Structural Elucidation Using HSQC Peaks | October 2020 Solution

problem of the month october 2020 n.w
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Learn how to analyze HSQC peaks for structural elucidation in this October 2020 problem solution. Identify key building blocks from NMR data and piece together the molecule like Lego bricks.

  • NMR
  • Structural Elucidation
  • HSQC Peaks
  • Molecule Building Blocks
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  1. Problem of the Month: October 2020 Solution

  2. If available, in most cases the HSQC is an ideal point to start a structure elucidation. The evaluation of an HSQC is a bit like picking out the right Lego bricks from the big box.

  3. Let's start with three well separated cross peaks. from 1H 7.73 7.43 6.63 ppm As a first step we extract the chemical shifts from the one-dimensional spectra. 1 1 111 1 Integral from 13C 102 102.65 104 106 108 110 112 13C 111.07 116 118 120 122 120.78 124 7.8 7.6 7.4 7.2 7.0 6.8 6.6 ppm 1H

  4. Let's start with three well separated cross peaks. from 1H 7.73 7.43 6.63 ppm According to the chemical shifts the first building blocks contains an sp2 hybridized carbon atom. One hydrogen atom is attached (integral). 1 1 111 1 Integral from 13C 102 102.65 104 106 108 C 102.65 H 110 112 13C 6.63 111.07 116 118 120 122 C 120.78 102.65 H 124 6.63 7.8 7.6 7.4 7.2 7.0 6.8 6.6 ppm 1H

  5. Let's start with three well separated cross peaks. 7.73 7.43 6.63 ppm same procedure for the next building block ... 1 1 111 1 Integral 102 102.65 104 106 108 H 7.43 110 112 13C 111.07 H C 7.43 111.07 C 111.07 116 118 120 122 C 120.78 102.65 H 124 6.63 7.8 7.6 7.4 7.2 7.0 6.8 6.6 ppm 1H

  6. Let's start with three well separated cross peaks. 7.73 7.43 6.63 ppm At the moment there is only a pile of unassigned building blocks. 1 1 111 1 Integral C 102 120.78 102.65 104 106 108 H7.73 H 7.43 110 112 13C 111.07 C 111.07 116 118 C 120 122 120.78 C 120.78 102.65 H7.73 H 124 6.63 7.8 7.6 7.4 7.2 7.0 6.8 6.6 ppm 1H

  7. Now its time to continue with the peaks in the lower third of the HSQC with very similar proton chemical shifts. from 1H 7.27 7.23 7.20 The procedure for the next three building blocks is the same as seen before. 1 1 1 from 13C C 120.78 119.87 120 H7.73 H 7.43 C 122 111.07 122.03 C 124 124.17 102.65 H 6.63 7.30 7.25 7.20

  8. Now its time to continue with the peaks in the lower third of the HSQC with very similar proton chemical shifts. 7.27 7.23 7.20 1 1 1 H 7.20 C 120.78 C 119.87 120 H7.73 H 7.20 119.87 C H 7.43 119.87 C 122 111.07 122.03 C 124 124.17 102.65 H 6.63 7.30 7.25 7.20

  9. Now its time to continue with the peaks in the lower third of the HSQC with very similar proton chemical shifts. 7.27 7.23 7.20 1 1 1 H 7.20 C 120.78 C 119.87 120 H7.73 119.87 H 7.43 C 122.03 C 122 111.07 122.03 H7.27 C 122.03 H7.27 C 124 124.17 102.65 H 6.63 7.30 7.25 7.20

  10. Now its time to continue with the peaks in the lower third of the HSQC with very similar proton chemical shifts. 7.27 7.23 7.20 1 1 1 H 7.20 C 120.78 C 119.87 120 H7.73 119.87 H 7.43 C 122.03 C 122 111.07 122.03 H7.27 H 7.23 H C 7.23 C 124 124.17 124.17 102.65 C 124.17 H 6.63 7.30 7.25 7.20

  11. Now lets connect the building blocks via the TOCSY. Fortunately two well separated spin systems are easily visible 6.6 H 7.20 C 6.8 120.78 C H7.73 7.0 119.87 H 7.2 7.43 C 122.03 1H C 111.07 H7.27 7.4 7.6 H 7.23 C 7.8 102.65 C 124.17 H 6.63 8.0 ppm 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 1H

  12. The spin system at higher field contains one cross peak only. Best to start here. H 7.20 C 120.78 C 6.7 H7.73 119.87 6.8 H 7.43 C 6.9 122.03 C 111.07 H7.27 7.0 7.1 H 7.23 C 7.2 102.65 C 124.17 H 6.63 7.3 7.3 7.2 7.1 7.0 6.9 6.8 6.7

  13. H 7.23 C First we have to search the two building blocks containing the proton signals, which show a neighbourhood within the TOCSY. 102.65 C 124.17 H 6.63 H 7.20 C 120.78 C 6.7 H7.73 119.87 6.8 H 7.43 C 6.9 122.03 C 111.07 H7.27 7.0 7.1 H 7.23 C 7.2 102.65 C 124.17 H 6.63 7.3 7.3 7.2 7.1 7.0 6.9 6.8 6.7

  14. H 7.23 C Having two fragments and one cross peak it s not that difficult to find the connection between the fragments. 102.65 C 124.17 H 6.63 H 7.20 C 120.78 C 6.7 H7.73 119.87 6.8 H 7.43 C 6.9 122.03 C 111.07 H7.27 7.0 7.1 H 7.23 C C 7.2 124.17 102.65 H 7.3 6.63 7.3 7.2 7.1 7.0 6.9 6.8 6.7

  15. H H 7.20 C 7.43 Four proton multiplets belong to the spin system at lower field. 122.03 C C C H7.27 111.07 120.78 First, once again we have to reorder the remaining four fragments according to their proton chemical shifts. 119.87 H7.73 H 7.20 C 120.78 C 7.2 H7.73 119.87 7.3 H 7.43 C 7.4 1H 122.03 C 111.07 H7.27 7.5 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  16. H H 7.20 C 7.43 A good starting point is the multiplet at 7.73 ppm, from which only one cross peak is visible in TOCSY. 122.03 C C C H7.27 111.07 120.78 119.87 H7.73 7.2 7.3 7.4 1H 7.5 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  17. H H H 7.20 7.20 C 7.43 first step 122.03 C C C C H7.27 111.07 120.78 119.87 119.87 H7.73 H 7.2 7.20 C C 120.78 7.3 119.87 H7.73 7.4 1H 7.5 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  18. H H 7.20 C C 7.43 second step 122.03 122.03 C C H7.27 H7.27 111.07 119.87 H 7.2 7.20 C C 120.78 7.3 119.87 H7.73 7.4 1H C 122.03 7.5 H7.27 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  19. H C 7.43 last step 122.03 C H7.27 111.07 H 7.2 7.20 C C 120.78 7.3 H 119.87 H7.73 7.43 7.4 1H C C 111.07 122.03 7.5 H7.27 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  20. H 7.2 7.20 C C 120.78 7.3 H 119.87 H7.73 7.43 7.4 1H C C 111.07 122.03 7.5 H7.27 7.6 H 7.23 C C 7.7 124.17 102.65 H 7.8 6.63 7.8 7.7 7.6 7.5 7.4 7.3 7.2

  21. molecular formula C8H7N a short interim result fragment 1 C4H4 C2H2 fragment 2 unassigned C2HN H 7.20 The two missing quaternary carbons may be extracted from the one dimensional carbon spectrum, since there are just two unassigned peaks remaining. C C 120.78 H 119.87 H7.73 7.43 C C 111.07 122.03 C C H7.27 127.91 135.84 H An the very last missing fragment is 7.23 C C 124.17 102.65 8.1 N H H 124.4 6.63

  22. Now the bricks have to be put together 127.91 C The two quaternary carbon atoms have to be the bridges between the three protoned fragments. H 7.20 There have to be correlations betwen these carbons and the four membered fragment, visible in the HMBC. C C H H 7.43 C C 7.73 H 7.27 C 135.84

  23. Which protons are adjacent to each of the quaternary carbons? 127.91 C 7.43 7.27 7.20 7.73 127 Let us first give the four protons and the associated signals different colors. 128 129 H 130 7.20 C C H H 131 7.43 C C 13C 7.73 H 133 7.27 134 135 136 C 137 ppm 135.84 7.8 7.7 7.6 7.5 7.4 7.3 7.2 1H

  24. Which protons shows a correlation with the carbon signal at 127.91 ppm? 127.91 C 7.43 7.27 7.20 7.73 127 127.91 128 129 H 130 7.20 C C H H 131 7.43 C C 13C 7.73 H 133 7.27 134 135 136 C .. 137 ppm dotted lines indicate a weaker, but clear existing correlation 135.84 7.8 7.7 7.6 7.5 7.4 7.3 7.2 1H

  25. Which protons shows a correlation with the carbon signal at 135.84 ppm? 127.91 C 7.43 7.27 7.20 7.73 127 127.91 128 129 H 130 7.20 C C H H 131 7.43 C C 13C 7.73 H 133 7.27 134 135 135.84 136 C .. 137 ppm dotted lines indicate a weaker, but clear existing correlation 135.84 7.8 7.7 7.6 7.5 7.4 7.3 7.2 1H

  26. 127.91 C Let us now try to connect the quaternary C atoms somehow with the structural fragment C4H4. H 7.20 C C H H 7.43 C C 7.73 We start with the carbon atom with the chemical shift of 127.93 ppm and try a linear structure. There are two possibilities. H 7.27 C 135.84

  27. 127.91 C 127.91 C H C C H H 7.43 C C H H 7.73 7.20 C C H H 7.43 C C 7.73 H H 7.27 C C H H 7.43 C C 7.73 Let us choose now two strong correlations from the HMBC. (The quaternary C-atom is intentionally marked green. H C 127.91

  28. two observed correlations within the first assumed linear structure 127.91 C 127.91 C H C C H H 7.43 C C H H 7.73 7.20 C C H H 7.43 C C 7.73 H H 7.27 C C H H 7.43 C C and two observed correlations within the second assumed linear structure 7.73 H C 127.91

  29. Correlation across 5 bonds! 127.91 C 127.91 C H HMBC correlations over 5 bonds are not excluded, but very rare. C C H H 7.43 C C H H 7.73 7.20 C C H H 7.43 C C 7.73 H H 7.27 C C H H 7.43 C C 7.73 H C Correlation across 5 bonds! 127.91 Both structural fragments are highly unlikely!

  30. 127.91 C H The alternative would be a ring structure. Are all labelled correlations within the range of up to four bonds? 7.20 C C H H 7.43 C C 7.73 H Let us try! 7.27

  31. H H H H 127.91 C C C C CC C CC C C C C 127.91 127.91 H H H H H 7.20 C C H H 7.43 C C 7.73 H H H 7.27 H C H C C CCC H C C CCC H C 127.91 127.91 Alltogether there are four ring structure fragments possible H H

  32. H H 4 3 3 H H 127.91 C C C 2 C CC 3 C CC C C C C 127.91 127.91 2 H H H H 3 H 4 7.20 C C H H 7.43 C C 7.73 H H H 4 3 7.27 3 2 H C H C C CCC H C C CCC H C 127.91 4 127.91 Where are the correlations observed in the HMBC within these partial structures? (2, 3, 4: number of bonds between the coupling partners) H H 3 2 3

  33. H H 4 3 3 H H 127.91 C C C 2 C CC 3 C CC C C C C 127.91 127.91 2 H H H H 3 H 4 7.20 C C H H 7.43 C C 7.73 H H H 4 3 7.27 3 2 H C H C C CCC H C C CCC H C 127.91 4 127.91 None of the four possible ring structures contains a correlation over 5 bonds. H H 3 2 3

  34. H H It is easy to verify that even starting from the quaternary carbon atom with the chemical shift of = 135.84 ppm no correlations over more than 4 bonds can be observed (only one example shown here). H H C C C CC C CC C C C C H H H H H 7.20 C C H H 7.43 C C 7.73 H H H 7.27 3 H C H C C CCC H C C CCC H C 4 135.85 H H C 3 135.84

  35. H H Let us neglect the order of the quaternary carbons for the moment and check, whether the five membered ring might be a reasonable partial structure or not. H H C C C CC C CC C C C C H H H H H 7.20 C C H H 7.43 C C 7.73 H H H 7.27 3 H C H C C CCC H C C CCC H C 4 135.85 H H C 3 135.84

  36. H H H H H C C N C CC C CC which finally results in C C C C C H C H H H H H N H Somewhat earlier we already found these structural fragments Remark: A total of eight permutations are possible regarding the allocation of the quaternary carbon atoms, the stereochemistry of the >NH-group relative to the five membered ring and the assignment of the -CH=CH- fragment. But the constitution is always the same. C C H H

  37. 7.73 ppm H 7.9 Hz H H H C H C CCC H C C N C CC C C 7.9 Hz C 8.1 Hz H H C H 8.1 Hz H H 4468.17 4467.24 4466.30 4465.37 4460.04 4459.09 4458.15 4457.21 4647.03 4646.10 4645.08 4639.15 4637.15 4636.20 4638.21 4644.11 Hz Hz 7.43 ppm A strange unsaturated heterocyclic four membered ring system Of course strange is no scientific argument. Would it be possible to decide about the order of the quaternary carbon atoms? But if we take a six membered ring as a starting point, we find two coupling constants very characteristic for six membered aromatic ring systems.

  38. 7.73 H H C 7.20 C CCC H 7.43 C 127.91 We have to distinguish between two possibilities. 135.84 H 7.27 7.73 H H C 7.20 C CCC H 7.43 C 135.84 127.91 H 7.27

  39. 7.73 H 127.91 C H C 7.20 C CCC H 7.43 C 127.91 We have to distinguish between two possibilities. 135.84 H 7.27 H 7.20 C C H H 7.43 C C 7.73 H 7.73 Four selected correlations from the HMBC might be helpful. H 7.27 H C 7.20 C CCC H 7.43 C 135.84 127.91 H 7.27 C 135.84

  40. 7.73 H 127.91 C H C 7.20 C CCC H 7.43 C 127.91 135.84 H 7.27 H 7.20 C C H H 7.43 C C 7.73 H 7.73 Four selected correlations form the HMBC might be helpful. H 7.27 H C 7.20 C CCC H 7.43 C 135.84 127.91 Solid lines mean intensive, dashed lines mean weak cross peaks. H 7.27 C 135.84

  41. 7.73 H Within the partial structure given above the intense cross peaks correlate with a coupling over three bonds. The weak cross peaks correlate with a coupling over four bonds. 3 127.91 C H 4 C 7.20 C CCC H 7.43 C 127.91 4 135.84 H 7.27 H 3 7.20 C C H H 7.43 As a crude rule of thumb, the intensity of the cross peaks decreases with the number of bonds between the coupling nuclei. C C 7.73 H 7.73 H 7.27 H C 7.20 C CCC H 7.43 C 135.84 Solid lines mean intensive, dashed lines mean weak cross peaks. 127.91 H 7.27 C 135.84 The partial structure seems to be reasonable.

  42. 7.73 H Within the partial structure given below the intense cross peaks correlate with a coupling over four bonds. The weak cross peaks correlate with a coupling over three bonds. 127.91 C H C 7.20 C CCC H 7.43 C 127.91 135.84 H 7.27 H 7.20 C C H H 7.43 As a crude rule of thumb, the intensity of the cross peaks decreases with the number of bonds between the coupling nuclei. C C 7.73 3 H 7.73 H 7.27 H C 7.20 C CCC H 7.43 C 4 135.84 This is not completely impossible, but very unlikely. 4 127.91 H 7.27 Unless you have good reason for doing otherwise, you should go with simplest (most probable) explanation. C 3 135.84

  43. 7.73 H Within the partial structure given below the intense cross peaks correlate with a coupling over four bonds. The weak cross peaks correlate with a coupling over three bonds. 127.91 C H C 7.20 C CCC H 7.43 C We remember 127.91 135.84 Two fragments, already found ( CH = CH and NH ) are still missing. H 7.27 H 7.20 C C H H 7.43 As a crude rule of thumb, the intensity of the cross peaks decreases with the number of bonds between the coupling nuclei. C C 7.73 3 H 7.73 H 7.27 H C 7.20 C CCC H 7.43 C 4 135.84 This is not completely impossible, but very unlikely. 4 127.91 H 7.27 Unless you have good reason for doing otherwise, you should go with simplest (most probable) explanation. C 3 135.84

  44. 7.73 H H C 7.20 C CCC H 7.43 C There are four possibilities to attach this fragment 127.91 135.84 H H 7.27 6.63 7.23 H C C 102.65 124.17 7.73 H H C 7.20 C CCC H 7.43 C 127.91 135.84 H 7.27

  45. The NOESY is one way to see the connectivity. 6.6 6.8 7.0 6.63 7.23 H H 7.2 C C 102.65 124.17 7.73 7.4 H 7.6 H C 7.20 C CCC H 7.43 C 7.8 127.91 8.0 135.84 H 7.27 8.2 8.4 ppm 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6

  46. In the crowded NOESY just one clearly separated peak is very helpful. 6.6 These protons have to be close in space to each other 6.8 7.0 6.63 H H 7.2 C C 7.73 7.4 H 7.6 H C C CCC H C 7.8 127.91 8.0 135.84 H 8.2 8.4 ppm 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6

  47. 6.6 These protons have to be close in space to each other 6.8 7.0 6.63 H H H H 7.2 C C C C 6.63 7.73 7.4 H 7.6 H C C CCC H C 7.8 127.91 8.0 135.84 H 8.2 8.4 ppm 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6

  48. There is then effectively only one possibility for inserting the last missing building block 6.6 8.1 N H 6.8 124.4 7.0 7.2 6.63 H H 7.73 7.4 H C C 7.6 H C C CCC H C 7.8 127.91 8.0 135.84 H 8.2 8.4 Finally this results in ppm 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6

  49. Indole 7.73 6.63 H H 102.65 7.20 120.78 H 119.87 CCC C 127.91 7.23 C 124.17 H C C 135.84 122.03 N H C H 124.4 111.07 H 7.27 7.43 8.09

  50. Let us check the structure with some information not yet used. 122 123 15N First some long-range 15N-1H correlations 124 125 H H 126 ppm H CCC 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 1H C H C 124.4 C C N H C H H 7.43 3978.9 4908.0 4467.4 4452.2 4348.5 4327.6 4811.1 Hz

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