenario on the grounds of insufficient/contradictory data to support it.

For the following 1H NMR spectrum, if the integral of the doublet at 7.42 ppm equates to 1 H atom from a single structure, then the 1H signals at 7.58-7.59 ppm integrating to 2.57 (and assuming all signals are accounted for) relate to overlapping signals (probably a doublet overlapping with a singlet) from a mixture of compounds at varying concentrations.

Another approach, as Adolfo has nicely provided, the magnitude of the strong coupling demonstrated by the signals at 7.58-7.59 ppm indicates a nearby partner on the left side circa 7.70 ppm. Since this appears not to be the case, then by process of elimination, the signals at 7.58-7.59 ppm relate to two overlapping multiplets.

 

Logic Puzzle #8: Strong Coupling or Peak Overlap?

The goal of this puzzle is to distinguish between strong coupling and peak overlap.

For the following 1H NMR spectrum, are the 1H signals at 7.58-7.59 ppm exhibiting strong coupling or are they two overlapping multiplets or both?

 

Logic Puzzle #7: Almost Missed It … Solution 2

With intense solvent signals present on a spectrum, a smaller signal(s) can easily be missed. If 2D NMR data is available, then this extra information can assist in clarifying whether a small signal(s) is obscured by larger signals.

On the 1H-13C HMBC below, the correlations for CDCl3/CHCl3 (due to 1J coupling responses and more) are more intense in comparison to the weak correlation at approximately 6.9 and 77.3 ppm. In this case, the weak correlation is attributed to a quaternary carbon obscured by a set of intense solvent signals.

 

Logic Puzzle #7: Almost Missed It … Solution

‘How many signals are present?’ is such a simple question, and yet, it is a fundamental question to an elucidator. Mistaken a signal or overlook one and the elucidator can run the risk of wasting time and effort.

The 13C [1H] NMR spectrum below shows 3 discernible signals that are attributed to the solvent CDCl3. In addition, one can begin to speculate on weaker signals; there might a fourth signal at ~77.2 ppm (most likely due to residual CHCl3), possibly a fifth at ~77.5 ppm, perhaps a sixth one at ~77.3 ppm and maybe more.

The next step is to examine additional data and verify whether the ‘weak’ signals are real or not. This can include:

1. comparing the weak signals to other structural signals,

2. applying deconvolution/peak fitting to this region,

3. checking 2D NMR data,

4. acquiring data in a different solvent,

5. modifying the acquisition parameters to exclude the solvent or increase S/N, etc.

Logic Puzzle #7: Almost Missed It

When dealing with small sample concentrations of an unknown compound, the NMR region where a large solvent signal appears rarely gets a second look. However, a large NMR signal can easily obscure a small signal. From one elucidator to another, check the solvent signal for any structural signals.

In the 13C [1H] NMR spectrum below, how many signals are present?

If the spectrum is zoomed in, how many signals can be seen now?

Logic Puzzle #6: Dealing with an Extra 13C Peak … Solution

Socrates is known for saying ‘Know thyself’, along the same line, chemists should ‘Know thy instrument’. The example below is one such case.

The 13C NMR [1H] spectrum below exhibits 6 signals. If an unknown compound comprises of 7 carbon atoms, then the following scenarios, or combinations thereof, are possible to account for missing or extra carbon peaks on the spectrum:

1. the 13C peaks are too weak to be clearly evident,

2. the 13C peaks are overlapping (equivalent or coincidental), and/or

3. the 13C peaks may pertain to instrument artefacts, mixtures or impurities.   

The carbon signals are 111 and 118 ppm may account for 2 carbons atoms each. This is based on the relative intensities of the peaks and this is a characteristic prevalent for aromatic carbons. The total count is now at 8 atoms. The higher atom count indicates the presence of an artefact or impurity. The signal at the exact centre of the spectrum, 100 ppm, can be attributed to a quadrature spike – an artefact produced from the instrument. If so, the total count matches the known carbon count.

Although this analysis is not conclusive, it is worth noting that there are several other possible interpretations and only additional data will help substantiate one possibility over the other.

Thank you Adolfo, Maxa and Serge for your comments.

Logic Puzzle #6: Dealing with an Extra 13C Peak

Structure elucidation by NMR involves a deep understanding of various technical aspects behind data acquisition. Being aware of how the instrument works can facilitate the process and reduce the aggravation.

For today’s puzzle, an unknown compound is known to comprise of 7 carbon atoms and exhibit the following 13C NMR spectrum with 1H decoupling. How can the 7 atoms be accounted for in the spectrum below?

Logic Puzzle #3: A Play on the Molecular Formulae

The goal of this puzzle is to determine how the molecular formulae of the intermediates may assist in reasoning out the final product.

In this puzzle, let’s consider the following one-pot synthetic reaction (solvents and additional reactants are not shown). The molecular formula (MF) and the RDBE information are also presented. The chemical reaction illustrates a C11 compound reacting to form a C9 compound and subsequently a C15 compound. The reaction continues and produces an unknown compound with a MF of C24 H23 N1 O2. Based on the given information, how can the MF of the unknown compound be explained?

 The unknown comprises of 24 carbon atoms and so if you add the carbons from the 2^nd intermediate with the carbons from the 3^rd intermediate you arrive at the 24 carbons (9+15=24). This is also evident for the nitrogen atom count (0+1=1) and the RDBE count (5+9=14). This is not the case for the hydrogen (10+15=25) and oxygen (2+1=3) atoms. However, if the loss of a H2O molecule is considered, the unknown can be a combination of the 2^nd and 3^rd intermediate.

Logic Puzzle #3: A Play on the Molecular Formulae

The goal of this puzzle is to determine how the molecular formulae of the intermediates may assist in reasoning out the final product.

In this puzzle, let’s consider the following one-pot synthetic reaction (solvents and additional reactants are not shown). The molecular formula (MF) and the RDBE information are also presented. The chemical reaction illustrates a C11 compound reacting to form a C9 compound and subsequently a C15 compound. The reaction continues and produces an unknown compound with a MF of C24 H23 N1 O2. Based on the given information, how can the MF of the unknown compound be explained?

 The unknown comprises of 24 carbon atoms and so if you add the carbons from the 2^nd intermediate with the carbons from the 3^rd intermediate you arrive at the 24 carbons (9+15=24). This is also evident for the nitrogen atom count (0+1=1) and the RDBE count (5+9=14). This is not the case for the hydrogen (10+15=25) and oxygen (2+1=3) atoms. However, if the loss of a H2O molecule is considered, the unknown can be a combination of the 2^nd and 3^rd intermediate.

Will the correct structure please stand up? … Part 2

Part 1 presented a challenge to determine an experiment to distinguish two very similar products from each other, namely 3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one. The products have identical formula weights and the LC/MS and 1H NMR are too similar to draw any conclusion from.

 

The first step is to determine what is different between the two products and then identify an experiment specifically designed to focus on that difference. The obvious difference between the two products is the position of the oxygen atom—an ester group verse a carbonyl group. An FT-IR experiment, as commented by the reader Felipe A., can be used to sort out the products.

 

Other experiments can include the use of reducing agents, 15N NMR, 1H -13C HMBC, 1D NOE, 1H-1H TOCSY, MS2, etc. Note free water, acids and sample concentration can inhibit the use of some of these experiments.

 

A 13C NMR experiment may appear to be another good choice when trying to identify a carbonyl group. However, the carbonyl is part of a conjugated system and so the 13C chemical shift is expected around 160 ppm, which also happens to be expected for the 13C chemical shift of the O-C=N group on the other product.

Will the correct structure please stand up? … Part 2

Part 1 presented a challenge to determine an experiment to distinguish two very similar products from each other, namely 3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one. The products have identical formula weights and the LC/MS and 1H NMR are too similar to draw any conclusion from.

 

The first step is to determine what is different between the two products and then identify an experiment specifically designed to focus on that difference. The obvious difference between the two products is the position of the oxygen atom—an ester group verse a carbonyl group. An FT-IR experiment, as commented by the reader Felipe A., can be used to sort out the products.

 

Other experiments can include the use of reducing agents, 15N NMR, 1H -13C HMBC, 1D NOE, 1H-1H TOCSY, MS2, etc. Note free water, acids and sample concentration can inhibit the use of some of these experiments.

 

A 13C NMR experiment may appear to be another good choice when trying to identify a carbonyl group. However, the carbonyl is part of a conjugated system and so the 13C chemical shift is expected around 160 ppm, which also happens to be expected for the 13C chemical shift of the O-C=N group on the other product.

Will the correct structure please stand up? … Part 1

Many organic chemists—if not all—check to see if a synthetic reaction is complete via TLC and LC/MS and/or 1H NMR. At the same time, the chemists are using the analytical data to verify that the final product is what they intended on making. In some cases, LC/MS and 1H NMR do not adequately distinguish one potential product from another. It then becomes a question of identifying a technique(s) that can clearly verify the correct product.

The chemical structures shown below (3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one) are two possible products for a synthetic reaction. They have an identical formula weight (FW) and a nearly identical MS and 1H NMR (not shown). What other experiments can a chemist/spectroscopist propose that will assist in identifying the correct structure and thus distinguish the ester from the carbonyl product?

 

I would like to give a special thanks to David C. Adams for proposing the idea.

Will the correct structure please stand up? … Part 1

Many organic chemists—if not all—check to see if a synthetic reaction is complete via TLC and LC/MS and/or 1H NMR. At the same time, the chemists are using the analytical data to verify that the final product is what they intended on making. In some cases, LC/MS and 1H NMR do not adequately distinguish one potential product from another. It then becomes a question of identifying a technique(s) that can clearly verify the correct product.

The chemical structures shown below (3-methyl-5-(pyridin-2-yloxy)pyridine and 5'-methyl-2H-1,3'-bipyridin-2-one) are two possible products for a synthetic reaction. They have an identical formula weight (FW) and a nearly identical MS and 1H NMR (not shown). What other experiments can a chemist/spectroscopist propose that will assist in identifying the correct structure and thus distinguish the ester from the carbonyl product?

 

I would like to give a special thanks to David C. Adams for proposing the idea.

The Stages behind Developing a New Drug in Industry … Part 5

In this final installment of the series on Drug Development, we examine stage 4 and the effort involved in Drug Manufacturing and Process. The 4th stage begins with a large scale production of the new drug, followed by formulation studies and then ending with regulatory reviews of the entire process before the drug can be marketed and sold.

The new drug is batched produced through a scale-up synthesis of the active drug component. At this point, new impurities may surface and thus warrant further investigations into its toxicity effects. Each impurity must be identified, elucidated, re-synthesized and re-tested to ensure all safety precautions were taken.

On the formulation side, further studies are done to ensure that the active drug ingredient and its impurities are combined with an excipient that is compatible and that the dosage upon intake is consistent. In addition, stress tests are performed on the mixture to check for any harmful degradation products that may occur during storage. These studies tend to overlap with the Drug Trials set in stage 3.

For good measures, all the analyses and tests are scrutinized by a team of internal and external experts. They verify that all the correct procedures were applied and the data is consistent with what is intended to be sold.

The Stages behind Developing a New Drug in Industry … Part 5

In this final installment of the series on Drug Development, we examine stage 4 and the effort involved in Drug Manufacturing and Process. The 4th stage begins with a large scale production of the new drug, followed by formulation studies and then ending with regulatory reviews of the entire process before the drug can be marketed and sold.

The new drug is batched produced through a scale-up synthesis of the active drug component. At this point, new impurities may surface and thus warrant further investigations into its toxicity effects. Each impurity must be identified, elucidated, re-synthesized and re-tested to ensure all safety precautions were taken.

On the formulation side, further studies are done to ensure that the active drug ingredient and its impurities are combined with an excipient that is compatible and that the dosage upon intake is consistent. In addition, stress tests are performed on the mixture to check for any harmful degradation products that may occur during storage. These studies tend to overlap with the Drug Trials set in stage 3.

For good measures, all the analyses and tests are scrutinized by a team of internal and external experts. They verify that all the correct procedures were applied and the data is consistent with what is intended to be sold.

The Stages behind Developing a New Drug in Industry … Part 3

The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.

In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.

The Stages behind Developing a New Drug in Industry … Part 3

The main focus surrounding the Drug Design stage (see diagram in Part 1) is to optimize the hit compound(s) and produce analogues that will increase the activity at the target site. Lead optimization is accomplished through minor modifications of the hit compound.

In Drug Design, medicinal chemists aim to build a diverse library of compounds using the hit compound(s) as a blue print for synthesis. On the flip side, an increase in the compound’s toxicity can have it rejected from the library. For this purpose, many pharmaceutical companies apply at this stage an early ADME/Tox (Absorption, Distribution, Metabolism, Elimination/Excretion and Toxicity) screening.

The Stages behind Developing a New Drug in Industry

Many new medicinal drugs produced by pharmaceutical companies follow a very similar pathway starting from the inception of the project idea and ending at the shelves of a pharmacy. Each stage in the development of the drug involves various types of chemists, each lending their expertise at synthesizing, extracting, analyzing and testing the new drug.

The following diagram presents a simplified summary in the development of a medicinal drug. The general stages are 1. Drug Discovery, 2. Drug Design, 3. Drug Trials and 4. Drug Manufacturing/Process.

 

 Please note that this overview may not apply to all cases.

The Stages behind Developing a New Drug in Industry

Many new medicinal drugs produced by pharmaceutical companies follow a very similar pathway starting from the inception of the project idea and ending at the shelves of a pharmacy. Each stage in the development of the drug involves various types of chemists, each lending their expertise at synthesizing, extracting, analyzing and testing the new drug.

The following diagram presents a simplified summary in the development of a medicinal drug. The general stages are 1. Drug Discovery, 2. Drug Design, 3. Drug Trials and 4. Drug Manufacturing/Process.

 

 Please note that this overview may not apply to all cases.

Evaluating a Peak’s Line Shape on a Chromatogram

The line shape of a peak on a chromatogram can offer some insight into the presence of a functional group. However, issues with the instrument are also known to affect the line shape for a peak.

The GC/MS EI+ Total Ion Chromatogram/Current (TIC) below shows five peaks. All of the peaks with the exception of the peak at 1.8 minutes exhibit a symmetrical line shape. The asymmetry of the peak at 1.8 minutes is typical for a structure containing an acidic group (i.e. -COOH).

The peak at 1.8 minutes is 2-ethylhexanoic acid.