Prelog strain
Encyclopedia
In organic chemistry
, transannular strain (also called Prelog strain) is the unfavorable interactions of ring substituents on non-adjacent carbons. These interactions, called transannular interactions, arise from a lack of space in the interior of the ring, which forces substituents into conflict with one another. In medium-sized cycloalkane
s, which have between 8 to 11 carbons constituting the ring, transannular strain is a major source of the overall strain
, to which there is also contribution from large-angle strain
and Pitzer strain. In larger rings, transannular strain drops off until the ring is sufficiently large that it can adopt conformations devoid of any negative interactions.
Transannular strain can also be demonstrated in other cyclo-organic molecules, such as lactone
s, lactam
s, ether
s, cycloalkene
s, and cycloalkynes. These compounds are not without significance, since they are particularly useful in the study of transannular strain. Furthermore, transannular interactions are not relegated to only conflicts between hydrogen atoms, but can also arise from larger, more complicated substituents interacting across a ring.
, like cyclopropane
and cyclobutane
, have significant tension caused by small-angle strain
, but there is no transannular strain. While there is no small-angle strain present in medium-sized rings, there does exist something called large-angle strain
. Large-angle strain is used by rings with more than nine members to relieve some of the distress caused by transannular strain.
As the plot to the left indicates, the relative energies of cycloalkanes increases as the size of the ring increases, with a peak at cyclononane (with nine members in its ring.) At this point, the flexibility of the rings increases with increasing size; this allows for conformations that can significantly mitigate transannular interactions. Some of this strain is certainly due to Pitzer strain and large-angle strain, but a large amount is still caused by transannular strain.
, SN2
, and free radical reaction
s compared to most smaller and normal sized rings. Five membered rings show an exception to this trend. On the other hand some nucleophilic addition
reactions involving addition to a carbonyl group in general show the opposite trend. Smaller and normal rings, with five membered rings being the anomaly, have faster reaction rates while those with transannular strain are slower.
One specific example of a study of rates of reactions for an SN1 reaction is shown on the right. Various sized rings, ranging from four to seventeen members, were used to compare the relative rates and better understand the effect of transannular strain on this reaction. The solvolysis
reaction in acetic acid involved the formation of a carbocation
as the chloride ion leaves the cyclic molecule. This study fits the general trend seen above that rings with transannular strain show increased reactions rates compared to smaller rings in SN1 reactions.
of water elimination is highly influenced by ring size. When water is eliminated from cyclic tertiary alcohol
s by an E1 route
, three major products are formed. The semicyclic isomer (so-called because the double bond is shared by a ring atom and an exocyclic atom) and the (E) endocyclic isomer are expected to predominate; the (Z) endocyclic isomer is not expected to be formed until the ring size is large enough to accommodate the awkward angles of the trans configuration. The exact population of each product relative to the others differs considerably depending upon the size of the ring involved. As the ring size increases, the semicyclic isomer decreases rapidly and the (E) endocyclic isomer increases, but after a certain point , the semicyclic isomer begins to increase again. This can be attributed to transannular strain; this strain is significantly reduced in the (E) endocyclic isomer because it has one less substituent in the ring than the semicyclic isomer.
of intramolecular ring closing using the simple nucleophilicsubstitution reaction of ortho-bromoalkoxyphenoxides. Specifically, they studied the ring closing of 5 to 10 carbon cyclic ethers. They found that as the number of carbons increased, so did the enthalpy
of activation for the reaction. This indicates that strain within the cyclic transition states is higher if there are more carbons in the ring. Since transannular strain is the largest source of strain in rings this size, the larger enthalpies of activation result in much slower cyclizations due to transannular interactions in the cyclic ethers.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
, transannular strain (also called Prelog strain) is the unfavorable interactions of ring substituents on non-adjacent carbons. These interactions, called transannular interactions, arise from a lack of space in the interior of the ring, which forces substituents into conflict with one another. In medium-sized cycloalkane
Cycloalkane
Cycloalkanes are types of alkanes that have one or more rings of carbon atoms in the chemical structure of their molecules. Alkanes are types of organic hydrocarbon compounds that have only single chemical bonds in their chemical structure...
s, which have between 8 to 11 carbons constituting the ring, transannular strain is a major source of the overall strain
Strain (chemistry)
In chemistry, a molecule experiences strain when its chemical structure undergoes some stress which raises its internal energy in comparison to a strain-free reference compound. The internal energy of a molecule consists of all the energy stored within it. A strained molecule has an additional...
, to which there is also contribution from large-angle strain
Angle strain
Angle strain, also called Baeyer strain in cyclic molecules, is the resistance associated with bond angle compression or bond angle expansion. It occurs when bond angles deviate from the ideal bond angles to achieve maximum bond strength in a specific chemical conformation...
and Pitzer strain. In larger rings, transannular strain drops off until the ring is sufficiently large that it can adopt conformations devoid of any negative interactions.
Transannular strain can also be demonstrated in other cyclo-organic molecules, such as lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
s, lactam
Lactam
A lactam is a cyclic amide. Prefixes indicate how many carbon atoms are present in the ring: β-lactam , γ-lactam , δ-lactam...
s, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
s, cycloalkene
Cycloalkene
A cycloalkene or cycloolefin is a type of alkene hydrocarbon which contains a closed ring of carbon atoms, but has no aromatic character. Some cycloalkenes, such as cyclobutene and cyclopentene, can be used as monomers to produce polymer chains. Unless the rings are very large, cycloalkenes are...
s, and cycloalkynes. These compounds are not without significance, since they are particularly useful in the study of transannular strain. Furthermore, transannular interactions are not relegated to only conflicts between hydrogen atoms, but can also arise from larger, more complicated substituents interacting across a ring.
Thermodynamics
By definition, strain implies discomfiture, so it should follow that molecules with large amounts of transannular strain should have higher energies than those without. Cyclohexane, for the most part, is without strain and is therefore quite stable and low in energy. Rings smaller than cyclohexaneCyclohexane
Cyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which being intermediates used in the production of nylon...
, like cyclopropane
Cyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms...
and cyclobutane
Cyclobutane
Cyclobutane is an organic compound with the formula 4. Cyclobutane is a colourless gas and commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes...
, have significant tension caused by small-angle strain
Angle strain
Angle strain, also called Baeyer strain in cyclic molecules, is the resistance associated with bond angle compression or bond angle expansion. It occurs when bond angles deviate from the ideal bond angles to achieve maximum bond strength in a specific chemical conformation...
, but there is no transannular strain. While there is no small-angle strain present in medium-sized rings, there does exist something called large-angle strain
Angle strain
Angle strain, also called Baeyer strain in cyclic molecules, is the resistance associated with bond angle compression or bond angle expansion. It occurs when bond angles deviate from the ideal bond angles to achieve maximum bond strength in a specific chemical conformation...
. Large-angle strain is used by rings with more than nine members to relieve some of the distress caused by transannular strain.
As the plot to the left indicates, the relative energies of cycloalkanes increases as the size of the ring increases, with a peak at cyclononane (with nine members in its ring.) At this point, the flexibility of the rings increases with increasing size; this allows for conformations that can significantly mitigate transannular interactions. Some of this strain is certainly due to Pitzer strain and large-angle strain, but a large amount is still caused by transannular strain.
Kinetics
Rates of reaction can be effected by the size of rings. Essentially each reaction should be studied on a case by case basis but some general trends have been seen. Rings with transannular strain have faster SN1SN1 reaction
The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular...
, SN2
SN2 reaction
The SN2 reaction is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step...
, and free radical reaction
Free radical reaction
A free radical reaction is any chemical reaction involving free radicals. This reaction type is abundant in organic reactions.Two pioneering studies into free radical reactions have been the discovery of the triphenylmethyl radical by Moses Gomberg and the lead-mirror experiment described by...
s compared to most smaller and normal sized rings. Five membered rings show an exception to this trend. On the other hand some nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
reactions involving addition to a carbonyl group in general show the opposite trend. Smaller and normal rings, with five membered rings being the anomaly, have faster reaction rates while those with transannular strain are slower.
| n | k1 h−1 at 25 °C | Relative rate |
|---|---|---|
| 4 | 0.00224 | 0.211 |
| 5 | 1.32 | 124 |
| 6 | 0.0106 | 1.00 |
| 7 | 1.15 | 108 |
| 8 | 3.03 | 286 |
| 9 | 0.465 | 43.9 |
| 10 | 0.188 | 17.7 |
| 11 | 0.127 | 12.0 |
| 13 | 0.0302 | 2.85 |
| 15 | 0.0192 | 1.81 |
| 17 | 0.0201 | 1.90 |
One specific example of a study of rates of reactions for an SN1 reaction is shown on the right. Various sized rings, ranging from four to seventeen members, were used to compare the relative rates and better understand the effect of transannular strain on this reaction. The solvolysis
Solvolysis
Solvolysis is a special type of nucleophilic substitution or elimination where the nucleophile is a solvent molecule. For certain nucleophiles, there are specific terms for the type of solvolysis reaction...
reaction in acetic acid involved the formation of a carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
as the chloride ion leaves the cyclic molecule. This study fits the general trend seen above that rings with transannular strain show increased reactions rates compared to smaller rings in SN1 reactions.
Influence On Regioselectivity
The regioselectivityRegioselectivity
In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where...
of water elimination is highly influenced by ring size. When water is eliminated from cyclic tertiary alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
s by an E1 route
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
, three major products are formed. The semicyclic isomer (so-called because the double bond is shared by a ring atom and an exocyclic atom) and the (E) endocyclic isomer are expected to predominate; the (Z) endocyclic isomer is not expected to be formed until the ring size is large enough to accommodate the awkward angles of the trans configuration. The exact population of each product relative to the others differs considerably depending upon the size of the ring involved. As the ring size increases, the semicyclic isomer decreases rapidly and the (E) endocyclic isomer increases, but after a certain point , the semicyclic isomer begins to increase again. This can be attributed to transannular strain; this strain is significantly reduced in the (E) endocyclic isomer because it has one less substituent in the ring than the semicyclic isomer.
Influence On Medium-Sized Ring Synthesis
One of the effects of transannular strain is the difficulty of synthesizing medium-sized rings. Illuminati et al. have studied the kineticsChemical kinetics
Chemical kinetics, also known as reaction kinetics, is the study of rates of chemical processes. Chemical kinetics includes investigations of how different experimental conditions can influence the speed of a chemical reaction and yield information about the reaction's mechanism and transition...
of intramolecular ring closing using the simple nucleophilicsubstitution reaction of ortho-bromoalkoxyphenoxides. Specifically, they studied the ring closing of 5 to 10 carbon cyclic ethers. They found that as the number of carbons increased, so did the enthalpy
Enthalpy
Enthalpy is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure.Enthalpy is a...
of activation for the reaction. This indicates that strain within the cyclic transition states is higher if there are more carbons in the ring. Since transannular strain is the largest source of strain in rings this size, the larger enthalpies of activation result in much slower cyclizations due to transannular interactions in the cyclic ethers.