Experimental Studies of Kinetik Solvent Deuterium Isotope Effects on Proton Abstraction in Alcohol Solution

AKADEMISK AVHANDLINGs3m med tillstånd av rektorsämbetet vid Umeå Universitet

för vinnande av filosofie doktorsexamen framlägges till offentlig granskning

vid Kemiska Institutionen, hörsal C, LU O, Umeå Universitet, fredagen den 27 september 1974 kl. 10.00

av

JAN-OLOF LEVINfil. kand.

UMEÅ 1974

Experimental Studies of

Kinetic Solvent Deuterium Isotope Effects

on Proton Abstraction in Alcohol Solution

by

JAN-OLOF LEVIN

UMEÅ 1974

The present dissertation is an account based on

investigations published in the following papers:

I. JAN-OLGF LEVIN and CHRISTOFFER RAPPE, Solvent Deuterium

Isotope Effects in Alcohols. I. Racemization of Phenyl

2,2-Diphenylcyclopropyl Ketone, 3-Nethyl-4-pheny1-2-bu-

tanone and 2-Nethy1-1 -indanone. Chem. Scr . , _1_, 233-235

(1971 ) .

II. 3AN-0L0F LEVIN, Solvent Deuterium Isotope Effects in

Alcohols. II. Effect of Solvent-Base System on Kinetic

Solvent Isotope Effects in Fiydrogen Abstraction Reactions.

Chem. Scr., 4, 85-88 (1973).

III. 3AN-0L0F LEVIN, Solvent Deuterium Isotope Effects in

Alcohols. III. Alkoxide Catalyzed Racemizations of

Indenes. Chem. Scr. , J5, 89-91 ( 1974).

IV. 3AN-DL0F LEVIN, Solvent Deuterium Isotope Effects in

Alcohols. IV. Fiydrogen Abstraction Reactions in Alcohols

Containing Amines. Chem. Scr., in press.

These papers will be referred to by the Roman numerals

I-IV.

Contents

1. Introduction ............................................................................ 7

2. Kinetic Solvent Isotope Effects (KSIE's)

in Hydrogen Abstraction Reactions in

Alcohols ............................................................................... 10

3. A Simple Qualitative Model for Estima­

tion of KSIE's in Alkoxide Catalyzed

Reactions .................................................................................... 16

4. Effect of Alcohol-Base System on KSIE's

in Alkoxide Catalyzed Reactions ........... .. 20

5. A Simple Qualitative Model for Estimation

of KSIE's in Amine Catalyzed Reactions ... 28

6. Effect of Solvent and Base on KSIE^s in

Reactions in Alcoho1-Amine Systems ................. 31

7 . Summary .................. 38

References 40

i. iNiRgpyçiioN

The discovery of a second isotope of hydrogen by Urey

(1) in 1932 prompted a great deal of research into deuterium

chemistry. It was soon observed that when a hydrogen in a

reactant molecule was replaced by deuterium, there was often

a change in the reaction rate of that molecule. Such changes

are now known as kinetic deuterium isotope effects (KIE's),

and are commonly expressed by the ratio k^/kp (2-4).

The zero-point vibrational energy of a chemical bond de­

pends on the mass of the atoms involved, and is lower for high

reduced mass values. Therefore, C-D, G-D, N-D bonds, etc.,

have lower energies in the ground state than the corresponding

C-H, Ü-H, N-H bonds, etc. Consequently, if such a bond is bro­

ken in the rate-determining step of a reaction, the rate will

be lowered by substitution of deuterium for hydrogen. This

kinetic isotope effect is commonly termed primary KIE, and it

provides a valuable tool for the determination of reaction

mechanism. For example in the bromination of acetone a KIE of

about 8 was found (5), which confirmed the postulate that en-

olization was the rate-determining step in the bromination re­

action :

OHt

CH3C0CH3 ;—..A CH3-C = CH2 |1

Primary deuterium isotope effects normally range from 1 to

7

about 10.

Kinetic isotope effects have also been found in reactions

where the C-H bond does not break. Such KIE's are called

secondary KIE's (6), and are often encountered in solvolysis

reactions. This effect is largest when the transition state

has considerable carbonium ion character, and it has been

adopted as a measure of the carbonium ion character of the

transition state. These secondary KIE's are small, ranging

only as high as 1.5 for monodeuterated compounds.

During the decade following the discovery of deuterium

a great deal of work was done concerning reactions carried

out in mixtures of light and heavy water. Early measurements

of acidity constants in H2O/D2O mixtures were carried out

by La Mer and Chittum (7), Gross et_. a_l . (8) and Butler and

co-workers (9). Thereafter followed a period during; which

the subject was largely neglected, but the last ten or fif­

teen years have seen a revival of interest, and kinetic

solvent isotope effects (KSIE's) in H2O/D2Ü have been ex­

tensively studied (10-14), In analogy with the primary iso­

tope effect ) > the KSIE is expressed by the ratio

ÌÌrOr/— ROD* ^or the system H2Û/D2O the KSIE has been found

to range from about 0.5 to about 2,0, but is often close

to unity.

The solvent isotope effect is caused by differences in

the degree of solute-solvent interaction and in particular

by changes in the frequencies and zero-point energies of

8

hydrogen (deuterium) bonded solute and solvent molecules.

For the H2O/D2O system fairly detailed models have been

presented by Bunton and Shiner (15-17) and by Swain and

co-workers (18-20). Excellent reviews have been given by

Gold (10) and Schowen (13).

Solvent systems other than H2O/D2O, however, have

received very little attention. Some examples of KSIE's

in alcohols can be found in the literature, MeOEI/MeOD be­

ing the solvent system most frequently used. Methoxide ion

catalyzed methanolysis of esthers and amides have been

performed in NeOH/MeGD by Henger (21), and by Schowen and

co-workers (22-24). These reactions gave KSIE's in the

order of 0.4 - 1.8. Other base catalyzed solvolysis re­

actions have been investigated by Dudek and Westheimer (25),

who found KSIE^s of 1.18 - 3.24 in the amine catalyzed

solvolysis of t etrabenzy lpyrophosphat e in n_-PrOH/n-PrOD ,

and by Schowen and Bacon (26), who found a KSIE of 1.9 in

the methoxide ion catalyzed solvolysis of triphenylsilane

in HeOH/HeOD, Solvent isotope effects in methanol solution

have also been reported by Tille and Pracejus (27) and by

Bernasconi (28).

An important class of reactions for which a number of

kinetic solvent isotope effects have been reported is the

ionization of weak carbon acids in alcohols. These reac­

tions will be discussed in the following section»

9

2. KÏMEIIÇ gOLVENI îggigeg EEEEÇIg I&SIE'gl lU ÜÏDBBS6W

ÔBSIRAÇIIüN REACTIONS^IN alcohols

Apart from the work described in papers I - IV, no

systematic study concerning kinetic solvent isotope effects

on proton abstraction in alcohols seem to have been attemp­

ted. However, a few investigations where KSIE's (_kpg^/kpQß)

of this kind have been observed are reported in the litera­

ture.

In 1964 Andreades (29) published a calculated KSIE of

0.68 in the methoxide ion catalyzed H-D exchange of triflu-

oromethane in MeOH/HeOD at 70.0 °C. In the same year Hunter

and Cram (30) reported a KSIE of 0.54 in the _t-butoxide ion

catalyzed isomerization of met hy Is t i lben e in _t-BuOHAt-BuOD

at 75.0 °C,Two years later Eia and Cram (31) found a KSIE

of 0.45 in the rearrengement of allylbenzene in the same

solvent-base system but at 25.0 °C. In 1967 Ford and co-

workers (32) reported a KSIE of 0,44 in the methoxide ion

catalyzed racemization reaction of optically active 2-(N,N-

dimethylcarboxamido)-9-methyIfluorene in HeOH/MeQD at 24,9 °C.

In 1968 Streitwieser and co-workers (33) found a KSIE of

0.44 in the methoxide ion catalyzed exchange of tritiated

pentafluorobenzene in NeOH/NeOO at 25.0 °C. The following

year Hine ejt. _al. (34) reported KSIE's of 0.52, 0.67 and

0.57 in the reaction between methylenebromide and alkoxide

ion in MeOH/NeOO, ji-Pr0H/_i-Pr00 and t,-Bu0H/t_-Bu00 respect­

10

ively at 36,0 °C. In 1970 Notes and Walborsky (35) reported

a calculated KSIE of 0,84 in the H-D exchange of phenyl 2,2-

diphenylcyclopropy1 ketone in NeQH/NeGD at 75.0 °C, and in

1971 Guthrie et, al, (36) found a KSIE of 0,53 in the tert.

butoxide ion catalyzed ionization of N-(neopenty1id ene)-a-

phenyl ethyl amine in t_-BuOH/jt-BuOD at 75.0 °C. Streitwieser

and co-workers (37) found a KSIE of 0.46 in the methoxide

ion catalyzed exchange of tritiated 9-methyIf 1uorene in

MeOH/MeOD at 50.0 °C. In 1971 Gold and Grist (38) reported

a KSIE of 0.49 in the methoxide ion catalyzed racemization

reaction of 3-methyl-1-phenylbytyl phenyl ketone in NeOH/

Me0D at 24.8 °C, and a KSIE of 0.44 in the ionization of

2-nitropropane under the same conditions (38).

The kinetic so 1vent , isotope effects accounted for above

are summarized in Table I. It can be seen from the table

that the KSIE's in the same solvent-base systems do not

differ much for different substrates. Futhermore, it is

noticeable that in all cases the KSIE is smaller than 1.0.

Most reactions are about twice as fast in the deuterated

alcohol. It is significant that the KSIE's from references

29 and 35 are not determined directly, but calculated from

experiments with tritiated substrates, (See below).

Since solvent isotope effects in alcohols were not

widely recognized until the late sixties, many early in­

vestigators failed to take KSIE's into account in their

investigations. One common example is the methoxide ion

Tabl

e I. Ki

netic

solv

ent is

otop

e effe

cts (K

SIE

's) ex

pres

sed a

s in v

ario

us alk

oxid

e

0p=j-p0P0

-P

c

u0-ppoCL0P

0Co

•H-pGCD0P

CG

Ü0P-p0JG0C0txO□P

T3>i

TD0N>i

i—I 0

0G

COCD

4-0x

<3* CO

• ^O CM

CD CO

■ <3-O CM

(\m4-0x

COm4-0x

co a^r

• aa in

n aLD

• LDa i\

LDm4-0x

aCO

- LOa i\

^rCQ

CJ 0o x

cm a (\ a r\ aLO CO LD

• co «co -COan on an

LU CL• i E CO 0 ^ (—

nn

4-0x

^ a• LO

a cm

CMn

4-0x

a

■ ^ro CM

n

4- 0 cr

an

4-0

oc

aCM

4-0X

co aa

• aa r\

lo a

• LDa cm

^ aLO

• LOa r\

-pc E X a 1 X Q0 0 CD a □ a a> 0 -p X CG 1 P p P G G

1—1 0 0 a CD a X X X CO COo 0 >. 0 0 0 1 i 1 1 1

CO JG 0 X £= X •H 1 •H 1 •H 1 -PI -p

-BuO

catalyzed exchange reaction formulated in Eqn 12 j.

—HR-H + CH3DD R-D + CH3DH \2\

—D

The foreward reaction (k.^) is carried out in NeOD and the

reverse reaction (_k^) in NeOH, making it impossible to com­

pare the two rate constants. Consequently, many primary iso­

tope effects _k[_|/jkp determined in this manner are therefore

too large.

This difficulty was recognized by Andreades (29) and

Notes and Walborsky (35), who by using a formula proposed by

Swain et_. .al. (39) calculated _k[_|/_kD in NeOH from the equation

VJsD = (W2'26 >3I

where _kp/_kj was obtained from the reaction

R-D

R-Tch3oh R-H ch3od

ch3gt

This method is, however, somewhat unreliable and may give

erroneous results. For example, the KSIE obtained by Notes

and Walborsky (35) of 0.84 in the methoxide ion catalyzed

H-D exchange of phenyl 2,2-diphenylcyclopropy1 ketone in

NeOH/NeOD at 75.0 °C is probably too close to 1.0 (Table I).

Notes and Walborsky also reported that optically active/

13

phenyl 2,2-diphenylcyclopropy1 ketone was deuterated with

27% retention of configuration using methoxide ion in metha­

nol, or in other words deuteration was faster than racemi-

zation(k /k = 1.37) (35).—ex —rac

So far no example is known, where k /k * 1 for a—ex —rac

ketone (40), which is in accordance with the well-known ke­

tone enolization mechanism outlined in Eqn |5|.

0i it

-C-C-

H

0i i

-c=c-BD

B"

0I it

-c-c-ID

5

In the experiments described in paper I, Notes and Wal-

borskys experiments were repeated, and the results are shown

in Table II.

Table II. Observed rate constants for methoxide

catalyzed reactions of (+)-phenyl 2,2- diphenylcyclopropy1 ketone at 50,0 °C

Solvent Base Cone .

(M)

Reaction k . '104—obs(s'1)

NeOH NeGNa 0.440 Racemization 2.1010.05

NeOD NeONa 0.440 Racemization 4.4 ±0.1

NeGD NeONa 0.440 Deuterat ion 4.2 ±0.2

14

From the data in Table II it is obvious that under

identical conditions, the rate of racemization of (+)-phenyl

2,2-diphenylcyclopropy1 ketone equals the rate of deutér­

ation within the limits of experimental error. It can also

be seen from Table II that the KSIE in the racemization re­

action is 0.48 at 50.0 °C, a value very different from Notes

and Walborskys calculated KSIE of 0.84 in the deuteration

reaction at 75.0 °C (35]. A probable source of error in

Notes and Walborskys investigation is that racemization was

conducted in NeOH and deuteration in NeOD, and that the

possible excistence of a solvent isotope effect was over­

looked.

Also in early studies on carbanion chemistry by Cram

(41) the solvent isotope effects seem not to have been taken

into account.

15

3. A SIMPLE QUöLimiVE BQDEL EQB SE E§ÎE = § IN

ALKOXIDE CATALYZED REACTIONS

As mentioned above, no systematic study concerning kin­

etic solvent isotope effects on proton abstraction in alco­

hols has been attempted. The KSIE's summarized in Table I

were when reported often explained in terms like ”the re­

sults reflect the effectively greater basicity of methoxide

ion in methanol-OD as compared to methanol-OH” (33).

In papers I and II a model was proposed, which predicts

the magnitude of the KSIE, defined as > to be

smaller than 1.0. Here _k is the rate constant for an alkoxide

catalyzed hydrogen abstraction reaction in alcohol solution.

In paper I it was suggested that the KSIE could best be ex­

plained on the basis of different strengths of the hydrogen

bonding in the initial and transition state of the reaction.

About the same time Gold and Grist (38) presented a model

which predicted the KSIE in a methoxide ion catalyzed hydro­

gen abstraction reaction in NeOH/MeOD on the basis of the

fractionation factor for deuterium in the MeOH/NeOD/MeO

system.

Fractionation factors, which can be obtained from n.m.r.

measurements (42-44), express the equilibrium abundance of

deuterium in solvent molecules hydrogen bonded to a solute

in isotopically mixed solutions. Gold and Grist determined

a fractionation factor of 0.74 for the equilibrium shown in

Eqn I 6| (45).

16

mCH30H I 6 JCHqO'(CHqOH) + mCH,0D^^CH,0 (CH-OD) +3 3 m — 3 3 3 m

This means that the equilibrium abundance of deuterium in

the solvent molecules hydrogen bonded to methoxide ion is

0.74 times that of the bulk solvent, _i._e. an enrichment of

the light isotope in the hydrogen bonds. Consequently,

methoxide ion should be more stable in NeOH and therefore

behave as a stronger base in NeGD, resulting in a KSIE that

is smaller than 1.0.

In the 'model presented in papers I and II a somewhat

different approach is used. According to this model, the

KSIE arises from the difference in zero-point vibrational

energy of the 0H(D) bond of the hydrogen bonded alcohol

molecules in the initial and the transition state of the

alkoxide ion catalyzed hydrogen abstraction reaction. The

situation is illustrated in Fig. 1.

The negatively charged alkoxide ion is strongly hydro­

gen bonded to alcohol molecules in the initial state of the

reaction. In the transition state a proton is being trans­

ferred from substrate to alkoxide ion. This means that charge

is being transferred from alkoxide ion to substrate. As a

result, the alcohol molecules will be less strongly hydrogen

bonded to the alkoxide ion. Where weaker hydrogen bonds occur

the vibrational frequency of the G-H(D) bond will be greater

(17) and the zero-point vibrational energy is increased.

However, This increase in energy will be greater for the 0-H

17

O-HZPE - levels for 0 - H and 0 — D vibrations in the T S

—\H (D) — 0— R

ROH <

0 — H ZPE levels for 0-H and 0-D vibrations in the IS

Reaction coordinate

Fig. 1. Initial and transition state of an alkoxide

catalyzed hydrogen abstraction reaction in an

alcohol RGH and in its O-deuterated analogue

R00 with zero-point energy levels indicated

for the 0-H and 0-0 bonds.

18

bond than for the 0-D bond (erf. Section 1), resulting in a

greater zero-point vibratinal energy difference between the

G-H and the G-D bond in the transition state than in the in­

itial state of the reaction. Hence the activation energy for

the reaction will be greater in the non-deuterated medium,

and the KSIE will be smaller than 1.0,

□f course the extent of proton transfer in the transi­

tion state will effect the magnitude of the KSIE. According

to the model (see Fig. 1) a reaction with a very reactant­

like transition state will therefore give a KSIE closer to

unity than a reaction with a product-like transition state.

In this model all hydrogen bonds except those between

alkoxide ion and alcohol are neglected, but this is justi­

fiable since these hydrogen bonds must be considered very

strong in comparison to for example those between substrate

and alcohol (15-17). It should be noted that this is only an

approximate model, which for instance pays no attention to

entropy differences, which in some cases can play an impor­

tant role (11, 12). The model has, however, proven useful

for the rationalization of KSIE's in a number of alcohol-

base systems.

19

4. gEFEci QE ÖUCQÖBU=BÖ§§ SÏSI5B BB Eglgis ÏB ÖBBB^iBBCATALYZED REACTIONS

The racemization of optically active compounds provides

a means for determining kinetic solvent isotope effects with

high degree of accuracy. In papers I-III a number of KSIE's

in alkoxide ion catalyzed racemization reactions of differ­

ent optically active substrates are reported. Optically

active ketones, nitriles and alkenes have been submitted to

racemization reactions in NeQH/NeGD, EtOH/EtOO, _i-PrOH/_i-PrOD

and ji-BuOH/t-BuGD using the corresponding alkoxides as bases.

The compounds studied are shown in Fig.' 2.

In Table III the KSIE^s in the alkoxide ion catalyzed

racemization reactions of compounds 1 - Z are summarized.

If comparisons between the different types of compounds

are to be made, it must be acertained whether or not the

same type of racemization mechanism is operating. One funda­

mental condition that has to be fulfilled is that the ratio

k /k must not be greater than 1.0. If exchange is faster

than racemization there will also be a primary isotope effect

in the racemization reaction, which makes it impossible to

determine the KSIE. Such is the case for most sulfones and

sulfoxides (46), and that is the reason why such compounds

were not included in the present investigation. Ketones are

the only class of compounds for which k /k has been found—ex —rac

to be unity for a variety of solvents and bases (40). In the

20

Ph Ph

O

Ph - CH2 - CH- C-CH3

ch3 H H

Phenyl 2,2-diphenylcyclo- 3-Meth yl -4-phenyl-2-butanone 2-Methyl-i-indanonepropyl keton

1 2 3

Ph—CHg— CH— CN

ch3

2 -Me thyl-3 -phenylpropionitrife

ch3

1,3 ~Di metyl indene

6

ch3- ch2- ch-cn

Ph

2-Phenylbutyronitrile

5

1-Met hyl inde ne

7

Fig » 2 . Compounds which have been prepared in optically

active states and submitted to base catalyzed

racemization reactions.

21

Tabl

e III,.

Sum

mar

y of ki

netic

solv

ent iso

tope

effec

ts (KS

IE's

) in al

koxi

de ca

taly

zed

[\nœcCDx

LD LDa aa o

ob Iacno-

a+ i

COCO■=3-

< a o

con

CDsoCD

_X

LO LOa aa o

o+ i

CMcn

oM-cn

LDaa

ab I CO CO LO

a

a

< CD CD a a

to□oLDCM

aax

-^1

LDII

CDCD

a

CMM-a

aX

-*1CD

L1J I—I CO X

•Hin

-P

m| n\CM v- CMcd a a

a a a+i +i +i

<3* CD *-in in co

a

a a a CD

tnCDso□

•H•PoCD0P

□

tnN

*HEœG f0 p

(Mil

0CO

-P0

MC

^-110CO□

■p0X

so E0 0> 0 -P

1—1 0 0o 0 >1

CO JD 0

CMOa

i-1cn

□

a

CD<,+ i

LD

CMo a

cd ahi +ia cnLD LD

CMa

ab icn

COo

a

aCD

-P<

-al

CD CD a a

CDo

a

0 aX CD X X CD X CO

g 0 CD CD a a CD aX CD X X CD X G P p D D D -Pa a a a CD □ X X X CO CO CO <0 0 0 -p -P -p 1 1 i 1 1 1X x x LU ÜJ LO •H 1 •H 1 •H 1 -PI -^1 -Pi 0|

solvent base systems considered here> nitriles 4 and 5 have

been shown to give _kex/_kra0 = 1 (47], while compounds like

I and Z have given Jtex/jirac = 0-7 - 1.0 (48) under the same

conditions. Consequently, it can be concluded that compounds

1 - Z are transformed to more or less symmetrically solvated

carbanions when alcohols are used as solvents and alkoxides

as bases .

A closer study of the model illustrated in Fig. 1 en­

ables many of the data in Table III to be rationalized.

Firstly, it can be seen from Table III that all KSIE's are

smaller than unity, which was predicted by the model.

Secondly, as predicted, there seems to be a correlation be­

tween the extent of proton transfer in the transition state

of the reaction and the KSIE.

It is possible to get a rough idea of the extent of

proton transfer in the transition state of a hydrogen abs­

traction from the pK difference between substrate and base — a

(49) . The pK of 1 is about 23 (35), the pK of 4 about 30— a - — a -

(50) , and the pK of '6 is probably about 22 (52). The alco-

hols used have £«a"s ranging from 16 to 19, jL.e.all three

substrates should give fairly product-like transition states

in the solvent-base systems considered.

Flore accurate information about transition state sym­

metry is obtained from primary isotope effect determinations

(2, 3). In Table IV primary isotope effects in some of the

reactions studied are shown.

23

Table IV. Primary isotope effects -(J^/kp) in certain

alkoxide catalyzed racemization reactions at 25.0 °C

Solvent-

base

system Ketone 1 Nitrile 4 Alkene 6

NeOH/MeONa 3.5 ± 0.2- 1.16 ± 0.05- 7.0 ± 0.4-

t-BuOH/t-BuOK 9.2 ± 0.2- 8.6 ± 0.5-

—From II —From Bergman (51) at 60,0 °C

—From Ohlsson ejt. al.. (53)

Hydrogen abstraction reactions with very symmetrical

transition states are known to give the largest primary iso­

tope effects (2, 3). The methoxide ion catalyzed racemization

reaction of nitrile 4 gives a very product-like transition

state (50), and consequently the reaction shows a very small

primary isotope effect. See Table IV. Therefore, the KSIE in

that reaction should have a numerical value smaller than in

the reactions of 1 and 6 in the NeOH/MeOO/MeONa system. The

reaction of 4 in methanol however, cannot be directly com­

pared to the reactions of 1 and 6 since it was carried out

at 80.0 °C (Table III). It is clear, however, that the KSIE's

in the reactions of 1 and 6 can be correlated to the primary

isotope effects in the same reactions. The reaction with the

24

more symmetrical transition state (less produet-1ike) has

a KSIE closer to unity, as can be seen from Tables III and

IV.

In the _t-butanol-j:-butoxide system the primary isotope

effect in the racemization of 4 has not been determined, but

it must certainly be smaller than in the racemizations of \

and g„ Hence the same correlation between primary effect and

KSIE is found in the t,-butanol~t_-butoxide system as in the

methanol-methoxide system. See Tables III and IV.

The variation of the KSIE in the series methanol, ethan­

ol, isopropanol and t_-butanol, with the corresponding alkox-

ide as catalyzing base, for a certain substrate, is not quite

so easy to rationalize. The use of a stronger base will re­

sult in a more symmetrical transition state as long as the

carbanion is a stronger base than the alkoxide (_cf. the pri­

mary isotope effects in Table IV) or, in other words, a less

product-like transition state. According to the* model this

will result in a KSIE closer to unity. However, two other

parameters must also be taken into consideration, viz, hydro­

gen bond strength and the number of alcohol molecules in the

alkoxide-alcohol complex RÜ (HÜR) .r m

According to the model, stronger hydrogen bonds will

result in a larger solvent isotope effect (lower KSIE value)

because of the increased G-H(D) vibrational frequency differ­

ence between initial and transition state. Blair and cowor­

kers (54) have found that the gas-phase hydrogen bonding ability

25

□f a molecule of alcohol in the complex RO (HDR) varies inm

the order NeOH < EtOH < i-PrOH < t_-BuOH. This means that hy­

drogen bond strength in the alkoxide-alcohol complex will

vary in the same manner. Consequently, the numerical value

of the KSIE in the different alcohols should vary in the

order Me > Et > _i-Pr > _t-Bu, the smaller KSIE value repre­

senting the larger solvent isotope effect.

Thus the two parameters transition state symmetry and

hydrogen bond strength seem to counteract one another.

From Table III it can be seen that the numerical value

of the KSIE in the reactions of 4 and 6 reaches a maximum

in the isopropoxide-isopropano 1 system. It seems reasonable

to believe that this is caused by a decrease in the number

of strongly hydrogen bonded alcohol molecules in the alkoxide-

alcohol complex.

In the commonly accepted model for methoxide ion~in

methanol solution, methoxide ion is hydrogen bonded to three

methanol molecules, one to each lone pair on oxygen (55,38,24),

i,e. m = 3 in Eqn |6| and Fig. 1. According to the model pro­

posed by Gold and Grist (38), the minimum KSIE value in the

methoxide-methano 1 system should be 0.74—, i,e. 0.41 for

m = 3 (_cf. p. 17).

It is likely that ethoxide ion in ethanol is strongly

hydrogen bonded to three ethanol molecules. However, in the

two solvent-base systems isopropano 1-isopropoxide and t-bu-

tanol-t_-butoxide, for steric reasons it is less probable that

26

three alcohol molecules should be strongly hydrogen bonded

to the alkoxide ion. These solvents also have considerably

lower di-electric constants than methanol and ethanol,hence

the metal alkoxides are much less dissociated, leaving only

two lone pairs on oxygen -free for hydrogen bonding (56).

If it is assumed that isopropoxide and _t-butoxide are

hydrogen bonded to two solvent molecules, and methoxide and

ethoxide to three,the solvent isotope effects in the two for­

mer solvent-base systems have to be increased (the KSIE val-

3/2ues decreased) to (kDnu/knnn) in order to make a compari- —KUH —KUU

son possible. This will give KSIE values which can be roughly

correlated to solvent gas-phase acidity (paper III).

However, as previously pointed out, the other important

parameter, transition state symmetry, will oppose this trend.

27

§. ô §ïïïeli Qmmim ïïqbie eqb üiisaiigm. qe b§ìì=§ inANINE CATALYZED REACTIONS

Few examples of KSIE's in reactions in alcohcl-amine

systems are reported in the literature. In amine catalyzed

solvolysis reactions Dudek and Westheimer (25), Schowen and

.Bacon (26) and Nenger (21) reported KSIE^s in the range 1-3.

In paper IV a model was proposed, which predicts the

KSIE in amine catalyzed reactions to be larger than or equal

to unity. This model is a modified version of the model de­

scribed in Section 3.

The situation with an amine catalyzed hydrogen abstrac­

tion reaction in alcohol solution is illustrated in Fig. 3.

In alcohol solution both amine and substrate are of

course hydrogen bonded, but there are no particularly strong

hydrogen bonds in the initial state of the reaction. The hy­

drogen abstraction reaction produces a carbanion, hydrogen

bonded to alcohol molecules, and the transition state has

some carbanion character. Thus a charge separation is cre­

ated in the transition state. This results in stronger hy­

drogen bonding to the substrate in the transition state than

in the initial state of the reaction. This will make the

zero-point vibrational energy difference between the 0-H and

the Ü-D bond smaller in the transition state compared to the

initial state, resulting in _kpqh^□ □ > ^ ■ 0 •

It must be emphasized, however, that the difference in

28

/R-H+- N —

\

Reaction coordinate

Fig^ 3. Initial and transition state of an amine cata­

lyzed hydrogen abstraction reaction in an alco­

hol ROH and in its O-deuterated analogue ROD

with zero-point energy levels indicated for the

0-H and 0-D bonds .29

hydrogen bonding between initial and transition state is

much smaller in this case than for alkoxide catalysis de­

scribed in Section 3. Therefore the KSIE in the alcohol-

amine system is smaller and more difficult to predict. How­

ever, it is possible to make some general predictions:

1. If charge is extensively delocalized in the transition

state of the reaction, hydrogen bonding will be weak and

hence the KSIE close to unity.

2. A greater pKa difference between substrate and amine will

give a more product-like transition state and hence the

KSIE will increase.

3. In a more acidic alcohol hydrogen bonding will be stronger

and hence the KSIE larger.

30

6. iEEiCI BB §gLV§9I Ô9B Bòli 99 Eili=§ Î9 BiôBIiBBB Î9

ÔB99b99iô9i9B BÏBIB9B

In paper IV a number ef KSIE>s in racemization reac­

tions carried out in alcohol-amine systems are reported.

Ketone 3, nitrile 5 and alkene 7 (see Fig. 2, p. 21) were

submitted to base catalyzed racemizations in different

alcohol-amine systems. Triethyl amine (TEA) and 1,4-diaza-

bicyclo [2.2.2]octane (DABCG) were used in NeGH(D), EtOH(G),

_i-PrOH ( 0 ) and t-BuOH(O). See Table V.

Several factors complicate the situation when the race­

mization reaction is carried out in an alcoho1-amine system.

Firstly, the model has some limitations, as pointed out in

the previous section. Secondly, the ratio _kex/_krac discussed

in Section 4 is sometimes found to be greater than unity in

these systems (57). The ketone gives, as mentioned above, a

ratio k /k of unity. Nitrile 5 has been found to give

k /k values of 0,2-0,8 in the solvent-base systems con- —ex —rac J

sidered here (58). The alkene Z is probably not deuterated

with retention of configuration (59).

Thirdly, the solvolysis reaction in Eqn |7| is always

present in an alcohol-amine system.

ROH + Am ' RO" + AmH+ | 7 |

Theoretically, two basic species are present, one of

31

Tabl

e V. Su

mm

ary o

f kine

tic so

lven

t isot

ope e

ffect

s (KS

IE's

) in ra

cem

izat

ion re

actio

ns in

CJo

aLDCM

4->(DcnE0

-pCD>!00c

■HECD

QJZ□G

I-1ID

^— ,r-CD a o CD

CD CD o ao + 1 +1 + 1 +1CJ m m ^—CD CD a CD o< ■ ■ ■ •

i\ii a a a V0c0_z1—1 <T~ CM CM< a CD a a

a a CD a+ i + i +1 +1<3- CD CM a

< CD CD a CDLU ■ ■ • •1— a a <r-

(D| -Olc— m mo a □o a aa +1 + i + i

CJ CO LD CDCD CM COmu < • - •

a Q <r- ^—o 0cn i—1

^ 1 •HuX -p G| n|

a •H CM a M-x a t— a-*1 ■ - •

o o a+ 1 + i +1LU ^— CO1—1 < CO LDcn LU • • ■iZ h- a <r- ^—

^—CD a a CDa o a ao + i + 1 +1 + i

CJ o m CMCD a a CD a< • ■ • •CD T- V- ^—

mu0c□ CM V- ^— CM-p CD a CD CD0 • ■ ■ «iZ a a a a

+ i + i +1 +1CD r— m m

< CD a a aLU • - • -L— v—

-pc E X CD X a0 0 a cd a a> -p X a X a p c. D D1—1 0 a a o a X X CD GOo >i 0 0 -p -p 1 1 1 1

cn 0 s: X LU LU •H 1 -H 1 -PI -P|

CJ□a

oCO

-p<

-al

CJ□a

a

-p<

(D|

32

which or both may catalyze the reaction. It is therefore of

fundamental importance to establish the identity of the cata­

lyzing base or bases. This was done for the racemization re­

actions of 2, § and Z in in the alcohol-amine systems metha-

nol-TEA and methanol-DABCO (paper IV).

The observed rate constant for the racemization reac­

tion is the sum of the terms for alkoxide and amine cataly­

sis according to Eqn |ö|.

-RQ'[RD J + -AnTArnl |6|

The equilibrium constant for the solvolysis reaction is de­

fined as

[AmH+] [RO ]K

[Am]

Also [R0_] = [AmH+] ! io I

Eqns I 9 I and |10| gives

[RQ ] = /[AmjK

Combination of Eqns |8| and |11j gives

-RCf^^M + ^AnTAml I 12 I

33

versusIt can be seen from Eqn I 121 that a plot of k—rac

/{AmJ gives a straight line if the reaction is catalyzed by

alkoxide ion alone. On the other hand, if the reaction is ca­

talyzed exclusively by amine, a plot of _^rac [Am] gives a

straight line.

The reactions of ketone 3 and a 1 ken e Z in the alcohol-

amine systems methanol-TEA and methano 1-DABCO were found to

be first order or approximately first order in amine, which

suggests that these reactions are catalyzed mainly by amine.

The reaction of nitrile 5 in the methanol-TEA system was not

first order in amine. See Fig. 4.

However, a plot of the rate of racemization of 5 vs the

square-root of [Am] gives a straight line, strongly suggest­

ing that this reaction is catalyzed by methoxide ion. See

Fig. 5.

In many base catalyzed hydrogen abstraction reactions

carried out in alcohol-amine systems, the identity of the ca­

talyzing base has not been established ( e , g . 21, 25, 26).

However, Bordwell and Carlson (60) found that the methano-

lysis of 1 -chloro-1,3-diphenylpropane-2-one with 2,6-luti-

dine/2,6-lutidinium ion buffer is catalyzed by amine only,

and Zoltewicz and Cantwell (61) showed, using the same method

described here, the H-D exchange of the 2,6 positions of N-

-methylpyridinium iodide in NeOD containing DABCÜ or morpho­

line to be methoxide ion catalyzed.

On basis of the predictions made in Section 5 and the

34

Fig. 4 . Plot of the pseudo first order rate constants for

the racemization of (-)-2-phenylbutyronitrile in MeOH at 25.0 °C vs. the amine concentration.

35

Fig. 5, Plot of the pseudo first order rate constants for

the racemization of (-)-2-phenylbutyronitrile in MeOH at 25.0 °C vs. the square-root of the amine

concentration.

36

discussion above, the KSIE's in Table V can be rationalized.

Almost all reactions of ketone 3, nitrile 5 and alkene

2 give KSIE's larger than or equal to 1.0 in the alcohol-

amine systems investigated. Only in one case is the KSIE sig­

nificantly smaller than 1.0, and in this instance the reac­

tion was found to be catalyzed by alkoxide ion, _i._e. the

KSIE should be smaller than unity according to the model

described in Section 3,

The ketone 3 and the alkene 7 are both capable of ex­

tensive charge de loca 1ization in the transition state of the

reaction. This would weaken hyrogen bonding in the transi­

tion state, and hence the kinetic solvent isotope effect in

the racemization of these compounds would be small (KSIE-1).

In the carbanion of a nitrile, charge is probably much less

delocalized (62), resulting in stronger hydrogen bonds in

the transition state and larger KSIE's. Also the nitrile 5

is the weakest acid of the three compounds considered (paper

IV), resulting in a very product-like transition state for

the amine catalyzed reaction. The weaker base DABCG, having

a pK of about 9 in HUO (63), produces a more product-like

transition state than TEA (pK in hUO about 11), and hence

a larger KSIE. See Table V.

As the solvent acidity decreases in the series methanol,

ethanol, isopropanol, the hydrogen bonding powers of the re­

spective alcohols decrease and hence the kinetic solvent iso­

tope effect also decreases. See Table V.

37

8. SUNNARY

1. Apart from this work no systematic study of kinetic sol­

vent deuterium isotope effects (KSIE's) in alcohol solu­

tion has been attempted.

2. Nany examples can be found in literture, where investi­

gators have reached erroneous conclusions because they

have failed to take the KSIE into account.

3. The racemization of optically active compounds provides

a tool for determining KSIE's with a high degree of

accuracy.

4. Optically active ketones, nitriles and alkenes have been

submitted to base catalyzed racemization reactions in

various alcohols and their O-deuterated analogues, and

KSIE's defined as Jìrqj-i/Jìrqq have been calculated.

5. A model has been proposed which predicts the magnitude of

the KSIE on basis of different strength in hydrogen bon­

ding in the initial and transition state of a hydrogen

abstraction reaction. The model predicts the KSIE to be

less than 1.0 with alkoxide catalysis and larger than 1.0

with amine catalysis.

6. The identity of the catalyzing base has been established

for some alcohol-amine systems.

7. The kinetic solvent isotope effect can give information

about the identity of the catalyzing base, and about the

degree of proton transfer in the transition state.

38

Açkgowl|yg|0|gts

To my teacher and friend Professor Christoffer

Rappe, I wish to express my sincerest gratitude for

his never failing interest in my work, and for all

facilities placed at my disposal.

Financial support to this work has been given

by the Swedish Natural Research Council through grants

to Professor Rappe, and by the Elisabet and Karl G,

Lennander Foundation through a grant to me, which is

gratefully acknowledged.

References

1. H. C. Urey, F. G. Brickwedde and G. M. Murphy, Phys. Rev.,

39., 1 64 ( 1932).

2. L. Melander, Isotope Effects on Reaction Rates, Ronald

Press Company, New York, 1960,

3. C. J. Collins and N. S- Bowman, (Eds.), Isotope Effects

in Chemical Reactions, Van Nostrand Reinhold, New York,

1 970 .

4. R. E. Carter and L. Melander, Adv. Phys . Qrg. Chem., 10,

1 (1973).

5. 0. Reitz and 0. Kopp, _Z. physik. Chem., A184, 429 (1939).

6. E. A. Halevi, Progr. Phys . Qrg. Chem. , J_, 109 ( 1 963).

7. V. K. La Mer and 0. P. Chittum, 3, Amer. Chem. Soc. , 56,

1642 (1936).

8. P. Gross, H. Steiner and F. Krauss, Trans. Faraday Soc.,

32, 677 (1936).

9. W. 0. L. Orr and 0. A. V. Butler, 3_. Chem. Soc. , 1937, 330

10. V. Gold, Adv. Phys. Qrg. Chem., 7, 259 (1969).

11. E. M. Arnett and D. R. McKelvey in Solute-Solvent Inter­

actions , 0. F. Coetzee and C. D. Ritchie, Eds,, Marcel

Dekker, New York, 1969, Chap. 6.

12. P. M. Laughton and R. E. Robertson in Solute-Solvent Inter

actions, J. F. Coetzee and C. D. Ritchie, Eds., Marcel

Dekker, New York, 1969, Chap. 7.

13. R. L. Schowen, Progr. Phys. Drg, Chem. , _9 , 275 ( 1 972).

40

14. J. R. Jones, The Ionisation of Carbon Acids, Academie

Press, London, 1973, Chap. 10.

15. C. A. Bunton and V. J. Shiner Jr, J. Amer. Chem.- Soc. ,

_03, 42 C1961D .

16. C. A. Bunton and V. J. Shiner Jr, J . Amer. Chem. Soc. ,

Ö3, 3207 (1961).

17 . C . A. Bunton and V. J. Shiner Jr, J . Amer. Chem. Soc . ,

83, 3214 (1961).

18. C. G. Swain, R. F. W. Bader and E. R. Thornton, T etrah edron

W, 1 82 ( 1960) .

19. C. G. Swain and E, R. Thornton, J. Amer. Chem. Soc., 83,

3884 (1961),

20. C. G. Swain and E. R. Thornton, _J. Amer. Chem. Soc » , 83,

3890 (1961).

21. F. n. Henger, _J. Amer. Chem. Soc. , 88, 5356 ( 1 966),

22. C. G. nitton, M. Grosser and R. L, Schowen, J_. Amer. Chem.

Soc . , 2045 ( 1 969) .

23. R. L. Schowen, C. R. Hopper and C. N» Bazikian, J.. Amer.

Chem. Soc. , 94, 3095 ( 1 972).

24. C. R. Hopper, R. L. Schowen, K. S. Ven katasubban and H.

Jayaraman, J_- Amer, Chem. Soc. , 9 5, 3280 ( 1973),

25. G. ü. Dudek and F. H. Westheimer, J_, Amer. Chem. Soc. , 81 ,

2641 (1959).

26. R. L. Schowen and R. Bacon, Tetrahedron Letters, 1970, 4177

27. A. Tille and H. Pracejus, Chem. Ber., 100, 196 (1967).

41

CO

CM c. F. Bernasconi, J . Amer. Chem. Soc., 90, 4982 (1968)

CD

CM s. Andreades, J. Amer . Chem . Soc., 86, 2003 (1964).

30. D. H. Hunter and □ . J . Cram , J, Amer. Chem, Soc., B6,

5478 (1964).

31. S. W. Ela and D. J. Cram, J_. Amer. Chem. Soc. , 88, 5791

( 1 966 ) .

32. W. T. Ford, E. W. Graham and D. 9. Cram, £. Amer. Chem.

Soc., £9, 4661 ( 1 967) .

33. A. Streitwieser Jr, 3. A. Eludson and F. Hares, J, Amer.

Chem. Soc. , 9 0 , 648 ( 1968).

34. J. Hine, R. B. Duke and E. F. Glod, J_. Amer. Chem. Soc. ,

jn, 231 6 ( 1969 ).

35. J. H. Hôtes and H. h. Walborsky, J_. Amer. Chem. Soc. ,

£2, 3697 (1970).

36. R, D. Guthrie, D. A. Jaeger, W. Heister and D. J, Cram,

J. Amer. Chem. Soc. , 9J3, 51 37 ( 1 971 ).

37. A. Streitwieser Jr, W. B. Elollyhead, A. H, Pudjaatmaka,

P. H. Gwens, T. L. Kruger, P. A. Rubenstein, R. A. HcQuarrii

H. L. Brokaw, W. K. C. Chu and H. H. Niemeyer, J_. Amer.

Chem. Soc . , 93, 5088 ( 1 971 ).

38. V. Gold and S. Grist, J. Chem. Soc. (B) , 1971 , 2282.

39. C. G, Swain, E. C. Stivers, J. F. Reuwer Jr and L. J.

Schaad, J. Amer. Chem. Soc. , 80, 5885 ( 1 958).

40. D. J. Cram, Fundamentals of Carbanion Chemistry, Academie

Press, New York, 1968, p. 93.

42

41. D. 3, Cram, C. C. Kingsbury and B. Rickborn, 3_. Amer.

Chem. Soc., ö^, 5835 (1959).

42. V. Gold, Proc. Chem. Soc., 1963, 141.

43. A. 3. Kresge and A. L. Allred, _3. Amer. Chem. Soc. , 85,

1541 (1963).

44. R. A. More O'Ferral, Chem. Commun., 1969, 114.

45. V. Gold and S. Grist, 3. Chem. Soc. (B), 1971, 1665.

CD D. 0. Cram, D. A. Scott and W. D. Nielsen , 3. Amer. Chem.

Soc * ; _83, 3696 (1961).

47. □ . 3 . Cram, B. Rickborn, C. A, Kingsbury and P. Haberfield

3_. Amer, Chem. Soc., 83, 3678 ( 1961 ),

48. Ref. 40, p. 88, p. 96.

49. R. P. Bell and D. N. Godali, Proc. Roy. Soc. (London),

Ser. A294, 273 (1966) .

50. L. Icelander and N.-Â. Bergman, Acta Chem. Scand. , 25,

2264 (1971).

51. N.-Â. Bergman, Acta Chem. Scand. , 25, 1 517 ( 1971 ).

52. _cf. 0. B. Conant and G. W. Wheland, _3. Amer. Chem. Soc. ,

54, 1212 (1932).

53. L. Ohlsson, S. Wold and G. Bergson, Arkiv Kemi, 29, 351

( 1968) .

54. L. K. Blair, P. C. Isolani and J. M. Riveros, J, Amer.

Chem. Soc. , 95, 1 057 ( 1 973).

55. C. H. Rochester, Quart. Rev., 20, 511 (1966).

56. Ref. 40, p. 34.

43

57. Ref. 40, p. 88

58. D. 3. Cram and L. Gosser, 3_. Amer. Chem. Soc., 86, 5457

(1964) .

59. A.-14. Weidler and G. Bergson, Acta Chem. Scand. , 18,

1487 (1964).

60. F. G. Bordwell and I4. W. Carlson, _3. Amer. Chem. Soc,,

92, 3370 (1970).

61. 3. A. Zoltewicz and V. W. Cantwell, 3_. Drg. Chem. , 38,

829 (1973).

62. Ref. 40, p. 11.

63. J. Hine, 3. C. Kaufmann and M. S. Cholod, 3.. Amer. Chem.

Soc., 94, 4590 (1972).