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CHAPTER 19: NMRgraph: Molecular Correlation Editor

NMRanalyst creates a numerical description of spin systems identified in multidimensional NMR spectra. An intuitive presentation of this information is the NMRgraph plot of identified molecular correlations. For example, the 2D INADEQUATE analysis results are displayed by NMRgraph as the identified molecular carbon skeleton. The AssembleIt module combines structural information from several spectrum types. Resulting structural information is displayed by NMRgraph. Molecular structures in Molfile or SDfile format can be displayed. Carbon and proton chemical shifts can be predicted and used to sort molecular structures by the agreement between observed and predicted shifts. NMRgraph is a structure editor and its interactive features are described in this chapter.

Carbon atoms are represented by their chemical shifts in parts per million (ppm). Heteroatoms show the element symbol potentially followed by the chemical shift. Correlations between atoms are represented as lines or arrows. The correlation labels show for DQF-COSY, HMBC, and INADEQUATE spectra the determined coupling constant in Hertz. For 3D spectra, the correlation label shows the chemical shift in the third dimension, and for all the other spectrum types the correlation label shows the signal integral of the detected spin system.

NMRgraph not only displays determined structures or atom correlations, but also allows modifying displayed structures. The AssembleIt workwindow allows specifying additional chemical knowledge for intermediate structures using the editing capabilities of NMRgraph. See CHAPTER 17: "AssembleIt Workwindow" for details.

19.1 Pull-Down Menus

NMRgraph has pull-down menus for accessing its structural display and editing functionality.

[Open...] allows opening a new file for display.

[Insert...] inserts structures read from an input file at the bottom of the current NMRgraph display.

[Save] saves changes to the current NMRgraph display in its original file format and name.

[Save Structure...] saves the current NMRgraph display in an NMRanalyst structure file. The filename can be specified through a Filebox and a .plot ending is appended if no filename ending is specified. The saved file can be redisplayed to continue the NMRgraph editing.

[Save Molfile...] saves the displayed structures in MDL Molfile format. A .mol ending is appended if no filename ending is specified. Created *.mol files can be imported by programs supporting the Molfile format such as by NMRgraph itself.

[Save SDfile...] saves the displayed structures in MDL SDfile format. A .sdf ending is appended if no filename ending is specified. Created *.sdf files can be imported by programs supporting the SDfile format, including NMRgraph itself.

[Save ChemDraw...] saves the displayed structures in CambridgeSoft Corporation binary ChemDraw eXchange (CDX) format. A .cdx ending is appended if no filename ending is specified. Created *.cdx files from all the supported platforms can be displayed under MS Windows with molecular drawing programs such as ChemOffice and ChemDraw (version 4 or later).1

[Save PostScript...] saves PostScript output of the currently displayed graph for printing or inclusion into other documents. A .ps ending is appended if no filename ending is specified. All the displayed molecular structures are scaled to fit on one page. The created PostScript file cannot be read back into NMRgraph for further modification. If further modifications are desired, use [Save Structure...] above.

[Print] prints the NMRgraph display in PostScript format. The graph is queued to the printer specified in the NMRanalyst Print Settings popup. See SECTION 21.9: "How can I get NMRanalyst printing to work?" for a description on how to print this PostScript file on a non-PostScript printer.

[Exit] exits from NMRgraph. NMRgraph windows started from NMRanalyst are exited when NMRanalyst exits.

The Edit menu items allow editing displayed structures.

The [Undo Change] reverses the last performed modification of the displayed structures. Then [Redo Change] is displayed to reverse the Undo Change modification.

[Clear] clears the current display. A shortcut is to use the keyboard [Shift] + [Delete] key combination.

[Remove Atom Labels] resets all the atom labels to the corresponding atom types.

[Remove Protons] deletes all the protons and their bonds from the NMRgraph display.

[Select All] selects all the displayed structures. See SECTION 19.4: "Mouse Operations" for possible manipulations of selected structures.

[Delete Selection] is activated when at least one atom or correlation is selected. It deletes the selected items. When deleting an atom, its correlations (bonds) are also removed. A shortcut is to use the keyboard [Delete] key.

[Invert Selection] is activated when at least one atom or correlation is selected. It deselects all the selected items and selects all the previously unselected items. For example, to delete all the displayed structures except one, select the structure of interest. Select [Invert Selection] and then [Delete Selection].

[Atom Properties...] is active when a single atom is selected. It starts the Atom Property Editor. Double clicking on an atom with left mouse button also starts its property editor. See SECTION 19.2: "The Atom Property Editor" for details.

[Correlation Properties...] becomes active when a single correlation (bond) is selected. It starts the Correlation Property Editor (described in SECTION 19.3: "The Correlation Property Editor"). Double clicking on a bond also starts its property editor.

Selecting [Preferences...] starts the shown popup. Selected atom and bond label sizes affect display and print sizes. Carbon and proton shift prediction can be based on rules2 or on up to six sphere HOSE codes.3 The order of applying these two methods can be selected. Clicking [OK] saves the current settings and the settings are effective for the current and future NMRgraph applications. [Cancel] closes the popup without applying changes.

The View menu contains items to alter the display of all structures.

NMRgraph's structure layout4 is applied at the start of NMRgraph when the input file does not contain atom coordinates or when selecting the [Redo Layout] menu item. Molecular structures are displayed by the layout algorithm from left to right and top to bottom. Reapplying the layout algorithm to the currently displayed structures is particularly useful after adding or removing structures, atoms, or correlations.

Selecting a percentage from the [Zoom] submenu enlarges or reduces the distance between atoms in the displayed structures accordingly. The size of the displayed atom and correlation labels remain unchanged. (The label size can be changed through [Preferences...] as described above.) Excessive zooming out can lead to overlap of displayed items. Switching the correlation labels off with the [Hide Correlation Labels] menu item can reduce the overlap. Selecting [Restore] from this submenu resets the display to the initial zoom level.5

[Hide Atom Labels / Show Atom Labels] toggles the display of atom labels on or off.

[Hide Correlation Labels / Show Correlation Labels] toggles the display of correlation labels on or off. For DQF-COSY, HMBC, and INADEQUATE, a correlation label shows the determined coupling constant in Hertz. For 3D spectra the correlation label shows the resonance frequency in the third dimension. For all the other spectrum types, a label shows the determined spin system integral.

[Hide Solid Correlations / Show Solid Correlations], [Hide Dotted Correlations / Show Dotted Correlations], [Hide Dashed Correlations / Show Dashed Correlations], and [Hide Dot Dashed Correlations / Show Dot Dashed Correlations] toggle the display of correlations with different line styles on or off. The meanings of the different correlation line styles are described in SECTION 19.3: "The Correlation Property Editor".

[Hide Predicted 1H Shifts / Show Predicted 1H Shifts] is enabled after proton shift prediction is requested from the Prediction menu. It toggles the display of predicted proton shifts on or off.

[Hide 1H Shift Differences / Show 1H Shift Differences] is enabled after proton shift prediction is requested from the Prediction menu. It toggles the display of differences between observed and predicted proton shifts on or off. When this menu item is selected, a carbon atom label is treated as the observed shift for the proton(s) attached to the carbon.

[Hide Predicted 13C Shifts / Show Predicted 13C Shifts] is enabled after carbon shift prediction is requested from the Prediction menu. It toggles the display of predicted carbon shifts on or off.

[Hide 13C Shift Differences / Show 13C Shift Differences] is enabled after carbon shift prediction is requested from the Prediction menu. It toggles the display of differences between observed and predicted carbon shifts on or off. When this menu item is selected, a carbon atom label is taken as the observed carbon shift.

The Structures menu contains items that apply to connected structures.

[Cut] copies the structures with selected atoms and/or correlations, or all the displayed structures in case that no atoms and correlations are selected, to the clipboard and removes the structures from the display. [Copy] is similar to [Cut] except that it does not remove the structures copied. [Paste] adds the structures on the clipboard to the display. These menu items can be used to transfer structures from one NMRgraph application to another.

If no atoms and correlations are selected, [Flip Horizontal] flips all displayed structures horizontally. If any atom or correlation is selected, only the structures containing at least one selected atom or correlation are flipped horizontally. [Flip Vertical] is similar, except that it flips structures vertically. [Rotate 90º] rotates structures clockwise by 90 degrees.

When only one correlation is selected, [Rotate Bond to Horizontal] and [Rotate Bond to Vertical] are enabled. They rotate the structure with the selected correlation so that at the end of the rotation the selected correlation is horizontal or vertical.

NMRgraph's layout algorithm attempts to obtain a natural two-dimensional representation of the molecular structure. But not every structure can be represented without crossing bonds or overlapping atoms. To optimize layout speed, NMRgraph does not explore all possible arrangements. It starts with one atom and positions additional atoms around it. To explore further layouts, select one atom in the structure and the [Layout Structure From Selected Atom] item becomes active. Click it and the structure is rearranged using the selected start atom.

[Sort by 1H Shift Agreement] and [Sort by 13C Shift Agreement] sort the structures by the average difference between predicted and observed proton or carbon shifts, respectively. The structures are repositioned from left to right and then from top to bottom. The structure with best agreement is positioned at the top left corner of the display area.

If no atoms and correlations are selected, [Molecular Formula and Weight...] displays in a popup the molecular formula and weight for each structure. If any atom or correlation is selected, molecular formula and weight are displayed only for the structures containing at least one selected atom or correlation.

[International Chemical Identifier...] displays in a popup the InChI (IUPAC International Chemical Identifier) for each structure if no atoms and correlations are selected, or only for the structures containing at least one selected atom or correlation if any atom or correlation is currently selected.

[1H Shifts] predicts shifts for protons connected to carbon atoms in the currently displayed structures. The predicted proton shifts are shown in square brackets beside each carbon atom label. [1H Shift Agreements...] displays in a popup the average difference between observed and predicted proton shifts for each structure. It takes a carbon atom label as the observed shift for the proton(s) attached to the carbon.

[1H Shift Details...] shows in a popup detailed derivation of predicted proton chemical shifts. If any atoms or bonds are selected in displayed structures, choosing this menu item brings up the shown popup. A user can choose whether to display proton shift prediction details for all structures, or only structures with selected atoms or bonds. Shift prediction details can be lengthy. If numerous structures are currently displayed, it may be more convenient to select a few interesting structures and only display their shift prediction details.

[13C Shifts] predicts carbon shifts for displayed structures. The predicted carbon shifts are shown in parentheses beside each carbon atom label. [13C Shift Agreements...] displays in a popup the average difference between observed and predicted carbon shifts for each structure. It treats a carbon atom label as the observed carbon shift. [13C Shift Details...] displays detailed derivation of predicted carbon chemical shifts in a popup. Similar to [1H Shift Details...], if any atoms or bonds are selected in displayed structures, a user can choose whether to display carbon shift prediction details for all structures, or only structures with selected atoms or bonds.

[1H Shift Agreements...], [1H Shift Details...], [13C Shift Agreements...] and [13C Shift Details...] display shift prediction related text information in a popup. Selected text in this popup can be copied to the clipboard or printed by clicking the right mouse button over the text and choosing [Copy Selection] or [Print Selection]. To select all text in this popup, choose [Select All]. To print all text independent of selection state, choose [Print All].

Selecting [Place Heteroatoms...] from the Prediction menu brings up the shown popup. Select possible heteroatom(s) to be placed into the displayed structure(s) to minimize the difference between predicted and observed carbon chemical shifts. For each selected heteroatom type, the maximum number of heteroatoms to be added can be specified. (Select the heteroatom to enable its input field.)

If the [Add Likely C-C Double Bonds] switch is selected, a single bond between two sp2 carbons is changed to a double bond if each of the two carbons has at least one free valence. A single bond representing a 2D INADEQUATE correlation with a coupling constant between 55 and 150 Hz is also turned into a double bond. Select [Order Structures by 13C Shift Agreement] to sort structures by average difference between predicted and observed carbon shifts. If all heteroatoms are deselected in the popup, clicking [OK] clears previously added heteroatoms from the displayed structure(s). If the [Add Likely C-C Double Bonds] switch is deselected, clicking [OK] restores the original single bonds. [Cancel] closes the popup without applying changes.

NMRgraph can display up to 7000 atoms. If this limit is exceeded during heteroatom placement, the shown popup appears. Clicking [OK] acknowledges the error and closes the popup.

[NMRgraph...] displays the current chapter. [Tutorial...] displays Tutorial II with application examples. NMRgraph is started by the Graphic workwindow. Files to be displayed by NMRgraph can be created by the Report or the AssembleIt workwindows. [Report Workwindow...], [AssembleIt Workwindow...], and [Graphic Workwindow...] display the manual chapters on these workwindows. [About NMRgraph...] shows program version information.

19.2 The Atom Property Editor

When one atom is selected in NMRgraph, the [Atom Properties...] menu item becomes active and starts the shown Atom Property Editor when clicked. The Atom Type and Atom Charge (None, Positive, Negative) can be chosen from the option menus. The Atom Label text field allows editing the atom label. The Number of Free Atom Valences option menu only applies to and hence is visible for carbon or nitrogen atoms. For carbon and nitrogen atoms, the atom label color indicates the number of free valences and the number of bonded hydrogens. The screen coordinates of an atom is also displayed in the editor.

The list at the bottom shows the label of each correlation and the label of each atom correlated to this atom. This connectivity information cannot be edited in this list. Use the Correlation Property Editor described below to edit the correlation labels and the functions described in SECTION 19.4: "Mouse Operations" to change the atom connectivities. [OK] in this editor applies the current settings, and [Cancel] discards all changes.

19.3 The Correlation Property Editor

When one correlation is selected in NMRgraph, the [Correlation Properties...] menu item becomes active and starts the shown Correlation Property Editor when clicked. The Correlation Label text field at the top of the editor allows editing the label. Bond Type (Single, Double, Triple, Up, Down), Line Style (Solid, Dotted, Dashed, Dot Dashed), and Arrow (None, Left, Right, Both) for the correlation can be chosen from the option menus. The current correlation settings are previewed in the text field at the bottom. [OK] in this editor applies the current settings, and [Cancel] discards all changes.

Correlations are drawn in four line styles: solid, dotted, dashed, and dot dashed. When correlations have directions, thy are shown as arrows. AssembleIt represents 2D INADEQUATE or DQF-COSY correlations as solid lines as they represent bonds. An ADEQUATE correlation is represented as a solid arrow as it represents a bond with an observed direction. A HSQC/HMBC derived correlation can be a bond or longer-range correlation and it has a direction. Without assignment ambiguity, the correlation is shown as a dotted, otherwise as a dashed line.

For final molecular structures, the Report workwindow reports detected bonds as solid lines. Bonds for which an ambiguity, phase mismatch, or correlation overlap warning was issued are shown in a dotted line style. In AssembleIt derived carbon skeletons, the dotted linestyle is used to indicate that the shown correlation might not be a direct bond but could contain another atom (such as an oxygen forming an ether group).

19.4 Mouse Operations

Mouse operations are provided to select, move, and add atoms and correlations (bonds). Selections are done using the left mouse button. To select a single item and to deselect all the currently selected items (if any), click on the desired item. To select or deselect items from the current set of selected items, press the [Ctrl] keyboard key while clicking on the desired items. A group of items can be selected by sweeping out an area (dragging) with pressed left mouse button.

To move a single atom, press the right mouse button (middle and right mouse buttons have the same function on a three-button mouse) over the item, drag the mouse with pressed mouse button to the desired location and then release the mouse button. Corresponding correlations follow the moved atom. To move groups of items, select the items first as described above, move one of the selected items, and the other selected items follow accordingly.

To add an atom, hold down the [Ctrl] keyboard key and press the right mouse button over an empty screen area. The new atom is placed at the current cursor location. Double-click on the atom label with the left mouse button to start its Atom Property Editor. From the editor, the atom type, atom label, atom charge, and number of free valences (for carbon and nitrogen only) can be set.

To add a correlation between two existing atoms, hold down the [Ctrl] keyboard key, press the right mouse button over one of the atoms, drag the mouse cursor to the other atom (a red dotted line appears), and release the mouse button and the [Ctrl] key. To set the correlation type, style, and label, double-click on it with the left mouse button and set its properties from the Correlation Property Editor.

To move a correlation between atoms, right click the correlation at the side of the atom to be disconnected, drag the correlation with pushed right mouse button to the new atom (a red dotted line appears intermediately), and release the mouse button. The correlation is moved to the new atom.

19.5 Keyboard Key Operations

Keyboard keys can be used to scroll the NMRgraph display. The following table describes supported key operations:

[Home]
scroll to the top-left display corner
[End]
scroll to the bottom-right display corner
[Page Down]
move display down by one screen
[Page Up]
move display up by one screen
[Ctrl][Page Down]
move display to right by one screen
[Ctrl][Page Up]
move display to left by one screen

19.6 Copyright InChI

Copyright (C) 2005 The International Union of Pure and Applied Chemistry: IUPAC International Chemical Identifier (InChI) (contact: secretariat@iupac.org).

The InChI program is free software; you can redistribute it and/or modify it under the terms of the GNU Lesser General Public License as published by the Free Software Foundation: http://www.opensource.org/licenses/lgpl-license.php.

19.7 Copyright NIH PubChem

ftp://ftp.ncbi.nlm.nih.gov/pubchem/README: -= Fair Use Disclaimer =-:

Databases of molecular data on the NCBI FTP site include such examples as nucleotide sequences (GenBank), protein sequences, macromolecular structures, molecular variation, gene expression, and mapping data. They are designed to provide and encourage access within the scientific community to sources of current and comprehensive information. Therefore, NCBI itself places no restrictions on the use or distribution of the data contained therein. However, some submitters of the original data may claim patent, copyright, or other intellectual property rights in all or a portion of the data they have submitted. NCBI is not in a position to assess the validity of such claims and, therefore, cannot provide comment or unrestricted permission concerning the use, copying, or distribution of the information contained in the molecular databases.

1Free download of MS Windows ChemOffice Net Viewer 2004 from http://chemstore.cambridgesoft.com.

2Fürst, A.; Pretsch, E.; Robien, W. Comprehensive parameter set for the prediction of the 13C-NMR chemical shifts of sp3-hybridized carbon atoms in organic compounds, Anal. Chim. Acta 1990, 233, 213-222.

2 Pretsch, E.; Fürst, A.; Robien, W. Parameter set for the prediction of the 13C-NMR chemical shifts of sp2- and sp-hybridized carbon atoms in organic compounds, Anal. Chim. Acta 1991, 248, 415-428.

2 Schaller, R. B.; Arnold, C.; Pretsch, E. New parameters for predicting 1H NMR chemical shifts of protons attached to carbon atoms, Anal. Chim. Acta 1995, 312, 95-105.

2 Matter, U. E.; Pascual, C.; Pretsch, E.; Pross, A.; Simon, W.; Sternhell, S. Estimation of the chemical shifts of olefinic protons using additive increments-II the compilation of additive increments for 43 functional groups, Tetrahedron 1969, 25, 691-697.

2 Beeby, J.; Sternhell, S.; Hoffmann-Ostenhof, T.; Pretsch, E.; Simon, W. Estimation of the chemical shifts of aromatic protons using additive increments, Anal. Chem. 1973, 45, 1571-1573.

2 Pretsch, E.; Bühlmann, P.; Affolter, C. Structure Determination of Organic Compounds Tables of Spectral Data, 3rd ed., Springer, Berlin, 2000.

3Bremser, W. Expectation ranges of 13C NMR chemical shifts, Magn. Reson. Chem. 1985, 23, 271-275.

3 Steinbeck, C.; Krause, S.; Kuhn, S. NMRShiftDB - constructing a free chemical information system with open-source components, J. Chem. Inf. Comput. Sci. 2003, 43, 1733-1739.

4NMRgraph's layout algorithm is derived from: Bley, K.; Brandt, J.; Dengler, A.; Frank, R.; Ugi, I. J. Chem. Research (S) 1991, 261 & J. Chem. Research (M) 1991, 2601-2689.

5Item positions are stored in screen pixels. When distances among atoms approach the screen resolution, rounding errors might become noticeable when zooming in or out.



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