Cahn-Ingold-Prelog Rules: Spiro Compounds

How to Manipulate JSmol Structures

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Fig. 1

1,7-Dioxaspiro[5.5]undecane

An asymmetric carbon of the type C(a,b,c,d), wherein the priorities are a>b>c>d (> = precedes or higher priority), is readily assigned an R/S configuration by Rule 1 of the Cahn-Ingold-Prelog (CIP) protocol. The spiro ketals, Figs. 1 and 2, are chiral, enantiomers of one another. [Rotate the structures to align them as mirror images.] These compounds have only two identical groups proximate to the spiro carbon: oxygen and CH2. Each ring bears an O and CH2 with the O having higher priority over the CH2. The priority order is a>a'>b>b'. It is irrelevant as to which ring is a,b and which one is a',b'. Fig.1 is of the R-configuration. Using your right hand, point your thumb toward b' along the C-b' axis. Your fingers will point from a > a' > b. Fig. 2 will prove to be of the S-configuration. Since a' (O) and b' (CH2) have been switched relative to Fig. 1, the configuration must change.


Fig. 2


Fig. 3

1,6-Dioxaspiro[4.5]decane

Fig. 3 has the same spatial arrangement as Fig. 1 except that the left hand ring has been reduced to 5-membered. The same is true of the relationship between Figs. 2 and 4. Reducing the ring size changes the configuration without altering the bonds attached to the spiro carbon! These spiro ketals are no longer of the a, a', b, b' type but rather an a, b, c, d type. Structure 3b bearing black dots is a digraph that makes it easier to evaluate the priorities of the groups. By successively, and mentally, cutting each of the bonds attached to the spiro carbon in 3a, stretching them out and capping the ends with black dots (duplicate spiro carbons), one can easily assign priorities to each of the chains. In digraph 3b the two chains labeled 1 and 2 are the top priorities (O > CH2) but which one is which? In chain 1 there is an extra CH2 group (the last one before the duplicate group; red arrow) while chain 2 has one fewer CH2 groups, i. e., CH2 > duplicate group. Chain 3 precedes chain 4 because, counting atoms outward from the spiro carbon, the fourth atom in chain 3 is oxygen (blue arrow) while chain 4 has a CH2 group as its fourth atom. That is, O > CH2. The spiro carbon in Fig. 3 is of the S-configuration. In Fig. 4 only the priority 1 and 4 switch positions. The spiro carbon in Fig. 4 is of the R-configuration.

A duplicate atom has the same atomic number as its non-duplicated atom except that the duplicate atom is attached to three "phantom" atoms of atomic number zero. Therefore, a non-duplicate atom > duplicate atom.

Fig. 4



Fig. 5

2,6-Dichlorospiro[3.3]heptane

The 2,6-dichlorospiro[3.3]heptane in Fig. 5 has axial chirality like an allene. [Click on "show carbon #". Orient the structure as in 5a so that C2 is on the right,] The axis passes through C2, C4 and C6. The chirality of the molecule may be designated as 2M but IUPAC rules prefer an R/S assignment. A 3b type digraph may be employed wherein C2 or C6 are each displayed as in the left side of digraph 5b. This procedure may be condensed to the analysis in 5a. Temporary assignments (R0/S0) are made at C2 and C6. With hydrogen as the lowest priority group and chlorine the highest. Pointing the thumb of your right hand to hydrogen, your fingers pass chlorine to C3, which received the designation R0. Likewise, your left hand assigns C1 as S0. The same procedure may be applied to C6. [Note that C2 and C6 are equivalent positions in that rotation of the structure 180o about an axis (z-axis) passing through C4 and perpendicular to the plane of the screen followed by a 90o rotation toward -z, reproduces the same structure.] Because R > S (R0 > S0) (Rule 5) and given the symmetry of the molecule, either R0 (C3 or C5) may be chosen as first and second priorities with the proviso that the third and fourth priorities be paired odd and even in separate rings. In 5a one has C5(1), C3(2),C7(3) and C1(4). The spiro carbon (C4) is of the R-configuration. Click on "show R/S" to confirm.

Click "show carbon #". Digraph 5b illustrates the configuration of C2. Carbon 4 is labelled r0 and s0, each one bears enantiomeric groups. The red dots are duplicate groups of C2; the blue dots of C4. The r0 assignment at C4 follows the priorities C1 > C6(R0) > S0(C6) > C3(duplicate). Similarly, C4 may be labeled s0 in the lower portion of 5b. Because r0 > s0, C2, as is C6, is of the S-configuration.

Spiro carbon C4 in 5c is of the R-configuration as determined by the method in Fig. 1. R0 precedes S0 and the odd and even priorities are derived from their respective rings. Likewise, 6c has a spiro carbon with the S-configuration.

Fig. 6 is the enantiomer of Fig. 5. Compare the two enantiomers.

Fig. 6


Fig. 7

7-Methylspiro[3.5]nonan-2-ol

Figs. 7 and 8 are enantiomeric analogs of Figs. 5 and 6 with two differences. The substituents are not identical, which is not an issue but the rings are of different sizes, a situation that causes some changes in priorities. Click on "show R/S" in Fig. 5. Note that the spiro carbon is of the S-configuration while the spiro carbon in Fig. 5 has an R-configuration. Take note that the R0/S0 assignments are the same in both as are the configurations at the carbons bearing substituents. Why the difference? Ring sizes make a difference! Notice that the priorities are different in 7a compared with 5a. Starting at the spiro carbon C4 and counting out two ring atoms in either ring, the 4-membered ring reaches C2 bearing a hydroxyl group, while the 6-membered ring has a methylene group at either C6 or C8 (Click on "show carbon #"; Rule 1). The cyclobutane ring has the top two priorities (R0 > S0; Rule 5) and the 6-membered ring has the two lowest priorities (R0 > S0). The spiro carbon is of the S-configuration with priorities C1 > C3 > C5 > C9.

In digraph 7b the chains bearing the red dots at C4 are the lowest priority with the remaining three ligands of C4 are R0 > S0 > -CH2CH2-. The configuration of C7 is S; r0( -CH2CH2-) > s0( -CH2CH2-) > -CH3 > H.

Digraph 7c at C4 has the following priorities: -CH2CH(OH)-, R0 > S0 > -CH2-red dot. The priorities at C2 are: OH > r0( -CH2-) > s0 ( -CH2-) > H. Carbon C2 has the S-configuration.

Convince yourself that the enantiomer represented by Fig. 8 has the R, R, R-configuration.

Fig. 8


Fig. 9

1,5,8,11-Tetraoxatetraspiro[2.0.24.0.27.0.210.03]dodecane

Figure 9 has three epoxide rings with the oxygens on the same side of the cyclobutane ring at C3, C7 and C10. The fourth epoxide ring at C4 has the methylene group on the same face of the cyclobutane ring as the oxygens in the other three epoxides. This compound is achiral with a plane of symmetry passing through C4 and C10. This plane will cause the configuration at C3 to be the opposite of C7. The compound is a cyclobutane analog of an inositol, which has six oxygens attached to each carbon atom of a cyclohexane. The assignment of configurations to all the inositols has been described in detail. Nonetheless, the basics will be reviewed here. Each stereocenter bears an oxygen atom and methylene group in the epoxide ring. The oxygen has the highest and the methylene the lowest priority. But how does one determine the second and third priorities? The digraphs for the four centers are on the right. Consider the top digraph for C3 (in red). Using structure 9a as a reference, the cyclobutane carbons to the left of C3 are successively C10 and C7 while to the right they are C4 and C7. The vertical lines below the atom numbers indicate the location of the oxygen atoms, either above or below the plane of the ring, which is the horizontal line. To assign temporary configurations for C3, one moves successively to the left around the ring from C10 --> C7 and, to the right, from C4 --> C7. At each carbon the configuration is determined assuming the target atom, in this example C3, has the second priority. Assignments are made by 1,2 comparisons to find like (lk)/unlike (ul) pairs (Rule 4). If none are found, then the nearest R0 is the second priority atom. Such a carbon will be achirotopic. For C3 S0S0 is a like (lk) pair while S0R0 is unlike (ul). Now lk > ul. Therefore for C3, C10 has second priority while C4 has third priority. Carbon 3 has an R-configuration.

The configuration of C7 can be solved using the digraph but, as mentioned above, C3 and C7 are mirror images of one another. Hence, C7 is S.

The digraphs for stereogenic, achirotopic atoms C4 and C10 display greater symmetry than digraphs for atoms C3 and C7. There is no possibility of a lk/ul comparison. Default is made to the nearest R0 neighbor and Rule 4, r > s (r0 > s0) prevails.

 

 

 



Fig. 10

3,9-Diethylidenespiro[5.5]undecane

Figures 10 and 11 are a pair of spiro enantiomers whose chirality is introduced by the presence of two ethylidene groups into the 6-membered rings at C3 and C9.The only difference between 10a and 11a is the orientation of the ethylidene moiety at C3. Like the dichlorospiroheptane above, these spiro compounds are not treated as examples of axial chirality, i.e., M/P, but rather by the R/S:E/Z protocol. Digraph 10b illustrates the assignment of chirality to the spiro carbon, C6. The double bonds are dissected into their E/Z-geometries as a function of pathway from C6 to C3 and C9. Rule 3 establishes the Z-chains as top priority over the E-chains. It does not matter which Z-chain has top priority as long as the odd-numbered priorities are derived from one ring and the even ones from the other one. Clearly, C6 is of the S-configuration. Conversely, digraph 11b results in an R-configuration for C6. The only difference in 11b is the exchange of the positions of the E- and Z-chains at C3, a result of the change of configuration of the ethylidene group in 11a.

To assign stereochemistry to the double bond at C3, the C9 containing ring is deconstructed to its E- and Z-double bond components (10c). The lower component of C6 is of the r0 configuration. The first priority group is the ethylidene chain owing to its greater substitution pattern than the disubstituted Z-double bond (2nd priority). The E-double bond is the third priority chain; the duplicate chain comes in in fourth place. The upper C6 spiro carbon follows the same rules resulting in an s0 assignment for this center. Rule 4 dictates that r>s (r0>s0) and Rule 3 states that seqcis>seqtrans. Thus, the C3 double bond is of the Z-configuration. In digraph 11c the C6 (r0) carbon is trans to the methyl group and, therefore, of the E-configuration.

 

 

Fig. 11



Fig. 12


1,12-Dioxatrispiro[4.2.2.411.28.25]nonadecane


The trispiro compound 12a is related to an allene in that the two cyclohexane rings function as cumulated double bonds. Consequently, the two tetrahydrofuran rings are in orthogonal planes. In terms of axial chirality, this enantiomer may bevdescribed as having the M-configuration. IUPAC rules prefer R/S descriptors. Digraph 12b illustrates how the assignment of the central spiro carbon, C8, is made. The duplicate groups represented by the colored dots are color coded to match the spiro carbons of 12a. While C8 is maintained intact, C5 and C11 are deconstructed into their respective components. In all four examples the first sphere displays O,C,C,C thereby assigning the top priority to the chain bearing the oxygen. Oxygen in the fourth sphere determines the second priority group while the carbon of C5, also in the fourth sphere, assigns the third priority group. The lowest priority group in all cases is the duplicate chain. Accordingly, auxiliary descriptors R0/S0 are assigned to the four centers. This spiro arrangement is of the C(a,a',b,b') type. Since R>S (R0>S0), either R0 group may be chosen as the top priority group, what is critical is that the odd and even numbered priorities be derived from their respective rings. The configuration of C8 is R.

The assignment of C5 and C11, which are equivalent, is detailed in 12c. The C5 deconstruction follows the priorities set forth in digraph 12b. The priorities for C8 are -chain>Ro>So>duplicate. The configuration at C11, the top two priorities are the chains derived from the tetrahydrofuran ring as has been described in 12b. The remaining two priorities are made by ro>so. Therefore, C11, as well as C5, has the S-configuration.