HOSE codes

One of the most widely used - and successful representations of the constitution, the topology, of a molecule is the HOSE code (Hierarchical Ordered description of the Substructure Environment) [9]. It is an atom-centered code taking into account... 

The HOSE code can be determined to various degrees of resolution, depending on how many spheres of neighbor atoms are considered. Figure 10.2-1 shows the first, second, and third spheres of neighbors for the carbon atom being considered, for C NMR spectra a HOSE code for each carbon atom in a molecule has to be determined. 

However, one of the most successfiil approaches to systematically encoding substructures for NMR spectrum prediction was introduced quite some time ago by Bremser [9]. He used the so-called HOSE (Hierarchical Organization of Spherical Environments) code to describe structures. As mentioned above, the chemical shift value of a carbon atom is basically influenced by the chemical environment of the atom. The HOSE code describes the environment of an atom in several virtual spheres - see Figure 10.2-1. It uses spherical layers (or levels) around the atom to define the chemical environment. The first layer is defined by all the atoms that are one bond away from the central atom, the second layer includes the atoms within the two-bond distance, and so on. This idea can be described as an atom center fragment (ACF) concept, which has been addressed by several other authors in different approaches [19-21]. 

The spectral signals are assigned to the HOSE codes that represent the corresponding carbon atom. This approach has been used to create algorithms that allow the automatic creation of "substructure-sub-spectrum databases that are now used in systems for predicting chemical structures directly from NMR. 

A useful empirical method for the prediction of chemical shifts and coupling constants relies on the information contained in databases of structures with the corresponding NMR data. Large databases with hundred-thousands of chemical shifts are commercially available and are linked to predictive systems, which basically rely on database searching [35], Protons are internally represented by their structural environments, usually their HOSE codes [9]. When a query structure is submitted, a search is performed to find the protons belonging to similar (overlapping) substructures. These are the protons with the same HOSE codes as the protons in the query molecule. The prediction of the chemical shift is calculated as the average chemical shift of the retrieved protons. 

The similarity of the retrieved protons to those of the query structure, and the distribution of chemical shifts among protons with the same HOSE codes, can be used as measures of prediction reliability. When common substructures cannot be found for a given proton (within a predefined number of bond spheres) interpolations are applied to obtain a prediction proprietary methods are often used in commercial programs. 

Bremser produced tables of these HOSE codes from NMR work that was carried out at BASF in Germany. Most modern carbon prediction routines still use this HOSE code today (albeit slightly modified from the original). Modem software hides all the HOSE code generation in the background so all you do is draw a structure and press the predict button and all the chemical shifts are calculated. 

Despite having been the earliest attempted prediction, proton prediction remains relatively poor. The reasons for this have been alluded to earlier but to summarise the proton chemical shift is often highly dependant on through-space effects (anisotropy) and has a very small distribution. There are four main commercial approaches to proton prediction currently Incremental parameters, HOSE code databases, semi-empirical and cib initio methods. 

Fig. 10.8. Spherical environments surrounding the 23-position of strychnine whose effects would be incorporated into the calculation of the C-23 chemical shift using a HOSE code approach.

Vast tabulations of 13C chemical shift data have been assembled in computer searchable form. These databases form the basis for 13C chemical shift prediction algorithms. For the most part, carbon chemical shifts can be calculated using what is referred to as a Hierarchically Ordered Spherical Environment (HOSE) code approach [28]. To calculate a given carbon s chemical shift, the influence of each successive spherical shell is applied to the starting chemical shift for that carbon to calculate its overall chemical shift. Typically, programs will calculate shifts for 3 or 4 layers, beyond which the effects of most substituents are negligible. The spherical layers surrounding the 23-position of strychnine are shown in Fig. 10.8. 

Advanced Chemistry Development Inc. has built a sizeable proton chemical shift database derived from published spectra (most commonly in CDCI3 solution). Their H NMR predictor programme accesses this database and allows the prediction of chemical shifts. Whilst this software takes account of geometry in calculating scalar couplings, in predicting chemical shifts it essentially treats the structure as planar. It would therefore seem doomed to failure. However, if closely related compounds, run at infinite dilution and in the same solvent, are present in the database, the conformation is implied and the results can be quite accurate. Of course, the results will not be reliable if sub-structures are not well represented within the database and the wide dispersion of errors (dependent on whether a compound is represented or not) can cause serious problems in structure confirmation (later). ACD are currently revising their strict adherence to HOSE codes for sub-structure identification and this will hopefully remove infrequent odd sub-structure selections made currently. 

Dubois et al. developed the Description, Acquisition, Retrieval, Computer-aided design-Elucidation by Progressive Intersection of Ordered Structures (DARC-EPIOS) system for structural elucidation.Their approach was based on C spectra. These were predicted using an additive method, but based on their DARC descriptor of environment, as opposed to the more common HOSE code. The EPIOS system was designed to take account of the diagnostic (or not) nature of the C spectrum with respect to environment, i.e., depending on the specific sub-structures. 

Consider a conventional encoding of chemical structures in C-NMR spectroscopy as introduced with the so-called HOSE code (hierarchically ordered spherical description of environment). Table 7.4 contains some symbol descriptions of this code. 

The molecule given in Figure 7.3 is to be coded by the HOSE code. 

Figure 7.3 Spheres around a carbon atom bold face) as the basis for encoding the structure by the hierarchically ordered spherical description of environment (HOSE) code.

Here the end of the sphere is characterized by the symbol /. Analogously, the third and fourth spheres are obtained and the HOSE code for all ofthe four spheres ofthe molecule in Figure 7.3 is... 

Hie HOSE code represents a linear notation of a chemical structure. Other codes are ROSDAL, SYBYL, and SMILES. The latter code is currently the most popular linear notation. 

Spectrum prediction is a frequently used technique during the structure elucidation process, but a detailed inspection of the results is necessary. Some programs offer the possibility to use different algorithms for spectrum prediction (usually HOSE code technology and neural networks). In such a situation both methods should be applied and the results obtained should be carefully compared [22]. At least in the case of different predictions a further critical evaluation of the result should be an obligation. 

Spectrum estimation using HOSE-code technology... 

Fig. 23.8 Spectrum prediction of podocarpane using HOSE-code technology with stereochemical information [22]. The chemical shift values of the methyl groups located at position 4 are predicted in good agreement with the literature data.

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