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.
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