Cyclohexane: a Strain-Free Cycloalkane

Organic Chemistry I

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

Organic Chemistry, Structure and Function (7th edition) By P. Vollhardt and N. Schore, Elsevier, 2014 1 CYCLOHEXANE: A STRAIN-FREE CYCLOALKANE

The chair conformation of cyclohexane is strain free A hypothetical planar cyclohexane would suffer from 12 H–H eclipsing interactions and sixfold bond-angle strain (a regular hexagon requires 120o bond angles). One conformation of cyclohexane, obtained by moving carbons 1 and 4 out of planarity in opposite directions, is in fact strain free. This structure is called the chair conformation of cyclohexane (because it resembles a chair), in which eclipsing is completely absent, and the bond angles are very nearly tetrahedral.

o -1 The calculated �H comb of cyclohexane (-944.4 kcal mol ) based on a strain-free (CH2)6 model is very close to the experimentally determined value (-944.5 kcal mol-1). Indeed, the C–C bond strength, �Ho = 88 kcal mol-1 (368 kJ mol-1), is normal.

The molecular model of cyclohexane enables to recognize the conformational stability of the molecule. If we view it along (any) one C–C bond, we can see the staggered arrangement of all substituent groups along it.

Because of its lack of strain, cyclohexane is as inert as a straight-chain alkane. 2 140 CHAPTER 4 Cycloalkanes

140 CHAPTER 4 Cycloalkanes Model Building 4-3 CYCLOHEXANE: A STRAIN-FREE CYCLOALKANE Model Building The cyclohexane4-3 ringCYCLOHEXANE: is one of the most common A STRAIN-FREE and important CYCLOALKANE structural units in organic chemistry. Its substituted derivatives exist in many natural products (see Section 4-7), and an understandingThe cyclohexane of its conformational ring is one of mobility the most is ancommon important and aspect important of organic structural chemistry. units in organic Table 4-2chemistry. reveals that, Its substituted within experimental derivatives error, exist cyclohexane in many natural is unusual products in that(see itSection is free 4-7), and of bond-anglean understanding or eclipsing ofstrain. its conformational Why? mobility is an important aspect of organic chemistry. Table 4-2 reveals that, within experimental error, cyclohexane is unusual in that it is free The chairof bond-angle conformation or eclipsing of strain. cyclohexane Why? is strain free kcal mol؊1 88 ؍ DH؇ A hypotheticalThe chair planar cyclohexaneconformation would sufferof cyclohexane from 12 H–H eclipsing is strain interactions free and kcal mol؊1 sixfold bond-angle strain (a regular hexagon requires 1208 bond angles). However, one 88 ؍ DH؇ conformationA hypothetical of cyclohexane, planar obtained cyclohexane by moving would suffer carbons from 1 and 12 H–H 4 out eclipsing of planarity interactions in and opposite sixfold directions, bond-angle is in fact strain strain (a free regular (Figure hexagon 4-5). requires This structure 1208 bond is called angles). the chairHowever, one conformationconformation of cyclohexane of cyclohexane, (because obtained it resembles by movinga chair), carbons in which 1 eclipsing and 4 out is of com- planarity in pletely absent,opposite and directions, the bond anglesis in fact are strain very nearly free (Figure tetrahedral. 4-5). As This seen structure in Table is 4-2, called the the chair 21 calculatedconformation DH 8comb of cyclohexane of cyclohexane (2944.4 (because kcal mol it resembles) based on a strain-free chair), in (CH which2)6 model eclipsing is is com- very closepletely to the absent,experimentally and the determined bond angles value are ( 2 very944.5 nearly kcal mol tetrahedral.21). Indeed, As the seen C–C in Tablebond 4-2, the strength, calculatedDH 8 5 88 D kcalH 8 mol of2 cyclohexane1 (368 kJ mol (221944.4), is normal kcal mol (Table21) based 3-2). on a strain-free (CH ) model is Chair comb 2 6 Lookingvery at close the molecularto the experimentally model of cyclohexane determined value enables (2 944.5us to kcalrecognize mol2 1the). Indeed, conforma- the C–C bond tional stabilitystrength, of DH the 8 molecule.5 88 kcal If mol we2 1 view (368 it kJ along mol2 (any)1), is normal one C–C (Table bond, 3-2). we can see the Chair staggered arrangementLooking at of the all molecular substituent model groups of along cyclohexane it. We can enables visualize us to this recognize arrangement the conforma- by drawingtional a Newman stability projection of the molecule. of that Ifview we (Figure view it 4-6). along Because (any) one of C–Cits lack bond, of strain, we can see the cyclohexanestaggered is as inertarrangement as a straight-chain of all substituent alkane. groups along it. We can visualize this arrangement by drawing a Newman projection of that view (Figure 4-6). Because of its lack of strain, Cyclohexanecyclohexane also is as has inert several as a straight-chain less stable alkane. conformations Cyclohexane also adopts other, less stable conformations. One is the boat form, in which carbons 1 andCyclohexane 4 are out of the plane also in thehas same several direction less (Figure stable 4-7). The conformations boat is less stable than Boat the chair Cyclohexaneform by 6.9 kcal also mol adopts21. One other, reason less stablefor this conformations. difference is the One eclipsing is the boatof eight form, hydro- in which car- A chair and a boat. Do you see gen atomsbons at the1 and base 4 are of theout boat.of the Another plane in isthe steric same hindrance direction (Section(Figure 4-7). 2-9) The due boat to the is less close stable than them in cyclohexane? Boat the chair form by 6.9 kcal mol21. One reason for this difference is the eclipsing of eight hydro- A chair and a boat. Do you see gen atoms at the base of the boat. Another is steric hindrance (Section 2-9) due to the close them in cyclohexane? H H HH 6 120° H Staggered 5 H H H HHH HHH H H 6 120° H Staggered 4 5 111.4°: 1 H H H H HH 1.536HH Å H H No angle H H strain H H 107.5° 2 3 4 1.121 Å H 111.4°: Staggered 1 H H H H 1.536 Å H No angle H H H H H strain 107.5° AB2 3 1.121 Å H CStaggered Planar cyclohexaneH H Chair Hcyclohexane H 120؇ bond angles; AB(Nearly tetrahedral bond angles; C) 12 eclipsing hydrogens) no eclipsing hydrogens) Planar cyclohexane Chair cyclohexane ,120؇ bondFigure angles; 4-5 Conversion of(Nearly the (A) tetrahedral hypothetical bond planar angles; cyclohexane into the (B) chair conformation) 12 eclipsing hydrogens)showing bond lengths and angles;no eclipsing (C) molecular hydrogens) model. The chair conformation is strain free.

Figure 4-5 Conversion of the (A) hypothetical planar cyclohexane into the (B) chair conformation, showing bond lengthsH and angles; (C) molecular model. The chair conformation is strain free. H H

H H H CH2 H H H H H H CH2 H Figure 4-6 View along one of the H CH2 H C – C bonds in the chair conformation of cyclohexane. Note the H H H H staggeredFigure arrangement 4-6 Viewof all along one of the H CH2 H substituents.C – C bonds in the chair conformation of cyclohexane. Note the H H H staggered arrangement of all substituents. 3 Cyclohexane also has several less stable conformations

Cyclohexane also adopts other, less stable conformations. In boat form, carbons 1 and 4 are out of the plane in the same direction. The boat is less stable than the chair form by 6.9 kcal mol-1. Reason: (a) eclipsing of eight hydrogen atoms at the base of the boat, (b) steric hindrance due to the close proximity of the two inside hydrogens in the boat framework.

The distance between these two hydrogens is only 1.83 Å, small enough to create an energy of repulsion of about 3 kcal mol-1 (13 kJ mol-1). This effect is an example of transannular strain, that is, strain resulting4-3 Cyclohexane:from steric A Strain-Freecrowding Cycloalkaneof two groupsCHAPTERacross 4 a ring141 (trans, Latin, across; anulus, Latin, ring). Steric repulsion: transannular strain

H H HH HH 1 4 6 5 65 H H 23 H H H H 4 1 H H H H H H 2 3 H H Eclipsing Planar cyclohexane Boat cyclohexane 4 Figure 4-7 Conversion of the hypothetical planar cyclohexane into the boat form. In the boat form, the hydrogens on carbons 2, 3, 5, and 6 are eclipsed, thereby giving rise to torsional strain. HHH H The “inside” hydrogens on carbons 1 and 4 interfere with each other sterically in a transannular interaction. The space-" lling size of these two hydrogens, re! ecting the actual size of their respec- tive electron clouds, is depicted in the ball-and-stick model on the right.

proximity of the two inside hydrogens in the boat framework. The distance between these two hydrogens is only 1.83 Å, small enough to create an energy of repulsion of about 3 kcal mol21 (13 kJ mol21). This effect is an example of transannular strain, that is, strain resulting from HHH H steric crowding of two groups across a ring (trans, Latin, across; anulus, Latin, ring). Boat cyclohexane is fairly ! exible. If one of the C–C bonds is twisted relative to another, this form can be somewhat stabilized by partial removal of the transannular interaction. The or or new conformation obtained is called the twist-boat (or skew-boat) conformation of cyclohexane (Figure 4-8). The stabilization relative to the boat form amounts to about 1.4 kcal mol21. Boat As shown in Figure 4-8, two twist-boat forms are possible. They interconvert rapidly, with the boat conformer acting as a transition state (verify this with your model). Thus, the boat cyclohexane is not a normally isolable species, the twist-boat form is present in very small amounts, and the chair form is the major conformer (Figure 4-9). The activation barrier HHH H separating the most stable chair from the boat forms is 10.8 kcal mol21. We shall see that the equilibration depicted in Figure 4-9 has important structural consequences with respect to the positions of substituents on the cyclohexane ring. Twist (skew) boat

How to Draw Chair Cyclohexanes 1. Draw the chair so as to place the C2 and C3 atoms below and slightly to the right of C5 and C6, with apex 1 pointing downward on the left and apex 4 pointing upward on the right. Ideally, bonds straight across the ring (namely, bonds 1–6 and 3–4; 2–3 and 5–6; Animation 1–2 and 4–5) should appear parallel to one another. Top right ANIMATION: Fig. 4-9, cyclohexane potential energy diagram Parallel 6 4 5

2 Parallel 1 3 Bottom left

*An equatorial plane is de" ned as being perpendicular to the axis of rotation of a rotating body and equidistant from its poles, such as the equator of the planet Earth. 4-3 Cyclohexane: A Strain-Free Cycloalkane CHAPTER 4 141

Steric repulsion: transannular strain

H H HH HH 1 4 6 5 65 H H 23 H H H H 4 1 H H H H H H 2 3 H H Eclipsing Planar cyclohexane Boat cyclohexane Figure 4-7 Conversion of the hypothetical planar cyclohexane into the boat form. In the boat Boatform,cyclohexane the hydrogens onis carbonsfairly flexible2, 3, 5, and. 6 are eclipsed, thereby giving rise to torsional strain. HHH H The “inside” hydrogens on carbons 1 and 4 interfere with each other sterically in a transannular interaction. The space-" lling size of these two hydrogens, re! ecting the actual size of their respec- If onetiveof electronthe clouds,C–C isbonds depicted isin thetwisted ball-and-stickrelative model toon theanother, right. this form can be somewhat stabilized by partial removal of the transannular interaction proximity of the two inside hydrogens in the boat framework. The distance between these two (twisthydrogens-boat isor onlyskew 1.83 Å,-boat small enoughconformation to create an energy). The of repulsionstabilization of about 3 relativekcal mol21 to the boat(13 kJform mol21).amounts This effect isto anabout example1 of.4 transannularkcal mol- 1strain,. that is, strain resulting from HHH H steric crowding of two groups across a ring (trans, Latin, across; anulus, Latin, ring). Boat cyclohexane is fairly ! exible. If one of the C–C bonds is twisted relative to another, Two twist-boat forms are possible. They interconvert rapidly, with the this form can be somewhat stabilized by partial removal of the transannular interaction. The or or boatnewconformer conformationacting obtainedas is acalledtransition the twist-boatstate (or. skew-boat) conformation of cyclohexane (Figure 4-8). The stabilization relative to the boat form amounts to about 1.4 kcal mol21. Boat As shown in Figure 4-8, two twist-boat forms are possible. They interconvert rapidly, with the Thus,boatthe conformerboat actingcyclohexane as a transitionis statenot (verifya normally this with yourisolable model). Thus,species, the boatthe twist-cyclohexaneboat form is notis present a normally isolablein very species,small theamounts, twist-boat formand is presentthe chair in veryform small is H the majoramounts,conformer and the chair. form is the major conformer (Figure 4-9). The activation barrier HHH separating the most stable chair from the boat forms is 10.8 kcal mol21. We shall see that the equilibration depicted in Figure 4-9 has important structural consequences with respect The toactivation the positionsbarrier of substituentsseparating on the cyclohexanethe most ring. stable chair from the boat Twist (skew) boat -1 forms is 10.8 kcal mol . Figure 4-8 Twist-boat to twist- Cyclohexane has axial and equatorial hydrogen atoms boat ! ipping of cyclohexane The chair-conformation model of cyclohexane reveals that the molecule has two types of proceeds through the boat conformation. hydrogens. Six carbon–hydrogen bonds are nearly parallel to the principal molecular axis 5 (Figure 4-10) and hence are referred to as axial; the other six are nearly perpendicular to the axis and close to the equatorial plane and are therefore called equatorial.* Being able to draw cyclohexane chair conformations will help you learn the chemistry of six-membered rings. Several rules are useful.

2 Parallel 1 3 Bottom left

*An equatorial plane is de" ned as being perpendicular to the axis of rotation of a rotating body and equidistant from its poles, such as the equator of the planet Earth. 142 CHAPTER 4 Cycloalkanes

Half chair Half chair

Boat

1.4 kcal mol−1 (6.3 kJ mol−1) E 10.8 kcal mol−1 (45.2 kJ mol−1)

Twist-boat Twist-boat 5.5 kcal mol−1 (23.0 kJ mol−1)

Chair Chair

6 Reaction coordinate to conformational interconversion of cyclohexane

Figure 4-9 Potential-energy diagram for the chair – chair interconversion of cyclohexane through the twist-boat and boat forms. In the progression from left to right, the chair is converted into a twist boat (by the twisting of one of the C – C bonds) with an activation barrier of 10.8 kcal mol21. The transition state structure is called a half chair. The twist-boat form " ips (as shown in Fig- ure 4-8) through the boat conformer as a transition state (1.4 kcal mol21 higher in energy) into another twist-boat structure, which relaxes back into the (ring-" ipped) chair cyclohexane. Use your molecular models to visualize these changes.

Molecular axis a a e e a e

e a e e a a Axial Equatorial Axial (a) and equatorial (e) positions positions positions

Figure 4-10 The axial and equatorial positions of hydrogens in the chair form of cyclohexane. The blue shading represents the equatorial plane encompassing the (blue) equatorial hydrogens. The yellow and green shaded areas are located above and below that plane, respectively. 142 CHAPTER 4 Cycloalkanes

Half chair Half chair

Boat

1.4 kcal mol−1 (6.3 kJ mol−1) E 10.8 kcal mol−1 (45.2 kJ mol−1)

Twist-boat Twist-boat 5.5 kcal mol−1 (23.0 kJ mol−1)

Chair Chair

Reaction coordinate to conformational interconversion of cyclohexane

Figure 4-9 Potential-energy diagram for the chair – chair interconversion of cyclohexane through the twist-boat and boat forms. In the progression from left to right, the chair is converted into a Cyclohexanetwisthas boataxial (by theand twistingequatorial of one of thehydrogen C – C bonds)atoms with an activation barrier of 10.8 kcal mol21. The transition state structure is called a half chair. The twist-boat form " ips (as shown in Fig- ure 4-8) through the boat conformer as a transition state (1.4 kcal mol21 higher in energy) into The chair-conformation another twist-boatmodel structure,of cyclohexanewhich relaxes backreveals into the that(ring-" theipped)molecule chair cyclohexane.has two Use types of hydrogens. your molecular models to visualize these changes.

Six carbon–hydrogen bonds are nearly parallel to the principal molecular axis and hence are referred to as axial; the other six are nearly perpendicular to the axis and close to the equatorial plane and are therefore called equatorial.*

Molecular axis a a e e a e

e a e e a a Axial Equatorial Axial (a) and equatorial (e) positions positions positions

Figure 4-10 The axial and equatorial positions of hydrogens in the chair form of cyclohexane. The blue shading represents the equatorial plane encompassing the (blue) equatorial hydrogens. 7 The yellow and green shaded areas are located above and below that plane, respectively. 4-3 Cyclohexane: A Strain-Free Cycloalkane CHAPTER 4 141

Steric repulsion: transannular strain

Figure 4-8 Twist-boat to twist- Cyclohexane has axial and equatorial hydrogen atoms boat ! ipping of cyclohexane The chair-conformation model of cyclohexane reveals that the molecule has two types of proceeds through the boat hydrogens. Six carbon–hydrogen bonds are nearly parallel to the principal molecular axis conformation. (Figure 4-10) and hence are referred to as axial; the other six are nearly perpendicular to the axis and close to the equatorial plane and are therefore called equatorial.* Being able to draw cyclohexane chair conformations will help you learn the chemistry How to Draw Chair Cyclohexanesof six-membered rings. Several rules are useful. How to Draw Chair Cyclohexanes 1. Draw the chair so as to place1.the DrawC 2theand chair soC as3 toatoms place thebelow C2 and C3and atomsslightly below andto slightlythe toright the rightof ofC C55 and C6, with apex 1 pointing downwardand C6, onwith theapex 1left pointingand downwardapex 4onpointing the left and apexupward 4 pointingon upwardthe right on the. right. Ideally, bonds straight across the ring (namely, bonds 1–6 and 3–4; 2–3 and 5–6; Animation Ideally, bonds straight across the ring1–2(namely, and 4–5) shouldbonds appear 1parallel–6 and to one3 another.–4; 2–3 and 5–6; 1–2 and 4– 5) should appear parallel to one another. Top right ANIMATION: Fig. 4-9, cyclohexane potential energy diagram Parallel 6 4 5

2 Parallel 1 3 Bottom4-3 left Cyclohexane: A Strain-Free Cycloalkane CHAPTER 4 143

*An equatorial plane is de" ned as being perpendicular to the axis of rotation of a rotating body and 2. Add all the axial bonds as verticalequidistantlines, from itspointing poles, such asdownward the equator of theat planetC 1Earth., C3, and C5 and upward 2. Add all the axial bonds as vertical lines, pointing downward at C1, C3, and C5 and upward at C2, C4, and C6. In otherat C2,words, C4, andthe C6. Inaxial other words,bonds thealternate axial bonds alternateup-down up-downaround around thethe ring.ring. Vertical line

6 4 5

2 1 Vertical line 3

3. Draw the two equatorial bonds at C1 and C4 at a slight angle from horizontal, pointing 8 upward at C1 and downward at C4, parallel to the bond between C2 and C3 (or between C5 and C6). Parallel

6 Parallel 5 4

2 1 3

4. This rule is the most dif! cult to follow: Add the remaining equatorial bonds at C2, C3, C5, and C6 by aligning them parallel to the C–C bond “once removed,” as shown below. Parallel 6 4 6 4 5 5 Parallel 2 2 Parallel 1 3 Parallel 1 3

Exercise 4-7 (a) Draw Newman projections of the carbon–carbon bonds in cyclopropane, cyclobutane, cyclopentane, and cyclohexane in their most stable conformations. Use the models that you prepared for Exercise 4-1 to assist you and refer to Figure 4-6. What can you say about the (approximate) torsion angles between adjacent C–H bonds in each? (b) Draw the following molecules in their chair conformation. Place the ring atom at the top of the " at stencils shown below so that it appears at the top right of the chair rendition.

O O

Conformational flipping interconverts axial and equatorial hydrogens What happens to the identity of the equatorial and axial hydrogens when we let chair cyclohexane equilibrate with its boat forms? You can follow the progress of conformational interconversion in Figure 4-9 with the help of molecular models. Starting with the chair structure on the left, you simply “" ip” the CH2 group farthest to the left (C1 in the preced- ing section) upward through the equatorial plane to generate the boat conformers. If you now return the molecule to the chair form not by a reversal of the movement but by the 4-3 Cyclohexane: A Strain-Free Cycloalkane CHAPTER 4 143

4-3 Cyclohexane: A Strain-Free Cycloalkane CHAPTER 4 143 2. Add all the axial bonds as vertical lines, pointing downward at C1, C3, and C5 and upward at C2, C4, and C6. In other words, the axial bonds alternate up-down around the ring. 2. Add all the axial bonds as vertical lines, pointing downward at C1, C3, and C5 and upward Vertical line at C2, C4, and C6. In other words, the axial bonds alternate up-down around the ring.

6 Vertical line 4 5

6 4 5 2 1 Vertical line 3 2 1 Vertical line 3. Draw the two equatorial3. Drawbonds the twoat equatorialC1 and3 bondsC4 at atC1 aandslight C4 at a angleslight anglefrom fromhorizontal, horizontal, pointingpointing upward at C1 and downwardupwardat Cat 4C1, paralleland downwardto theat C4,bond parallelbetween to the bondC between2 and C2C and3 (or C3 (orbetween between C5 3. Draw the two equatorialC5 and bonds C6). at C1 and C4 at a slight angle from horizontal, pointing and C6). upward at C1 and downward at C4, parallel to the bond between C2 andParallel C3 (or between C5 and C6).

Parallel6 Parallel 5 4

6 Parallel 5 42 1 3

2 4. This rule is the1 most dif! cult to 3follow: Add the remaining equatorial bonds at C2, C3, C5, 4. This rule is the most difficultand C6 toby aligningfollow :themAdd parallelthe remainingto the C–C bondequatorial “once removed,”bonds as shownat Cbelow.2, C3, C5, and C6 by 4.aligning This rulethem is the mostparallel dif! cultto tothe follow:C– AddC bond the remaining“onceParallel equatorialremoved,” bondsas at C2,shown C3, C5,below . 6 4 6 4 and C6 by aligning them parallel to the C–C5 bond “once removed,” as shown below. 5 Parallel Parallel 6 6 42 24 5 5 Parallel 1 3 Parallel 1 3 Parallel 2 2 Parallel 1 3 Parallel 1 3

Exercise 4-7 9 (a) Draw Newman projections of the carbon–carbon bonds in cyclopropane, cyclobutane, Exercise 4-7 cyclopentane, and cyclohexane in their most stable conformations. Use the models that you prepared for Exercise 4-1 to assist you and refer to Figure 4-6. What can you say about the (a) Draw Newman (approximate) projections of torsion the carbon–carbon angles between bonds adjacent in cyclopropane,C–H bonds in cyclobutane,each? (b) Draw the following cyclopentane, and cyclohexanemolecules in in their their chair most conformation. stable conformations. Place the Use ring the atom models at the that top you of the " at stencils prepared for Exerciseshown 4-1 tobelow assist so you that and it appears refer to at Figure the top 4-6. right What of thecan chair you sayrendition. about the (approximate) torsion angles between adjacent C–H bonds in each? (b) Draw the following molecules in their chair conformation. Place the ring atom O at the top ofO the " at stencils shown below so that it appears at the top right of the chair rendition. NH O O

NH Conformational flipping interconverts axial and equatorial hydrogens What happens to the identity of the equatorial and axial hydrogens when we let chair Conformationalcyclohexane flipping equilibrate interconverts with its boat forms? axial You and can follow the progress of conformational equatorial hydrogensinterconversion in Figure 4-9 with the help of molecular models. Starting with the chair What happens to structure the identity on the of left, the you equatorial simply and“" ip” axial the CH hydrogens2 group farthest when weto the let left chair (C1 in the preced- cyclohexane equilibrateing section) with its upward boat forms? through You the can equatorial follow the plane progress to generate of conformational the boat conformers. If you interconversion in now Figure return 4-9 the with molecule the help to of the molecular chair form models. not by Starting a reversal with of the the movement chair but by the structure on the left, you simply “" ip” the CH2 group farthest to the left (C1 in the preced- ing section) upward through the equatorial plane to generate the boat conformers. If you now return the molecule to the chair form not by a reversal of the movement but by the Conformational flipping interconverts axial and equatorial hydrogens

What happens to the identity of the equatorial and axial hydrogens when chair cyclohexane equilibrate with its boat forms?

Cyclohexane undergoes chair–chair interconversions (“flipping”) in which all axial hydrogens in one chair become equatorial in the other and vice versa. The activation energy for this process is 10.8 kcal mol-1. This value is so low at room temperature, the two chair forms interconvert rapidly (approximately 200,000 times per second). 144 CHAPTER 4 Cycloalkanes The two chair forms are identical. Axial

Equatorial Equatorial

Ring flip

−1 Axial Ea = 10.8 kcal mol

Figure 4-11 Chair – chair interconversion (“ring ! ipping”) in cyclohexane. In the process, which 10 is rapid at room temperature, a (green) carbon at one end of the molecule moves up while its counterpart (also green) at the other end moves down. All groups originally in axial positions (red in the structure at the left) become equatorial, and those that start in equatorial positions (blue) become axial.

equally probable alternative—namely, the ! ipping downward of the opposite CH2 group (C4)—the original sets of axial and equatorial positions have traded places. In other words, Animation cyclohexane undergoes chair–chair interconversions (“! ipping”) in which all axial hydrogens in one chair become equatorial in the other and vice versa (Figure 4-11). The activa- ANIMATION: Fig. 4-11, cyclohexane ring ﬂ ip tion energy for this process is 10.8 kcal mol21 (Figure 4-9). As suggested in Sections 2-8 and 2-9, this value is so low that, at room temperature, the two chair forms interconvert rapidly (approximately 200,000 times per second). The two chair forms shown in Figure 4-11 are, except for the color coding, identical. We can lift this degeneracy by introducing substituents: Now the chair with a substituent in the equatorial position is different from its conformer, in which the substituent is axial. The preference for one orientation over the other strongly affects the stereochemistry and reactivity of cyclohexanes. We will describe the consequences of such substitution in the next section. In Summary The discrepancy between calculated and measured heats of combustion in the cycloalkanes can be largely attributed to three forms of strain: bond angle (deformation of tetrahedral carbon), eclipsing (torsional), and transannular (across the ring). Because of strain, the small cycloalkanes are chemically reactive, undergoing ring-opening reactions. Cyclohexane is strain free. It has a lowest-energy chair as well as additional higher-energy conformations, particularly the boat and twist-boat structures. Chair–chair interconversion is rapid at room temperature; it is a process in which equatorial and axial hydrogen atoms interchange their positions.

4-4 SUBSTITUTED CYCLOHEXANES

We can now apply our knowledge of conformational analysis to substituted cyclohexanes. Let us look at the simplest alkylcyclohexane, methylcyclohexane. Axial and equatorial methylcyclohexanes are not equivalent Combustion of hydrocarbons (Sections 3-11 and 4-2) in energy typically starts with the In methylcyclohexane, the methyl group occupies either an equatorial or an axial position. abstraction of an H atom by Are the two forms equivalent? Clearly not. In the equatorial conformer, the methyl group O2. Methylcyclohexane burns extends into space away from the remainder of the molecule. In contrast, in the axial con- particularly well, because of former, the methyl substituent is close to the other two axial hydrogens on the same side of the presence of the relatively the molecule. The distance to these hydrogens is small enough (about 2.7 Å) to result in weak tertiary C–H bond steric repulsion, another example of transannular strain. Because this effect is due to axial (Section 3-1), and is therefore substituents on carbon atoms that have a 1,3-relation (in the drawing, 1,3 and 1,39), it is called used as an additive to jet fuel. a 1,3-diaxial interaction. This interaction is the same as that resulting in the gauche confor- SUBSTITUTED CYCLOHEXANES

Axial and equatorial substituents are not equivalent in energy

The chair with a substituent in the equatorial position is different from its conformer, in which the substituent is axial. The preference for one orientation over the other strongly affects the stereochemistry and reactivity of cyclohexanes.

In methylcyclohexane, the methyl group occupies either an equatorial or an axial position. In the equatorial conformer, the methyl group extends into space away from the remainder of the molecule. In contrast, in the axial conformer, the methyl substituent is close to the other two axial hydrogens on the same side of the molecule.

The distance to these hydrogens is small enough (about 2.7 Å) to result in steric repulsion, another example of transannular strain.

11 Because this effect is due to axial substituents on carbon atoms that have a 1,3-relation (1,3 and 1,3’), it is called a 1,3-diaxial interaction.

This interaction is the same as that resulting in the gauche conformation of butane. Thus, the axial methyl group is gauche to two of the ring carbons (C3 and C3’); when it is in the equatorial position, it is anti to the same nuclei.

The two forms of chair are in equilibrium. The equatorial4-4 Substitutedconformer Cyclohexanesis more stableCHAPTERby 1. 74 kcal 145 mol-1 (7.1 kJ mol-1) and with a ratio of 95:5 at 25 oC. The activation energy for chair–chair interconversion ismationsimilar of butaneto that (Sectionin 2-9).cyclohexane Thus, the axial methylitself group[about is gauche11 tokcal two ofmol the -ring1 ( 46 kJ mol-1)], and equilibrium betweencarbonsthe (C3two and conformersC39); when it is inis therapid equatorialat position,room ittemperature is anti to the same. nuclei. H H H H H H H 2′ 3 H H C H H ′ H H Model Building Axial methyl H H H H H H 2 H 3 H H 1 H H H C Equatorial methyl H H H

No 1,3-Diaxial interactions 1,3-Diaxial interactions More stable Less stable 12 Ratio = 95:5

Exercise 4-8 Calculate K for equatorial versus axial methylcyclohexane from the DG8 value of 1.7 kcal mol21. Use the expression DG8 (in kcal mol21) 5 21.36 log K. (Hint: If log K 5 x, then K 5 10x.) How well does your result agree with the 95:5 conformer ratio stated in the text?

Equatorial Y Axial Y

1,3-Diaxial interactions H H H H H H H Y H H Y H H H H H

Eye

1,3-Diaxial interactions

Figure 4-12 A Newman projec- H H H Y tion of a substituted cyclohexane. The conformation with an axial Y H CH2 Y H CH2 H substituent is less stable because of 1,3-diaxial interactions, only one of which is shown (see the “eye” H CH H H CH H for the choice of the Newman 2 2 projection). Axial Y is gauche to H H H H the ring bonds shown in green; Anti to Y Gauche to Y equatorial Y is anti. 4-4 Substituted Cyclohexanes CHAPTER 4 145

mation of butane (Section 2-9). Thus, the axial methyl group is gauche to two of the ring carbons (C3 and C39); when it is in the equatorial position, it is anti to the same nuclei.

H H H H H H H 2′ 3 H H C H H ′ H H Model Building Axial methyl H H H H H H 2 H 3 H H 1 H H H C Equatorial methyl H H H

No 1,3-Diaxial interactions 1,3-Diaxial interactions More stable Less stable Ratio = 95:5

The two forms of chair methylcyclohexane are in equilibrium. The equatorial conformer is more stable by 1.7 kcal mol21 (7.1 kJ mol21) and is favored by a ratio of 95:5 at 258C (Section 2-1). The activation energy for chair–chair interconversion is similar to that in cyclohexane itself [about 11 kcal mol21 (46 kJ mol21)], and equilibrium between the two conformers is established rapidly at room temperature. The unfavorable 1,3-diaxial interactions to which an axial substituent is exposed are readily seen in Newman projections of the ring C–C bond bearing that substituent. In contrast with that in the axial form (gauche to two ring bonds), the substituent in the equatorial conformer (anti to the two ring bonds) is away from the axial hydrogens (Figure 4-12). The unfavorable 1,3-diaxial interactions to which an axial substituent is exposed are readily seen in Newman projectionsExercise 4-8of the ring C–C bond bearing that substituent. Calculate K for equatorial versus axial methylcyclohexane from the DG8 value of 1.7 kcal mol21. Use In contrast with that inthe expressionthe axial DG8 (in formkcal mol21() gauche5 21.36 log K.to (Hint:two If log Kring 5 x, thenbonds), K 5 10x.) Howthe well substituent in the does your result agree with the 95:5 conformer ratio stated in the text? equatorial conformer (anti to the two ring bonds) is away from the axial hydrogens.

Equatorial Y Axial Y

1,3-Diaxial interactions H H H H H H H Y H H Y H H H H H

Eye

1,3-Diaxial interactions

In many cases (but not all), particularly for alkyl substituents, the energy difference between the146two formsCHAPTERincreases 4 withCycloalkanesthe size of the substituent, a direct consequence of increasing unfavorable 1,3-diaxial interactions.

Change in Free Energy on Flipping from the Cyclohexane Conformer with the Indicated Substituent Table 4-3 Equatorial to the Conformer with the Substituent Axial [(Substituent ⌬G؇ [kcal mol؊1 (kJ mol؊1)] Substituent ⌬G؇ [kcal mol؊1 (kJ mol؊1 H 0 (0) F 0.25 (1.05)

CH3 1.70 (7.11) 8 Cl 0.52 (2.18) G D CH3CH2 size 1.75 (7.32) Br 0.55 (2.30) Increasing Increasing (CH3)2CH 2.20 (9.20) Increasing I 0.46 (1.92) (CH3)3C < 5 (21) O HO 0.94 (3.93) B HOC 1.41 (5.90) CH3O 0.75 (3.14) O H2N 1.4 (5.9) B CH3OC 1.29 (5.40) Note: In all examples, the more stable conformer is the one in which the substituent is equatorial. 14

The energy differences between the axial and the equatorial forms of many monosubsti- tuted cyclohexanes have been measured; several are given in Table 4-3. In many cases (but not all), particularly for alkyl substituents, the energy difference between the two forms increases with the size of the substituent, a direct consequence of increasing unfavorable 1,3- diaxial interactions. This effect is particularly pronounced in (1,1-dimethylethyl)cyclohexane (tert-butylcyclohexane). The energy difference here is so large (about 5 kcal mol21) that very little (about 0.01%) of the axial conformer is present at equilibrium.

Working with the Concepts: Building Models to Solved Exercise 4-9 Visualize Sterics The DG8 value for the equatorial to axial ! ip of cyclohexylcyclohexane is the same as that for (1-methylethyl)cyclohexane, 2.20 kcal mol21. Is this reasonable? Explain.

Strategy When trying to deal with conformational problems, a good strategy is to build molecular models.

Solution • Molecular models reveal that cyclohexylcyclohexane may be viewed as a cyclic analog of (1-methylethyl)cyclohexane, in which the two methyl groups have been connected by a (CH2)3 chain (Section 4-1). • Both structures are ! oppy and have several conformers, but you will " nd that the seemingly H more bulky (chair) cyclohexyl substituent in (cyclohexyl)cyclohexane can rotate away from H3C the cyclohexane core in such a way as to avoid 1,3-diaxial contact beyond that encountered by its (1-methylethyl) counterpart. Thus, the equivalence of the free energy changes is reasonable.

A Exercise 4-10 Try It Yourself The isomeric hydrocarbons A and B (see margin) both exhibit preferred conformations in which 21 H3C the methyl groups are equatorial, yet B is more stable than A by 2.3 kcal mol . What is the H origin of this difference? (Caution: Are A and B ring ! ip isomers? Hint: Build models and look at the nature of the conformations of the methyl substituted cyclohexane ring.) B

Model Building Substituents compete for equatorial positions To predict the more stable conformer of a more highly substituted cyclohexane, the cumulative effect of placing substituents either axially or equatorially must be considered, in addition to their potential mutual 1,3-diaxial or 1,2-gauche (Section 2-9) interactions. For Substituents compete for equatorial positions

To predict the more stable conformer of a more 4-4highly Substitutedsubstituted Cyclohexanescyclohexane,CHAPTERthe 4 147 cumulative effect of placing substituents either axially or equatorially must be considered, in addition to theirmany potential cases, we canmutual ignore1 , the3- diaxial last twoor and1 ,2 simply-gauche applyinteractions the values of. Table 4-3 for a prediction. In 1,1-dimethylcyclohexane,Let us look at someone isomersmethyl ofgroup dimethylcyclohexaneis always equatorial to illustrateand thisthe point.other Inaxial . The two chair forms1,1-dimethylcyclohexane, are identical, and onehence methyltheir groupenergies is always are equatorialequal and. the other axial. The two chair forms are identical, and hence their energies are equal.

Axial CH3 Equatorial CH3

CH3 Equatorial Axial CH3

One CH3 axial One CH3 axial One CH3 equatorial One CH3 equatorial 1,1-Dimethylcyclohexane (Conformations equal in energy, equally stable)

Similarly, in cis-1,4-dimethylcyclohexane, both chairs have one axial and one equatorial substituent and are of equal energy. 15 H H The bonds to both methyl CH3 H C 3 groups point downward; they H H are cis (i.e., on the same face Equatorial Equatorial Axial of the ring) regardless of Axial CH CH 3 3 conformation. One axial, one equatorial One axial, one equatorial cis-1,4-Dimethylcyclohexane

On the other hand, the trans isomer can exist in two different chair conformations: one having two axial methyl groups (diaxial) and the other having two equatorial groups (diequatorial).

Axial: ϩ1.7 kcal molϪ1 H Equatorial CH3 The bond to one methyl group CH H 3 points downward, the other H3C H upward. They are trans (i.e., Ϫ1 Equatorial Axial: ϩ1.7 kcal mol on opposite faces of the ring) H CH3 regardless of conformation. Diequatorial methyls Diaxial methyls (More stable Less stable: ؉3.4 kcal mol؊1 (14.2 kJ mol؊1 trans-1,4-Dimethylcyclohexane

Experimentally, the diequatorial form is preferred over the diaxial form by 3.4 kcal mol21, exactly twice the DG 8 value for monomethylcyclohexane. Indeed, this additive behavior of the data given in Table 4-3 applies to many other substituted cyclohexanes. For e x a m p l e , t h e DG 8 (diaxial 34 diequatorial) for trans-1-! uoro-4-methylcyclohexane is 21 21 21 21.95 kcal mol [2(1.70 kcal mol for CH3 plus 0.25 kcal mol for F)]. Conversely, in cis-1-! uoro-4-methylcyclohexane, the two groups compete for the equatorial positions and the corresponding DG 8 5 21.45 kcal mol21 [2(1.70 kcal mol21 minus 0.25 kcal mol21)], with the larger methyl winning out over the smaller ! uorine.

Ϫ1 Axial: ϩ1.7 kcal molϪ1 CH3 F Axial: ϩ0.25 kcal mol H ⌬GЊ ϭ Ϫ1.45 kcal molϪ1 (Ϫ6.07 kJ molϪ1) F CH3

Equatorial H Equatorial Large group axial Small group axial Small group equatorial Large group equatorial Less stable More stable cis-1-Fluoro-4-methylcyclohexane 4-4 Substituted Cyclohexanes CHAPTER 4 147 4-4 Substituted Cyclohexanes CHAPTER 4 147

many cases, we can ignore the last two and simply apply the values of Table 4-3 for a prediction.many cases, we can ignore the last two and simply apply the values of Table 4-3 for a prediction.Let us look at some isomers of dimethylcyclohexane to illustrate this point. In 1,1-dimethylcyclohexane, Let us look at some one isomers methyl group of dimethylcyclohexane is always equatorial andto illustrate the other this axial. point. The In two1, 1-dimethylcyclohexane, chair forms are identical, one and methyl hence their group energies is always are equatorialequal. and the other axial. The two chair forms are identical, and hence their energies are equal. Axial CH3 Axial CH3 Equatorial CH3 Equatorial CH 3 CH3 Equatorial CHAxial3 Equatorial CH3 Axial One CH3 axial One CH3 axialCH3 One CH3 equatorial One CH3 equatorial One CH3 axial One CH3 axial One CH3 equatorial1,1-Dimethylcyclohexane One CH3 equatorial (Conformations1,1-Dimethylcyclohexane equal in energy, equally stable) Similarly, in cis-1,4-dimethylcyclohexane,(Conformationsboth equal in energy,chairs equallyhave stable) one axial and one equatorial Similarly, in cis-1,4-dimethylcyclohexane, both chairs have one axial and one equatorial substituent andsubstituentareSimilarly,of equal and are in energycisof -1,4-dimethylcyclohexane,equal energy.. both chairs have one axial and one equatorial substituent and are of equal energy. H H H H The bonds to both methyl CH3 H3C groupsThe point bonds downward; to both methyl they H CH3 H3C H are cisgroups (i.e., pointon the downward; same face they Equatorial Equatorial Axial H HAxial of theare ring) cis (i.e.,regardless on the ofsame face CH3 CH3 Equatorial Equatorial Axial conformation.of the ring) regardless of AxialOne axial,CH one equatorial One axial, one equatorialCH 3 3 conformation. One axial, one equatorialcis-1,4-Dimethylcyclohexane One axial, one equatorial cis-1,4-Dimethylcyclohexane On the other hand, the trans isomer can exist in two different chair conformations: one having On the other hand,twoOn axial thethe othermethyltrans hand, groupsisomer the (diaxial)trans canisomer andexist canthe otherexistin intwohaving twodifferent differenttwo equatorial chairchair conformations: groupsconformations (diequatorial). one having: one having two axial methyl twogroups axial methyl(diaxial) groupsand (diaxial)the andother the otherhaving havingtwo twoequatorial equatorial groupsgroups (diequatorial).(diequatorial). Axial: ϩ1.7 kcal molϪ1 H CH Equatorial 3 Axial: ϩ1.7 kcal molϪ1 H Equatorial CH3 The bond to one methyl group CH3 H pointsThe downward, bond to one the methyl other group H C CH H H 3 3 upward.points They downward, are trans the (i.e., other Equatorial Axial: ϩ1.7 kcal molϪ1 H3C H on oppositeupward. faces They of are the trans ring) (i.e., H CH3 Ϫ1 Equatorial Axial: ϩ1.7 kcal mol regardlesson opposite of conformation. faces of the ring) DiequatorialH methyls Diaxial methyls CH .More stable Less stable: ؉3.4 kcal mol؊1 (14.2 kJ mol3؊1) regardless of conformation Diequatorial methyls Diaxial methyls (More stabletrans-1,4-DimethylcyclohexaneLess stable: ؉3.4 kcal mol؊1 (14.2 kJ mol؊1 trans-1,4-Dimethylcyclohexane 21 Experimentally, the diequatorial form is preferred over the diaxial form by 3.4 kcal mol , 16 exactlyExperimentally, twice the D theG 8 diequatorialvalue for monomethylcyclohexane. form is preferred over the Indeed, diaxial this form additive by 3.4 behaviorkcal mol 21, of exactly the data twice given the in D G Table 8 value 4-3 for applies monomethylcyclohexane. to many other substituted Indeed, cyclohexanes.this additive behavior For e x aof m p the l e , data t h e D givenG 8 (diaxial in Table 34 diequatorial) 4-3 applies to for many trans other-1-! uoro-4-methylcyclohexane substituted cyclohexanes. is For 21 21 21 21.95 e x a m kcal p l e , mol t h e D G[2 8 (1.70(diaxial kcal 34 mol diequatorial) for CH3 plus for 0.25trans kcal-1-! uoro-4-methylcyclohexanemol for F)]. Conversely, is in 2cis1.95-1-! kcaluoro-4-methylcyclohexane, mol21 [2(1.70 kcal mol the21 twofor groupsCH plus compete 0.25 kcal for themol equatorial21 for F)]. positions Conversely, 21 3 21 21 andin the cis corresponding-1-! uoro-4-methylcyclohexane, DG 8 5 21.45 kcal molthe two [2 groups(1.70 kcal compete mol forminus the 0.25 equatorial kcal mol positions)], withand the the larger corresponding methyl winning DG 8 5 2out1.45 over kcal the mol smaller21 [2(1.70 ! uorine. kcal mol21 minus 0.25 kcal mol21)], with the larger methyl winning out over the smaller ! Ϫuorine.1 Axial: ϩ1.7 kcal molϪ1 CH3 F Axial: ϩ0.25 kcal mol Ϫ1 Axial: ϩ1.7 kcal molϪ1 CHH 3 F Axial: ϩ0.25 kcal mol ⌬GЊ ϭ Ϫ1.45 kcal molϪ1 (Ϫ6.07 kJ molϪ1) F H CH3 ⌬GЊ ϭ Ϫ1.45 kcal molϪ1 (Ϫ6.07 kJ molϪ1) F CH3 Equatorial H Equatorial EquatorialLarge group axial Small group axialH Small group equatorial Large group equatorial Equatorial LessLarge stable group axial MoreSmall stable group axial Small groupcis -1-Fluoro-4-methylcyclohexaneequatorial Large group equatorial Less stable More stable cis-1-Fluoro-4-methylcyclohexane 4-4 Substituted Cyclohexanes CHAPTER 4 147

many cases, we can ignore the last two and simply apply the values of Table 4-3 for a prediction. Let us look at some isomers of dimethylcyclohexane to illustrate this point. In 1,1-dimethylcyclohexane, one methyl group is always equatorial and the other axial. The two chair forms are identical, and hence their energies are equal.

Axial CH3 Equatorial CH3

CH3 Equatorial Axial CH3

One CH3 axial One CH3 axial One CH3 equatorial One CH3 equatorial 1,1-Dimethylcyclohexane (Conformations equal in energy, equally stable)

Similarly, in cis-1,4-dimethylcyclohexane, both chairs have one axial and one equatorial substituent and are of equal energy. H H The bonds to both methyl CH3 H C 3 groups point downward; they H H are cis (i.e., on the same face Equatorial Equatorial Axial of the ring) regardless of Axial CH CH 3 3 conformation. One axial, one equatorial One axial, one equatorial cis-1,4-Dimethylcyclohexane

On the other hand, the trans isomer can exist in two different chair conformations: one having two axial methyl groups (diaxial) and the other having two equatorial groups (diequatorial).

Axial: ϩ1.7 kcal molϪ1 H Equatorial CH3 The bond to one methyl group CH H 3 points downward, the other H3C H upward. They are trans (i.e., Ϫ1 Equatorial Axial: ϩ1.7 kcal mol on opposite faces of the ring) H CH3 regardless of conformation. Diequatorial methyls Diaxial methyls -1 , Experimentally, Morethe stablediequatorial formLess stable:is preferred؉3.4 kcal mol؊1 (14.2over kJ molthe؊1) diaxial form by 3.4 kcal mol exactly twice the �Go valuetrans-1,4-Dimethylcyclohexanefor monomethylcyclohexane.

21 Experimentally,o the diequatorial form is preferred over the diaxial form by 3.4 kcal mol , -1 The �exactlyG (diaxial twice the⇌ Ddiequatorial)G 8 value for monomethylcyclohexane.for trans-1-fluoro-4- methylcyclohexaneIndeed, this additive behavioris -1. 95 kcal mol [- -1 -1 (1.70ofkcal the mol data givenfor CH in 3 Tableplus 4-30.25 applieskcal mol to manyfor otherF)]. substituted cyclohexanes. For e x a m p l e , t h e DG 8 (diaxial 34 diequatorial) for trans-1-! uoro-4-methylcyclohexane is 21 21 21 Conversely,21.95 kcalin molcis-1 -[fluoro2(1.70- 4kcal-methylcyclohexane, mol for CH3 plus 0.25the kcaltwo molgroups for F)].compete Conversely,for the equatorial positionsin cis-1-and! uoro-4-methylcyclohexane,the corresponding � Gtheo two= - 1groups.45 kcal competemol for-1 [the-(1 .equatorial70 kcal positionsmol-1 minus 0.25 kcal 21 21 21 mol-1and)], withthe correspondingthe larger DmethylG 8 5 2winning1.45 kcal molout over [2(1.70the kcalsmaller mol minusfluorine 0.25. kcal mol )], with the larger methyl winning out over the smaller ! uorine.

Ϫ1 Axial: ϩ1.7 kcal molϪ1 CH3 F Axial: ϩ0.25 kcal mol H ⌬GЊ ϭ Ϫ1.45 kcal molϪ1 (Ϫ6.07 kJ molϪ1) F CH3

Equatorial H Equatorial Large group axial Small group axial Small group equatorial Large group equatorial Less stable More stable cis-1-Fluoro-4-methylcyclohexane 17 LARGER CYCLOALKANES

It is not possible for medium-sized rings to relieve all of these strain-producing interactions (bond-angle distortion, partial eclipsing of hydrogens, and transannular steric repulsions) in a single conformation.

Essentially strain-free conformations are attainable only for large-sized cycloalkanes, such as cyclotetradecane. In such rings,150the carbonCHAPTERchain adopts 4 aCycloalkanesstructure very similar to that of the straight-chain alkanes, having staggered hydrogens and an all-anti configuration.

Transannular single conformation. Instead, a compromise solution is found in which the molecule equilibrates strain among several geometries that are very close in energy. One such conformation of cyclodecane, which has a strain energy of 14 kcal mol21 (59 kJ mol21), is shown in the margin. Essentially strain-free conformations are attainable only for large-sized cycloalkanes, such 114.7° as cyclotetradecane (Table 4-2). In such rings, the carbon chain adopts a structure very similar to that of the straight-chain alkanes (Section 2-7), having staggered hydrogens and an all-anti con! guration. However, even in these systems, the attachment of substituents usually introduces various amounts of strain. Most cyclic molecules described in this book are not strain free. Eclipsing Ring strain strain Cyclodecane 4-6 POLYCYCLIC ALKANES 18 The cycloalkanes discussed so far contain only one ring and therefore may be referred to as monocyclic alkanes. In more complex structures—the bi-, tri-, tetra-, and higher polycyclic hydrocarbons—two or more rings share carbon atoms. Many of these compounds exist in nature with various alkyl or functional groups attached. Let us look at some of the CH3 wide variety of possible structures. CH 3 Polycyclic alkanes may contain fused or bridged rings Ϫ2 H Ring-fusion Molecular models of polycyclic alkanes can be readily constructed by linking the carbon carbon atoms of two alkyl substituents in a monocyclic alkane. For example, if you remove two hydrogen atoms from the methyl groups in 1,2-diethylcyclohexane and link the resulting two CH2 groups, the result is a new molecule with the common name decalin. In decalin, Ring-fusion two cyclohexanes share two adjacent carbon atoms, and the two rings are said to be fused. carbon Compounds constructed in this way are called fused bicyclic ring systems and the shared Decalin carbon atoms are called the ring-fusion carbons. Groups attached to ring-fusion carbons are called ring-fusion substituents. Model Building When we treat a molecular model of cis-1,3-dimethylcyclopentane in the same way, we obtain another carbon skeleton, that of norbornane. Norbornane is an example of a bridged bicyclic ring system. In bridged bicyclic systems, two nonadjacent carbon atoms, the bridgehead carbons, belong to both rings.

Bridgehead carbon CH3

−2 H or same as or

CH3 Bridgehead carbon

Norbornane Norbornane

If we think of one of the rings as a substituent on the other, we can identify stereochemical relations at ring fusions. In particular, bicyclic ring systems can be cis or trans fused. The stereochemistry of the ring fusion is most easily determined by inspecting the ring-fusion substituents. For example, the ring-fusion hydrogens of trans-decalin are trans with respect to each other, whereas those of cis-decalin have a cis relation (Figure 4-13).

Exercise 4-15 Construct molecular models of both cis- and trans-decalin. What can you say about their conformational mobility? POLYCYCLIC ALKANES

In more complex structures—the bi-, tri-, tetra-, and higher polycyclic hydrocarbons—two or more rings share carbon atoms. Many of these compounds exist in nature with various alkyl or functional groups attached.

Polycyclic alkanes may contain fused or bridged rings

In decalin, two cyclohexanes share two adjacent carbon atoms, and the two rings are said to be fused.

Compounds constructed in this way are called fused bicyclic ring systems and the shared carbon atoms are called the ring-fusion carbons. 4-7 Carbocyclic Products in Nature CHAPTER 4 151 Groups attached to ring-fusion carbons are called ring-fusion substituents. H H Figure 4-13 Conventional % % drawings and chair conformations of trans- and cis-decalin. The trans isomer contains only equato- ≥ 0 rial carbon – carbon bonds at the H H ring fusion, whereas the cis isomer possesses two 19equatorial C – C H bonds (green) and two axial C – C H linkages (red), one with respect to each ring.

H H % H Equatorial C–C bonds Axial C–C bonds Equatorial C–C bonds trans-Decalin cis-Decalin 0 H kcal mol؊1 66.5 ؍ Strain Bicyclobutane Do hydrocarbons have strain limits? Seeking the limits of strain in hydrocarbon bonds is a fascinating area of research that has C(CH33 ) resulted in the synthesis of many exotic molecules. What is surprising is how much bond- angle distortion a carbon atom is able to tolerate. A case in point in the bicyclic series is bicyclobutane, whose strain energy is 66.5 kcal mol21 (278 kJ mol21), making it remarkable 33C(CH) C(CH33 ) that the molecule exists at all. Yet it can be isolated and stored. A series of strained compounds attracting the attention of synthetic chemists possess a C(CH33 ) kcal mol؊1 129 ؍ carbon framework geometrically equivalent to the Platonic solids: the tetrahedron (tetrahe- Strain drane), the hexahedron (cubane), and the pentagonal dodecahedron (dodecahedrane; see mar- Tetrakis(1,1-dimethylethyl)- gin). In these polyhedra, all faces are composed of equally sized rings—namely, cyclopropane, tetrahedrane cyclobutane, and cyclopentane, respectively. The hexahedron was synthesized ! rst in 1964, a C8H8 hydrocarbon shaped like a cube and accordingly named cubane. The experimental strain energy [166 kcal mol21 (695 kJ mol21)] is more than the total strain of six cyclobutanes. Although tetrahedrane itself is unknown, a tetra(1,1-dimethylethyl) derivative was synthesized Tetrahedrane (C H ) 21 21 4 4 in 1978. Despite the measured strain (from DHcomb8 ) of 129 kcal mol (540 kJ mol ), the compound is stable and has a melting point of 1358C. The synthesis of dodecahedrane was achieved in 1982. It required 23 synthetic operations, starting from a simple cyclopentane derivative. The last step gave 1.5 mg of pure compound. Although small, this amount was kcal mol؊1 166 ؍ suf! cient to permit complete characterization of the molecule. Its melting point at 4308C is Strain

extraordinarily high for a C20 hydrocarbon and is indicative of the symmetry of the compound. Cubane (C8H8) For comparison, icosane, also with 20 carbons, melts at 36.88C (Table 2-5). As you might expect on the basis of its component ! ve-membered rings, the strain in dodecahedrane is “only” 61 kcal mol21 (255 kJ mol21), much less than that of its lower homologs. In Summary Carbon atoms in bicyclic compounds are shared by rings in either fused or bridged arrangements. A great deal of strain may be tolerated by carbon in its bonds, particularly to other carbon atoms. This capability has allowed the preparation of molecules in ؊1 kcal mol 61 ؍ which carbon is severely deformed from its tetrahedral shape. Strain Dodecahedrane (C20H20)

4-7 CARBOCYCLIC PRODUCTS IN NATURE

Let us now take a brief look at the variety of cyclic molecules created in nature. Natural products are organic compounds produced by living organisms. Some of these compounds, such as methane, are extremely simple; others have great structural complexity. Scientists have attempted to classify the multitude of natural products in various ways. Generally, four schemes are followed, in which these products are classi! ed according to (1) chemical structure, (2) physiological activity, (3) organism or plant speci! city (taxonomy), and (4) biochemical origin. 150 CHAPTER 4 Cycloalkanes

150 CHAPTER 4 Cycloalkanes Transannular single conformation. Instead, a compromise solution is found in which the molecule equilibrates strain among several geometries that are very close in energy. One such conformation of cyclodecane, which has a strain energy of 14 kcal mol21 (59 kJ mol21), is shown in the margin. Essentially strain-free conformations are attainable only for large-sized cycloalkanes,Transannular such single conformation. Instead, a compromise solution is found in which the molecule equilibrates 114.7 ° as cyclotetradecane (Table 4-2). In such rings, the carbon chain adopts a structure very similarstrain among several geometries that are very close in energy. One such conformation of cyclodecane, to that of the straight-chain alkanes (Section 2-7), having staggered hydrogens and an all-anti which has a strain energy of 14 kcal mol21 (59 kJ mol21), is shown in the margin. con! guration. However, even in these systems, the attachment of substituents usually introduces Essentially strain-free conformations are attainable only for large-sized cycloalkanes, such various amounts of strain. Most cyclic molecules described in this book114.7 are° not strain free. as cyclotetradecane (Table 4-2). In such rings, the carbon chain adopts a structure very similar Eclipsing Ring strain to that of the straight-chain alkanes (Section 2-7), having staggered hydrogens and an all-anti strain con! guration. However, even in these systems, the attachment of substituents usually introduces Cyclodecane 4-6 POLYCYCLIC ALKANES various amounts of strain. Most cyclic molecules described in this book are not strain free. Eclipsing Ring The cycloalkanes discussed so far contain only one ring and therefore may be referred to strain as monocyclic alkanes. In more complex structures—the bi-, tri-, tetra-,strain and higher polycyclic hydrocarbons—two or more rings share carbon atoms. Many of theseCyclodecane compounds 4-6 POLYCYCLIC ALKANES exist in nature with various alkyl or functional groups attached. Let us look at some of the CH3 wide variety of possible structures. The cycloalkanes discussed so far contain only one ring and therefore may be referred to CH 3 Polycyclic alkanes may contain fused or bridged rings as monocyclic alkanes. In more complex structures—the bi-, tri-, tetra-, and higher polycyclic hydrocarbons—two or more rings share carbon atoms. Many of these compounds Ϫ2 H Molecular models of polycyclic alkanes can be readily constructed by linking the carbon Ring-fusion exist in nature with various alkyl or functional groups attached. Let us look at some of the carbon atoms of two alkyl substituents in a monocyclic alkane. For example, if you remove two CH3 wide variety of possible structures. When we treat hydrogena molecular atoms from the methylmodel groups of in 1,2-diethylcyclohexanecis-1,3- and link the resulting CH dimethylcyclopentanetwoin CHthe2 groups,same the resultway, is a wenew moleculeobtain withanother the common name decalin. In decalin,3 Polycyclic alkanes may contain fused or bridged rings carbon skeleton,Ring-fusion that twoof norbornanecyclohexanes share. two adjacent carbon atoms, and the two rings are said to be fused. carbon Ϫ2 H Compounds constructed in this way are called fused bicyclic ring systems and the sharedRing-fusion Molecular models of polycyclic alkanes can be readily constructed by linking the carbon Decalin carbon atoms are called the ring-fusion carbons. Groups attached to ring-fusion carbonscarbon atoms of two alkyl substituents in a monocyclic alkane. For example, if you remove two Norbornane is an exampleare calledof ring-fusiona bridged substituents.bicyclic ring system. In hydrogen atoms from the methyl groups in 1,2-diethylcyclohexane and link the resulting Model Building When we treat a molecular model of cis-1,3-dimethylcyclopentane in the same way, we bridged bicyclic systems, two nonadjacent carbon atoms, the two CH2 groups, the result is a new molecule with the common name decalin. In decalin, obtain another carbon skeleton, that of norbornane. Norbornane is an example of a bridged bridgehead carbons, belong to both rings. Ring-fusion two cyclohexanes share two adjacent carbon atoms, and the two rings are said to be fused. bicyclic ring system. In bridged bicyclic systems, two nonadjacent carbon atoms, the carbon Compounds constructed in this way are called fused bicyclic ring systems and the shared bridgehead carbons, belong to both rings. Decalin carbon atoms are called the ring-fusion carbons. Groups attached to ring-fusion carbons are called ring-fusion substituents. Bridgehead Model Building When we treat a molecular model of cis-1,3-dimethylcyclopentane in the same way, we carbon CH3 obtain another carbon skeleton, that of norbornane. Norbornane is an example of a bridged bicyclic ring system. In bridged bicyclic systems, two nonadjacent carbon atoms, the −2 H or same as or bridgehead carbons, belong to both rings.

CH3 Bridgehead Bridgehead carbon carbon CH3 Norbornane Norbornane −2 H 20 or same as or If we think of one of the rings as a substituent on the other, we can identify stereochemical relations at ring fusions. In particular, bicyclic ring systems can be cis orCH trans3 fused. The stereochemistry of the ring fusion is most easily determined by inspecting the Bridgehead ring-fusion substituents. For example, the ring-fusion hydrogens of trans-decalin are trans carbon with respect to each other, whereas those of cis-decalin have a cis relation (Figure 4-13). Norbornane Norbornane

Exercise 4-15 If we think of one of the rings as a substituent on the other, we can identify stereo- Construct molecular models of both cis- and trans-decalin. What can you say about their confor- chemical relations at ring fusions. In particular, bicyclic ring systems can be cis or trans mational mobility? fused. The stereochemistry of the ring fusion is most easily determined by inspecting the ring-fusion substituents. For example, the ring-fusion hydrogens of trans-decalin are trans with respect to each other, whereas those of cis-decalin have a cis relation (Figure 4-13).

Exercise 4-15 Construct molecular models of both cis- and trans-decalin. What can you say about their conformational mobility? If we think of one of the rings as a substituent on the other, we can identify stereochemical relations at ring fusions. In particular, bicyclic ring systems can be cis or trans fused.

The stereochemistry of the ring fusion is most easily determined by inspecting the ring- fusion substituents. For example, the ring-fusion hydrogens of trans-decalin are trans with 4-7 Carbocyclic Products in Nature CHAPTER 4 151 respect to each other, whereas those of cis-decalin have a cis relation.

H H Figure 4-13 Conventional % % drawings and chair conformations of trans- and cis-decalin. The trans isomer contains only equato- ≥ 0 rial carbon – carbon bonds at the H H ring fusion, whereas the cis isomer possesses two equatorial C – C H bonds (green) and two axial C – C H linkages (red), one with respect to each ring.

H H % H Equatorial C–C bonds Axial C–C bonds Equatorial C–C bonds trans-Decalin cis-Decalin 0 H kcal mol؊1 66.521 ؍ Strain Bicyclobutane Do hydrocarbons have strain limits? Seeking the limits of strain in hydrocarbon bonds is a fascinating area of research that has C(CH33 ) resulted in the synthesis of many exotic molecules. What is surprising is how much bond- angle distortion a carbon atom is able to tolerate. A case in point in the bicyclic series is bicyclobutane, whose strain energy is 66.5 kcal mol21 (278 kJ mol21), making it remarkable 33C(CH) C(CH33 ) that the molecule exists at all. Yet it can be isolated and stored. A series of strained compounds attracting the attention of synthetic chemists possess a C(CH33 ) kcal mol؊1 129 ؍ carbon framework geometrically equivalent to the Platonic solids: the tetrahedron (tetrahe- Strain drane), the hexahedron (cubane), and the pentagonal dodecahedron (dodecahedrane; see mar- Tetrakis(1,1-dimethylethyl)- gin). In these polyhedra, all faces are composed of equally sized rings—namely, cyclopropane, tetrahedrane cyclobutane, and cyclopentane, respectively. The hexahedron was synthesized ! rst in 1964, a C8H8 hydrocarbon shaped like a cube and accordingly named cubane. The experimental strain energy [166 kcal mol21 (695 kJ mol21)] is more than the total strain of six cyclobutanes. Although tetrahedrane itself is unknown, a tetra(1,1-dimethylethyl) derivative was synthesized Tetrahedrane (C H ) 21 21 4 4 in 1978. Despite the measured strain (from DHcomb8 ) of 129 kcal mol (540 kJ mol ), the compound is stable and has a melting point of 1358C. The synthesis of dodecahedrane was achieved in 1982. It required 23 synthetic operations, starting from a simple cyclopentane derivative. The last step gave 1.5 mg of pure compound. Although small, this amount was kcal mol؊1 166 ؍ suf! cient to permit complete characterization of the molecule. Its melting point at 4308C is Strain

4-7 CARBOCYCLIC PRODUCTS IN NATURE